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Immunology and Microbiology » "Biology of Myelomonocytic Cells", book edited by Anirban Ghosh, ISBN 978-953-51-3124-3, Print ISBN 978-953-51-3123-6, Published: May 10, 2017 under CC BY 3.0 license. © The Author(s).

Chapter 6

Myelomonocytic Cell Lines in Modeling HIV-1 Infection of the Bone Marrow

By Michael R. Nonnemacher, Shane Quiterio, Alexander G. Allen, Anthony R. Mele, Vanessa Pirrone and Brian Wigdahl
DOI: 10.5772/67596

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Differentiation of CD34+ stem cells. CD34+ stem cells can be differentiated into all of the cell types that are found in the blood. Cells have to go through a number of differentiated stages of progenitor and immature cells to finally become a mature blood cell. As a cell differentiates it commits to numerous cell lineages. Adapted from Ref. [31].
Figure 1. Differentiation of CD34+ stem cells. CD34+ stem cells can be differentiated into all of the cell types that are found in the blood. Cells have to go through a number of differentiated stages of progenitor and immature cells to finally become a mature blood cell. As a cell differentiates it commits to numerous cell lineages. Adapted from Ref. [31].
Differentiation of monocytes-macrophages from CD34+ stem cells. The monocytic differentiation pathway and growth factors are involved, as well as the sites where the differentiation takes place is depicted. The majority of the cell differentiation stages occur within the bone marrow. As the CD34+ cell differentiates, it commits to the myeloid lineage at various branch points for other lineages, such as the lymphoid, erythroid, and granulocytic lineages. A number of cytokines that influence and promote cell differentiation are also shown. Certain cell lines and the point at which they are located in the cell differentiation pathway are also indicated. Once the cells have differentiated into monocytes, they can travel through the blood and migrate into tissues where they can become tissue macrophages or dendritic cells and also be activated.
Figure 2. Differentiation of monocytes-macrophages from CD34+ stem cells. The monocytic differentiation pathway and growth factors are involved, as well as the sites where the differentiation takes place is depicted. The majority of the cell differentiation stages occur within the bone marrow. As the CD34+ cell differentiates, it commits to the myeloid lineage at various branch points for other lineages, such as the lymphoid, erythroid, and granulocytic lineages. A number of cytokines that influence and promote cell differentiation are also shown. Certain cell lines and the point at which they are located in the cell differentiation pathway are also indicated. Once the cells have differentiated into monocytes, they can travel through the blood and migrate into tissues where they can become tissue macrophages or dendritic cells and also be activated.
Hematopoiesis within the bone marrow. Hematopoiesis occurs within the bone marrow and begins with stem cells associated with stromal cells that nourish them and supply growth factors. Stem cells differentiate through various stages of progenitor cells and commit to various cell lineages eventually entering the blood circulation. Adapted from Ref. [79].
Figure 3. Hematopoiesis within the bone marrow. Hematopoiesis occurs within the bone marrow and begins with stem cells associated with stromal cells that nourish them and supply growth factors. Stem cells differentiate through various stages of progenitor cells and commit to various cell lineages eventually entering the blood circulation. Adapted from Ref. [79].

Myelomonocytic Cell Lines in Modeling HIV-1 Infection of the Bone Marrow

Michael R. Nonnemacher1, 2#, Shane Quiterio1, 2#, Alexander G. Allen1, 2, Anthony R. Mele1, 2, Vanessa Pirrone1, 2 and Brian Wigdahl1, 2, 3
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Human immunodeficiency virus type 1 (HIV-1), the etiologic agent of acquired immunodeficiency syndrome (AIDS), primarily infects T cells and cells of the monocyte-macrophage lineage. This is due to the presence of the cell surface receptor CD4 and the coreceptors, CXCR4, and CCR5. While the T-cell has classically been the cell type associated with HIV-1 disease progression, cells of the monocyte-macrophage lineage have also been shown to play a major role in this viral pathologic process. Classically, this has involved monocytic cells in the peripheral blood and tissue macrophages, however, over the course of HIV disease, the promyelomonocytic cells of the bone marrow (BM) have also been shown to play a role in pathogenesis retroviral disease in that they play an integral role in the reseeding of the periphery and end-organ tissues. This has involved an initial infection of the bone marrow hematopoietic progenitor cells. Given this observation, over the years there have been a number of cell lines that have been developed and provided valuable insights into research questions surrounding HIV-1 infection of the monocyte-macrophage cell lineage. In this regard, we will examine the biological and immunological properties of these BM-derived cell lines with respect to their utility in exploring the pathogenesis of HIV-1 in humans.

Keywords: HIV-1, HL-60, TF-1, myelomonocytic cells, latency

1. Introduction

Human immunodeficiency virus type 1 (HIV-1) has been shown to primarily infect cells of the lymphoid and myeloid lineages in the peripheral blood and bone marrow (BM). One of the roles of the bone marrow serves to repopulate the peripheral blood with fresh circulating cells in response to stimuli. During HIV-1 disease, the BM has been shown to be dysfunctional leading to the pathology commonly observed in the acquired immunodeficiency syndrome (AIDS), with thrombocytopenia, anemia, monocytopenia, and neutrocytopenia [1, 2]. HIV-1 infection of bone marrow stromal cells, changes in the cytokine milieu of the bone marrow, and cytotoxic effects of HIV-1 proteins are pathogenic mechanisms involved in the impairment of the differentiation and growth of hematopoietic progenitor cells (HPCs), ultimately leading to hematopoietic defects [35] during the course of HIV disease. Interestingly, HIV-1 DNA was not detected in bone marrow–derived CD34+ HPCs in HIV-1–infected patients on combination antiretroviral [6]. However, other investigators have detected HIV-1 DNA in CD34+ HPCs in patients who are on antiretroviral therapy [7]. Numerous coinfections, as well as some lymphomas commonly observed in AIDS patients [8], have been shown to further impact hematopoiesis in HIV-1–infected individuals. Direct HIV-1 infection of hematopoietic progenitor cells may contribute to hematopoietic abnormalities; however, the extent of infection in the bone marrow compartment remains controversial [9]. Numerous studies have demonstrated the susceptibility of CD34+ bone marrow–derived cell populations to HIV-1 both in vivo and in vitro [1013]. In general, the permittivity of CD34+ HPCs has been shown to depend on the state of differentiation, with the committed progenitor cells being the most susceptible and the quiescent stem cells being the most refractile to HIV-1 infection [14, 15]. In this regard, it has been shown that macrophage colony stimulating factor (M-CSF) [11] induces HIV-1 infection of HPCs and subsequent virus production involving increased CD4 expression and enhanced viral replicative processes, respectively, emphasizing the crucial role that physiological changes in the bone marrow environment have on the HIV-1 susceptibility replicative capabilities of this cellular compartment.

During the course of chronic HIV-1 infection, there is a characteristic loss of CD4+ T cells over time in the absence of effective therapy. However, with the era of highly active antiretroviral therapy (HAART), this trend has been reversed. Interestingly, over the course of this time, cells of the myeloid lineage, even though CD4+, have been shown to less susceptible to virus-induced cytopathic effect and cell death with a drop in cell numbers much less evident during disease progression [16]. In addition, this cell lineage has been shown to be able to traverse various endothelial cell barriers, including the blood-brain barrier, allowing the infected circulating cell of the monocytic lineage to transport HIV into tissues as perivascular macrophages [17, 18]. Once in tissues, the emerging infectious HIV-1 particle can then go on to infect other resident cells of that tissue. As these cells migrate to other tissues and as the immune response causes a general state of inflammation, the bone marrow is involving in replacing cells lost to infection and to facilitate the immunologic response to HIV infection. Given that there are reports of HPCs becoming infected in the bone marrow, one intriguing possibility is that mature progenitor cells or cells that are committed to the monocyte lineage but still capable of a limited number of cell divisions, may be infected by HIV-1 while still in the bone marrow and subsequently migrate to the blood and subsequently into peripheral tissues thereby contributing to the continued viral dissemination [19].

Given these observations, we will briefly review hematopoiesis to define how myeloid cells differentiate from hematopoietic stem cells (HSCs). We will then review the literature that demonstrates the bone marrow as a site of HIV-1 infection. This approach will provide a framework to review and assess the literature concerning a number of cell lines that are currently available to be used to model virus-host interactions, as well as experimental paradigms that have utilized these cell lines to understand basic virologic and immunologic concepts relevant to HIV infection. Finally, it will conclude by discussing the next most important pressing experiments to be performed and what questions these experiments will answer to understand HIV-1 infection of the bone marrow compartment and myeloid lineage of cells.

2. CD34+ hematopoietic stem and progenitor cells

All cells of the hematopoietic system are derived from a common precursor cell, the hematopoietic stem cell (Figure 1) [20]. Stem cells are defined as single cells that are clonal precursors of more stem cells of the same type, as well as a defined set of differentiated progeny cells [20, 21]. Stem cells normally represent only about 0.05% of cells in the bone marrow, and their population is maintained at a constant level through self-renewal [22]. CD34+ progenitor cell populations, which are heterogeneous cell population containing true pluripotent stem cells and other more mature cells, are often used for hematopoietic stem cell transplantation [23]. The ability of the hematopoietic stem cells to home to the bone marrow following intravenous injection is mediated by the interactions of selectins on bone marrow endothelial cells with integrins on the hematopoietic cells [24]. The CD34 sialomucin receptor is one of the several adhesions involved in the intra and extramedullary homing of progenitor cells into distinct microenvironments [25, 26]. The CD34 antigen is expressed on primitive human hematopoietic cells capable of both self-renewal and differentiation into diverse blood cell lineages [27]. HPCs normally reside in the bone marrow in close contact with the cells of stroma that provide cytokines, extracellular matrix proteins, and adhesion molecules [28]. Progenitor cells are compartmentalized in different areas of the bone marrow based on their degree of commitment and lineage differentiation [29]. Bone marrow–derived CD34+ cells isolated from HIV-1–infected individuals have a diminished colony potential [30]. Studying infection of CD34+ progenitor cells is important in understanding the cytopenias and impaired colony growth in advanced stage HIV-1–infected patients [8].


Figure 1.

Differentiation of CD34+ stem cells. CD34+ stem cells can be differentiated into all of the cell types that are found in the blood. Cells have to go through a number of differentiated stages of progenitor and immature cells to finally become a mature blood cell. As a cell differentiates it commits to numerous cell lineages. Adapted from Ref. [31].

CD34+ cells are a heterogeneous population of multipotent hematopoietic progenitors at different stages of differentiation, residing in the adult bone marrow [32]. The CD34+CD38 immunophenotype defines a rare, quiescent (when a cell is neither dividing nor preparing to divide, remaining in the G0 cell phase) subpopulation of primitive progenitor cells than can be functionally distinguished from committed CD34+/CD38+ progenitor cells by sustained clonogenicity in a long-term culture [33]. The more primitive CD34+CD38 cells are resistant to infection while the more committed CD34+CD38+ cells are more susceptible to HIV-1 infection [14]. Primitive hematopoietic cells are not directly infected though their function is markedly disturbed by the presence of virus [34]. HIV-1–infected individuals have been shown to have a decrease in the fraction of CD34+/CD38 stem cells in the bone marrow, compared to the healthy individuals [35]. No CD4 expression was detectable on the more primitive CD34+CD38 cells and no evidence for infection of these cells was demonstrated [14].

Hematopoietic stem cells are characterized by an extensive capacity for proliferation and differentiation, as well as the ability to self-renew. Stem cells give rise to daughter cells, which undergo irreversible differentiation along a number of different hematopoietic cell lineages [36]. Hematopoiesis consists of a cascade of finely regulated events by which totipotent stem cells differentiate to all cells present in the blood [37]. Lineage commitment, differentiation, maturation, and release of cells into the blood are under the control of a number of hematopoietic growth factors. Differentiation of hematopoietic stem and progenitor cells involves a series of molecular changes that result in progressive loss of self-renewal ability and pluripotency, and in parallel acquisition of specialized functions characteristic of mature blood cells [38]. Stem cells undergo two sequential differentiating processes; the first is commitment, by which stem cells lose their self-renewing capability and differentiate to other cells with a more limited differentiating potential. The second process is maturation, which allows the terminal differentiation of those cells committed to a specific terminal lineage [39]. Both the commitment and the maturation of hematopoietic cells arise from the gradual expression of lineage-specific genes. Commitment is defined as the decision a cell makes to enter, or generate progeny that enters, a particular maturation lineage at some future time [36]. This decision does not necessarily have to be accompanied by any immediate change in morphology or expression of novel membrane proteins or regulator receptors. Hematopoietic commitment is likely to be extrinsically regulated, but there is only limited evidence, and probably only a limited opportunity, for hematopoietic regulators to be involved in the commitment events [36]. Once established, maturation programs do not seem to be qualitatively altered by the particular growth factors that activate mature cell production [36]. Most of the cell differentiation pathway takes place in the bone marrow. As CD34+ cells differentiate, they can commit to a specific lineage at specifically defined branch points (Figure 1). A number of cytokines influence and promote the cell differentiation process. Once the cells have differentiated to monocytes, they can travel through the blood and migrate into tissues where they can become tissue macrophages or dendritic cells (Figure 2).


Figure 2.

Differentiation of monocytes-macrophages from CD34+ stem cells. The monocytic differentiation pathway and growth factors are involved, as well as the sites where the differentiation takes place is depicted. The majority of the cell differentiation stages occur within the bone marrow. As the CD34+ cell differentiates, it commits to the myeloid lineage at various branch points for other lineages, such as the lymphoid, erythroid, and granulocytic lineages. A number of cytokines that influence and promote cell differentiation are also shown. Certain cell lines and the point at which they are located in the cell differentiation pathway are also indicated. Once the cells have differentiated into monocytes, they can travel through the blood and migrate into tissues where they can become tissue macrophages or dendritic cells and also be activated.

3. Cells of the monocyte-macrophage lineage

Monocytes belong to the mononuclear phagocytic system and constitute 3–8% of the peripheral blood leukocytes. Monocytic nuclei are eccentric, either oval or kidney shaped and contain small vacuoles in the cytoplasm that are lysosomes filled with degradative enzymes. Monocytes originate from promonocytes, which are rapidly dividing precursors in the bone marrow. When the mature cells enter the peripheral blood, they are termed monocytes (Figure 2). The monocytes often leave the blood and infiltrate tissues, undergoing additional changes and are then referred to as macrophages [40]. Macrophages act as effector cells, attacking microorganisms and neoplastic cells and removing foreign material, as well as presenting antigen to lymphocytes [41]. Macrophages contain receptors for antibody and complement, which enhance their ability to phagocytose organisms. Macrophages produce an enormous number of soluble factors that are important in the immune response and in the process of inflammation.

Monocytic cells are generated in the bone marrow from pluripotent stem cells that can differentiate into multiple hematologic cell types. Within the bone marrow, cytokines induce stem cells to divide and to produce lineages committed to differentiating into monocytic, granulocytic, erythroid, or megakaryocytic cell types (Figure 2) [42, 43]. The pluripotent progenitor cell, called the granulocyte-erythroid-megakaryocyte-macrophage colony forming unit (GEMM-CFU), becomes further committed toward either the granulocytic or monocytic phenotype in the presence of IL-1 and/or IL-3, becoming the granulocyte-macrophage colony forming unit (GM-CFU) (Figure 2) [39, 42, 43]. The granulocytic and monocytic lineages are closely bound together throughout hematopoiesis and are commonly referred to as the myelomonocytic lineage [42, 43]. Repopulation of the myelomonocytic GM-CFU occurs in the presence of IL-3 or granulocyte-macrophage colony stimulating factor (GM-CSF) [37]. Commitment toward the macrophage lineage requires the presence of macrophage colony stimulating factor (M-CSF), along with IL-3 or GM-CSF [44, 45]. The committed promonocytic cells mature into smaller monocytic cells that can enter the blood. Monocytes circulate within the blood for 8–72 hours before migrating into a number of different tissues where they complete their development, becoming mature tissue macrophages (Figure 2) [4648]. Macrophages are larger in diameter than monocytes and possess increased lysosomal content and hydrolytic enzymes [49]. Macrophages are capable of division and can be a self-sustaining population.

The phenotype and function of the macrophage is dependent on the tissue in which it resides. Therefore, resident macrophages are often defined by the tissue-specific environment in which they ultimately reside. Specific types of macrophages include: the microglial cells of the brain, the Kupffer cells in the liver, the Langerhans cells of the skin, the alveolar macrophages of the lung, the mesangial cells of the kidney, and the sinus macrophages of the spleen [5052].

4. Bone marrow hematopoiesis disorders associated with HIV-1 infection

Hematologic abnormalities are very common in HIV-1–infected individuals and they occur at all stages of disease, but the mechanisms by which HIV-1 contributes to these abnormalities are poorly understood [53, 54]. HIV-1 affects the hematopoietic system, causing a number of peripheral blood cytopenias [55, 56]. HIV-1–infected patients suffer from many hematologic disorders and exhibit uni or multilineage suppression of bone marrow hematopoiesis including anemia, lymphocytopenia, thrombocytopenia, granulocytopenia, monocytopenia, and neutropenia that can be attributed to malfunction or premature death of the specific hematopoietic cells [8, 5759]. The hematopoietic disorders are frequently associated with impaired HPC growth, BM dysplasia, plasmacytosis, and lymphoid infiltrates [57, 60], and they suggest virus-induced abnormalities in the bone marrow microenvironment [6163]. T cell depletion in AIDS is thought to be, at least in part, due to the failure of T cell development from lymphohematopoietic stem cells [14].

A large number of studies have been conducted to identify and characterize the pathophysiologic mechanisms leading to bone marrow dysfunction in patients with AIDS. HIV-1 may affect hematopoietic stem cells (HSCs) by both direct and indirect mechanisms leading to defects in maturation of CD34+ cells and the numerous cytopenias. A number of indirect mechanisms for HIV-1–induced suppression of hematopoiesis have been proposed, such as: the stimulation of abnormal cytokine production by HIV-1 infection [30, 64], the suppressive effects of viral gene products [65, 66], and the activation of apoptosis by gp120-mediated cross-linking of CD4 [67]. Hematologic abnormalities in the majority of infected individuals could result from indirect effects of HIV-1, such as cytokine dysregulation, rather than HIV-1 expression in the bone marrow itself [53]. HIV-1 Tat has been shown to decrease differentiation in an HPC line [68]. In addition, the viral accessory protein Nef has been shown to decrease hematopoiesis in vitro [69]. Studies have also demonstrated that HIV-1 may induce apoptosis in hematopoietic cell lines [70, 71]. Modification of the behavior of hematopoietic accessory cells by HIV-1 infection may indirectly alter the growth and differentiation of adjacent uninfected lymphoid, myeloid, and primitive hematopoietic cell populations and account for HIV-1–mediated suppression of hematopoiesis [72]. Infection of auxiliary cells, particular macrophages, and microvascular endothelial cells, induces a substantial alteration in the supportive function of the hematopoietic stromal tissues, indirectly influencing the survival and growth of hematopoietic progenitors [8].

5. Role of growth factors, cytokines, and cellular activation in HIV-1 pathogenesis in the bone marrow

Stem cells, progenitor populations, and their progeny are largely defined by their cytokine responsiveness and cytokine receptor phenotype. Cytokines are soluble glycoproteins that act through cell surface receptors at very low concentrations and control the production of stem cells. The most prominent cytokines are erythropoietin for the production of red blood cells, GM-CSF for granulocytes and macrophages, G-CSF for granulocytes, thrombopoietin for platelets, and M-CSF or CSF-1 for monocyte-macrophage production and function. Cytokines may be stimulatory or inhibitory and may show additive or synergistic effects on the renewal, proliferation, survival, and differentiation of cells. They can also modulate cell migration and adherence. Cytokines are important components of the immunoregulatory network and have been demonstrated to play a major role in the regulation of HIV-1 expression in vitro. Potent modulation of HIV-1 expression has been demonstrated either by manipulating endogenous cytokines or by adding exogenous cytokines to culture. The net level of virus replication in an HIV-1–infected individual reflects, in part, the balance between inductive and suppressive host factors that are mediated mainly by cytokines. Reverse transcription, integration, and virus spread are much more efficient in cells that have been activated by cytokines.

Cytokines and growth factors function by activating a number of different transcription factors. Sequentially ordered activation of transcription factors controls lineage commitment. Once a particular set of transcription factors has been induced, reversibility is limited. In the early phases of differentiation, the regulatory roles of the growth factors overlap [36]. Later in development, some growth factors are lineage-specific, and govern the maturation of single lineages. Hematopoietic cells have distinctive patterns of growth factor receptor expression that evolve as the cells differentiate [36]. Binding of the growth factors to their receptors leads to activation of intracellular kinases and triggers cell proliferation [73, 74]. Hematopoietic growth factors not only stimulate cell proliferation, but also prolong cell survival by exhibiting antiapoptotic effects. Growth factors, such as G-CSF and GM-CSF, can stimulate early hematopoietic cell proliferation, increase the number of cells produced by the bone marrow, prolong the life span of cells, and augment cell function [75]. In the marrow, blood cells develop in two phases: the proliferative and the maturational phases. During cell proliferation, the precursors of blood cells normally undergo cell division at intervals of about 18–24 hours. In the maturational phase, cell division ceases, but additional modifications occur before the cell enters the blood. Progenitor cells exhibit a higher proliferative rate and more lineage restriction than stem cells. They are also responsive to a smaller subset of cytokines. The production of all cell types is controlled by a negative feedback mechanism. When demand for specific cell types increases, or peripheral levels of the cells fall, then stimulatory cytokines are released to generate new cells within a few days.

6. Organization of bone marrow and its role as a viral reservoir

Hematopoietic cells develop within the medullary space, which has a rich vascular supply and is populated by many cell types including: adipocytes, vascular endothelial cells, fibroblasts, and stromal cells (Figure 3). The frequency of HSCs in the bone marrow is relatively constant [76, 77]. Vascular endothelial cells, marrow fibroblasts, and stromal cells produce hematopoietic growth factors and chemokines that regulate blood cell production [78]. Vascular endothelial cells form a barrier that keeps immature cells in the marrow and permits mature cells to enter the blood. Macrophages in the bone marrow remove dead or apoptotic cells and clear the blood of foreign materials that enter the marrow (Figure 3). Stem cells and primitive cells bind tightly to the stroma, while maturing precursors and terminally differentiated cells are nonadherent.


Figure 3.

Hematopoiesis within the bone marrow. Hematopoiesis occurs within the bone marrow and begins with stem cells associated with stromal cells that nourish them and supply growth factors. Stem cells differentiate through various stages of progenitor cells and commit to various cell lineages eventually entering the blood circulation. Adapted from Ref. [79].

The bone marrow may serve as an important reservoir of HIV-1 in the body. Previous results have suggested that the bone marrow macrophages may act as a reservoir for HIV, and infection of this cell population may affect hematopoiesis, either by transmission of HIV infection to developing progenitor cells or by altering the ability of the stroma to support normal development [80]. The circulating CD34+ progenitor cell population may be infected in vivo and may serve as a reservoir for HIV-1 that is capable of trafficking the virus to diverse anatomic compartments [13]. Peripheral blood–derived CD34+ progenitor cells may also be infected and disseminate HIV-1 to sites throughout the body. Integration of proviral DNA into stem cell genomes could lead to the spread of HIV-1 infection through the expansion of infected clones or interference with normal stem cell maturation and proliferation, resulting in the interruption of normal hematopoiesis [14]. Studies have shown that primary CD34+ progenitor cells are susceptible to infection by diverse strains of HIV-1, particularly as they begin to differentiate, and infection can be sustained for prolonged periods in vitro [13, 32]. This may contribute to a chronically infected pool of functionally altered cells containing viruses of different tropism across different cell lineages [32].

7. Direct infection of CD34+ hematopoietic progenitor cells by HIV-1

Direct involvement of HIV-1 infection may be important in leading to HSC failure and bone marrow dysfunction [59]. Direct infection and destruction of hematopoietic stem or progenitor cells may explain the defective hematopoiesis in HIV-1–infected individuals [81]. Attempts to understand HIV-1–mediated bone marrow dysfunction have yielded inconsistent results regarding the susceptibility of bone marrow progenitors to viral infection [14]. Conflicting studies have been reported regarding the susceptibility of human CD34+ cells to HIV-1 infection both in vivo and in vitro, and there has been a significant controversy regarding whether HIV-1 can infect HSCs directly, leading to bone marrow dysfunction and the cytopenias. A number of studies of HIV-1–infected individuals have failed to detect productively infected CD34+ progenitor cells from the bone marrow [54, 82, 83], while other studies have shown that rare infection of CD34+ progenitor cells can occur [84, 85] and may be more prevalent in patients with advanced disease [86].

Direct infection of the primitive progenitor cells, which represent 0.01% of bone marrow cells, is difficult to detect [13]. Several reports have described that bone marrow CD34+ stem and/or progenitor cells are infected with HIV-1 at low frequencies in some patients [84]. Purified CD34+ HPCs from adult peripheral blood were reported to be susceptible to HIV-1 infection, as shown by PCR analysis for the presence of proviral sequences in the ensuing myeloid and erythroid colonies or by virus production in culture [13, 81, 87]. Several studies have shown successful in vitro infection of the CD34+ population [11, 88], although studies in this area have focused on hematological consequences of HIV-1 infection and its effects on progenitor cells [10, 81, 88]. HIV-1 infection in vitro has been reported in highly purified bone marrow–derived CD34+ cells [89] and in CD34+ progenitor cells that coexpress CD4 [70]. Based on a number of reports, it was found that a low fraction of progenitor cells is able to be infected ex vivo by HIV-1 under certain conditions, the growth of the few cells infected by HIV-1 may not be impaired as a result of the infection, while in vivo infection of progenitor cells occurs rarely, if ever [8].

The number of HIV-positive HPCs may sharply increase in advanced AIDS because of widespread HIV-1 infection, thus explaining the reports on in vivo HIV-positive CD34+ cells in the advanced disease [85, 86]. Studies suggest that HIV-1-expressing cells are present in the bone marrow during late stages of disease [53]. In individuals with advanced HIV-1 infection, about 1 in 500 CD34+ cells were shown to be infected with HIV-1 [86]. The CFU capacity of the bone marrow stem cells was impaired especially in patients with advanced disease, even if HIV-1 does not directly infect these cells [90]. Depletion of primitive progenitors observed in later stages of HIV-1 disease may represent a virus-induced alteration in progenitor cell differentiation [9193].

Multiple and potentially synergistic mechanisms may be responsible for the resistance of CD34+ cells to HIV-1 infection [28]. Most studies indicate that bone marrow–derived HSCs cannot be infected by HIV-1 until they undergo modest differentiation in order to express the appropriate receptors to enable virus entry and subsequent replication [59]. Studies have demonstrated the presence of both CD4 [94] and the chemokine receptors CXCR4 and CCR5 [95] on CD34+ cells. The most primitive bone marrow HPCs lack the surface molecules CD4, CXCR4, and CCR5, which are required for HIV-1 infection, so they cannot be infected with HIV-1 [14]. CD4+ cells were found only within the more mature CD34+CD38+ cell population, explaining their susceptibility to infection [14]. Cell surface expression of CXCR4 and CCR5 has been found on peripheral blood–derived CD34+ progenitor cells [13]. When CD4 expression is low, infection becomes dependent on coreceptor expression levels. High chemokine receptor levels can compensate for low surface expression of CD4 in mediating HIV-1 infection [13]. T-tropic strains of HIV-1 have been shown to infect cultures of purified CD34+ progenitor cells in vitro, suggesting the presence of the CXCR4 coreceptor on the cells [62, 81]. The natural chemokine ligands for the major HIV-1 coreceptors are able to readily block entry of HIV-1 [96]. The CC-chemokines RANTES, MIP-1α, and MIP-1β are the natural ligands for CCR5 and block the entry of R5 viruses, whereas SDF-1, the natural ligand for CXCR4, blocks the entry of X4 viruses, thus inhibiting the infection and spread of the virus. The mechanisms relevant to inhibition of HIV-1 infection involve the blocking of binding of the virus to its coreceptor, thus blocking viral entry.

8. Specific viral populations within the CNS suggest bone marrow origination

Because the CNS has been shown to be more “immunologically privileged” than many other organs, it has been suggested that virus enters the CNS early after primary infection and then replicates there beyond the control of the peripheral immune system to a great degree. In addition, some antiretroviral drugs such as protease inhibitors have trouble crossing the blood-brain barrier [97, 98]. Inefficient drug delivery combined with an “immunologically privileged” site leads to viral reservoirs remaining in the CNS throughout the duration of infection. Viral genome sequence analysis supports the notion that CNS-specific or neurotropic forms of virus exist [99103]. Recent studies demonstrate that viral sequences within specific CNS regions match, phylogenetically, with sequences found in the bone marrow [104, 105]. This supports the hypothesis that virus could be transported into the CNS in hematogenous-derived cells.

HIV-1 gp160 sequences from postmortem tissues collected from a patient with HIV-1 dementia were isolated and analyzed for sequence similarity [105]. Gartner and colleagues found that the gp160 sequences from patients with dementia demonstrate remarkable sequence similarity between isolates from subcortical regions of the brain (particularly in deep white matter (DWM)) and those of the bone marrow [104]. Phylogenetic analysis showed that the sequences from DWM were more closely related to those from bone marrow and peripheral blood monocytes. Sequences from DWM and monocytes clustered together, indicating greater homology between the HIV-1 species in these groups, as well as a more recent evolutionary divergence between them, relative to the species in other tissues. The phylogenetic tree showed that the bone marrow sequences were clustered with the DWM and monocyte group, although the bone marrow species diverged at an earlier time. Viral species from the DWM were more closely related to those in bone marrow than those in other tissues, with the DWM, monocyte, and bone marrow sequences clustering together as a group. These observations suggest that of bone marrow–derived monocytes traffic into the DWM of the brain during late stage infection. Bone marrow–derived monocytes within the circulation may enter the DWM and become perivascular macrophages, potentially transmitting HIV-1 to neighboring cells [106]. A critical step toward the development of HIV-associate dementia may be an increase in monocyte trafficking into the brain [107]. This process may be either initiated and/or accelerated during late-stage infection, which could explain why dementia occurs at this time. These observations point to the bone marrow as the likely source of virus entering the CNS in terminal stages. The frequency and extent of infection and the kinetics of virus replication in bone marrow are not well classified.

9. Cell lines to model HIV infection of bone marrow

A number of different monocytic progenitor cell lines have been derived that can be used as experimental tools (Figure 2). These cell lines will be discussed from the least differentiated to the most differentiated cellular phenotype.

9.1. KG-1

The KG-1 cell line is a CD34+/CD38+ myelomonocytic progenitor cell line that was derived from the bone marrow of a patient with acute myelogenous leukemia [108]. A variant CD34+/CD38 cell line, called the KG-1a subline, morphologically and histochemically resembles undifferentiated blast cells. The KG-1 cell line is composed predominantly of myeloblasts and promyelocytes [109]. KG-1 cells can be induced to differentiate into dendritic-like cells by the addition of GM-CSF and TNF-α, or phorbol 12-myristate 13-acetate (PMA) with ionomycin or TNF-α [110]. KG-1 cells can be induced to differentiate into macrophage-like cells in response to phorbol esters such as 12-O-tetradecanoylphorbol-13-acetate (TPA), while the KG-1a cells are resistant to the effects of TPA [111, 112]. With respect to studies of HIV-1 pathogenesis and disease, this cell line has not been as widely used as you will see for HL-60 and TF-1 cell lines due to a very low to no expression of CD4 on the cell surface [113, 114]. However, many researchers who examine regulation of CD4, CCR5, and CXCR4 on the myeloid cell lineage use this cell line in combination with HL-60, TF-1, and others. Interestingly, a number of studies have examined coinfection of human herpesvirus type 6 (HHV6) and HIV-1 and demonstrated that if KG-1 cells were first infected with HHV6, this would induce CD4 expression thereby facilitating subsequent HIV-1 infection by viruses that use either CCR5 or CXCR4 as the coreceptor [113115]. They have also been used for studies surrounding toxicity of drugs [116] or for alteration of normal cell function [117] for bone marrow myeloid lineage of cells potentially to be used for HIV treatments.

9.2. TF-1

The TF-1 cell line was established by Kitamura and colleagues in 1987 from a bone marrow aspiration sample of a 35 year old Japanese male with erythroleukemia and severe pancytopenia [118]. TF-1 cells, which have been shown to express several erythroid and myeloid markers, are CD34+/CD38+ erythro-myeloid HPCs blocked at an early stage of hematopoietic differentiation [118, 119]. The cells have also been shown to be completely dependent on IL-3 or GM-CSF for long-term growth [118]. Erythropoietin (EPO) also sustains the short-term growth of TF-1 cells but does not induce erythroid differentiation [119]. TF-1 cells can be induced to differentiate into two different pathways, and, depending on the type of inducer, are capable of differentiating into either mature erythroid cells or macrophage-like cells [118]. Hemin and δ-aminolevulinic acid can induce erythroid differentiation with hemoglobin synthesis in TF-1 cells, while PMA induces dramatic differentiation into macrophage-like cells [118]. TF-1 cells consist of a relatively homogenous population of medium-sized cells with the appearance of blasts [120]. They contain moderate amounts of dark basophilic, agranular cytoplasm with frequent small cytoplasmic vacuoles, and have a smooth cytoplasmic border. The nuclei are oval with fine chromatin and 1–3 macronucleoli. Many binucleated and occasional multinucleated forms are present [120].

The TF-1 cell line has provided a useful tool and in vitro model system to examine HIV-1 infection of a progenitor cell population during differentiation into monocytic cells. Previous studies have demonstrated that TF-1 cells can be productively infected by the R5-dependent BAL and YU-2 strains of HIV-1, but not by the X4-dependent LAI HIV-1 strain [121]. Differentiation of TF-1 cells down the myeloid pathway or the presence of higher levels of the CCR5 coreceptor as compared to the CXCR4 coreceptor could explain why a productive HIV-1 infection only occurred in cells infected with HIV-1 R5-dependent strains. PMA-induced macrophage-like differentiation of TF-1 cells, characterized by a decrease in nuclear size, an increase in the amount of nuclear chromatin condensation, absence of nucleoli, and increased cytoplasm [120]. The majority of the cells have moderately abundant light basophilic, agranular to finely granular cytoplasm with irregular cytoplasmic borders [120].

TF-1 cells have been used extensively to understand host pathogen interactions between the HIV-1 protein Nef and numerous cellular pathways [122, 123]. These studies have led to a further understanding of how replication is differed between cell types. Specifically, these studies helped identify factors such as STAT3 that are affected by Nef and allow for the survival of TF-1 cells [124]. Like with KG-1 cells, TF-1 cells were also used to confirm that human herpesvirus 6 coinfection with HIV can lead to susceptibility of TF-1 cells to HIV-1 infection [113, 114]. In addition, it was shown in TF-1 cells that lymphocyte function-associated antigen 1 (LFA-1) was needed to confer susceptibility to HIV-1 infection [125]. TF-1 cells have also been used to assess transcriptional activation of the HIV-1 LTR in a number of activation and differentiation states of these cells. This demonstrated the importance of the C/EBP transcription factor in CD34+ progenitor cells for driving LTR activation [126]. In addition, the transcription factors NF-κB and Sp were shown to be important when TF-1 cells were activated by phorbol 12-myristate 13-acetate (PMA), conditioned medium from PMA-treated TF-1 cells, or IL-1² [127, 128].

9.3. HL-60

The HL-60 cell line, obtained by leukapheresis from the peripheral blood of a patient with acute promyelocytic leukemia, is a promyelocytic cell line [129]. In culture, the cells can be stained as promyelocytes or myeloblasts, although only about 10% of the cell population can progress to more mature cells [130]. Differentiation can be induced by a number of agents such as dimethyl sulfoxide (DMSO), butyrate, hypoxanthine, PMA, actinomycin D, and retinoic acid. The cells have the ability to differentiate into either granulocytic or monocytic cells, depending on whether they are treated with either DMSO or PMA, respectively [131133]. Monocytic differentiation can also be induced by treatment with 1-25 dihydroxyvitamin D3 or lymphokine [134, 135]. HL-60 cells exhibit increased adherence following differentiation toward either the monocytic or granulocytic pathways [131]. When HL-60 cells have been treated with PMA, they have been shown to exhibit morphologic changes that are characteristic of monocytic cells, including the appearance of pseudopodia, cerebriform nuclei, and the disappearance of azurophilic granules. However, they fail to produce secondary granules that are typical of mature cells indicating incomplete maturation [136]. Following chemically induced monocytic differentiation, increased production of acid phosphatase, β-glucuronidase, and myeloperoxidase has been observed [137]. Thus, the HL-60 cell line exhibits characteristics of an undifferentiated myeloid progenitor. Because of its ability to differentiate toward both granulocytic and monocytic cell types, HL-60 cells are considered a model for cells of the myelomonocytic lineage.

These cells have been widely used in studies on HIV-1 infection. This is because of their ability to be infected in an unactivated state as well as because of the development of the OM-10.1 cell, a clonally derived cell line from HIV-1–infected HL-60 promyelocytes which harbor a single integrated provirus that is silent until activated [138]. In the beginning of the epidemic, a number of studies were conducted with the HL-60 and OM-10.1 cells to determine and characterize the viral infection and replication dynamics within cells of this lineage [138143]. These cells have been shown to retain CD4, CXCR4, and CCR5 expression and retain CD4 expression unless viral replication is active [138]. Given this observation, the HL-60 and OM-10.1 cell lines have been used in several studies that simply aim at examining the levels of CD4, CXCR4, and CCR5 or other surface markers under various cellular physiological conditions and drug treatments [138, 144159]. These cells have also been used to screen methodologies or drugs that may inhibit HIV-1 infection or reduce transcriptional activation of the virus [117, 160173]. These cell lines have also been used in studies of drug toxicity, permeability, and/or effects on cellular activation and differentiation to gain an understanding of what specific drugs might do to cells in the bone marrow [144, 154, 174183], as well as determining what signaling pathways may play a role or become dysregulated [184189]. Additionally, other studies have been completed that utilize these cells to examine the role that distinct viral determinants as well as specific host factors have on cellular tropism, cellular differentiation, and cytopathology [190193]. They have also been used in examining the role of CDK9 and characterizing its function based on known interactions with Tat [166] as well as how Nef manipulates intracellular Ca(2+) stores through SH3-mediated interactions in myelomonocytic cells [194].

Because of the more recent interest in HIV-1 latency, the OM-10.1 cell line has been used to understand drugs that may activate latent viral reservoirs for shock and kill or kick and kill type therapeutics. Some specific examples include a small molecule activator of protein phosphatase-1 (SMAPP-1) [195], NCH-51 [196], hybrid liposomes (HL) composed of dimyristoylphosphatidylcholine (DMPC) and polyoxyethylene alkyl [197], or contact with T cells [198]. Additionally, these cells have been used to characterize the mechanisms involved in maintaining HIV-1 latency [199]. The integrated provirus in these cells seems to be latent due to a transcriptional control mechanism and can be induced by TNF-α, suggesting a potential NF-κB-mediated control [200].

9.4. U-937 and THP-1

U-937 cells are an immature monocytic cell line derived from the pleural effusion of a patient with histiocytic lymphoma [201]. U-937 cells exhibit the morphologic and histochemical characteristics of monoblastic cells, including the expression of ²-glucuronidase and the release of lysozyme into the culture [201, 202]. Only a small percentage of undifferentiated U-937 cells are phagocytic. Furthermore, U-937 cells lack the ability to kill cells expressing foreign antigen presented by MHC class I [203, 204]. U-937 cell lines exhibit characteristics of monoblastic cells in their undifferentiated state, and can be induced to differentiate toward a more mature macrophagic cellular phenotype by a number of chemical agents. PMA can induce differentiation of U-937 cells toward a more mature monocytic phenotype [205, 206]. Differentiated U-937 cells have increased adherence and ramification, along with greater phagocytic activity and the induction of lysozyme and nonspecific esterase activity [206, 207]. Other chemical agents can also be used to induce macrophage differentiation of U-937 cells. Treatment with retinoic acid or 1-25 dihydroxyvitamin D3 can induce the differentiation of U-937 cells. Like the HL-60 cell line, a U-937 cell line carrying integrated HIV-1 proviral DNA has been constructed with the integrated viral genome in a quiescent configuration that has been shown to be capable of being activated into a transcriptionally active state capable of driving the production of infectious virus. This cell line was termed U1 [208]. Like with HL-60, the U-937 cell line has been used in several types of experiments including experiments to examine what is needed to reactivate the integrated virus [209214] and most recently in using CRISPR/cas9 technology to excise HIV out of cells as a potential “cure” strategy [215].

THP-1 cells are a monocytic cell line derived from the peripheral blood of a 1-year old male patient who had acute monocytic leukemia [216]. The difference between THP-1 cells and U-937 cells is the origin and maturation stage of both cell lines. U-937 cells are of tissue origin and are therefore at a more mature stage. THP-1 cells are derived from a blood leukemia which represents a less mature stage. There is extensive literature describing the use of vitamin D3 or PMA to differentiate THP-1 cells into macrophages [216]. Recent literature has determined a protocol for PMA that seems to be the most effective to allow differentiation of THP-1 monocytes into macrophages [217]. Interestingly, comparing peripheral blood mononuclear cells (PBMC) monocytes and THP-1 cells has uncovered slight variations in their response to various stimuli. Upon stimulation with Lipopolysaccharide (LPS), PBMC monocytes produce a greater amount of proinflammatory cytokines such as, TNF-α, IL-6, and IL-8 compared to THP-1 cells [218]. These variations in response become much more similar when PBMC and THP-1 monocytes are differentiated into macrophages [219]. Interestingand important for several lines of experimentation, THP-1 cells can be polarized to the M1 or M2 phenotype depending on the stimuli provided.

Due to the differentiation state of U-937 and THP-1 cells, they have been used very widely to mimic HIV-1 infection of peripheral blood monocytes. Due to this, we will not review their use in HIV-1 research in depth as this review focused on promyelomonocytic cell systems. However, there have been some recent reviews that have focused more specifically on the peripheral blood monocytes as well as their utility in studies of HIV-1 latency [220223].

10. Conclusion

Although HIV-1 may not be able to infect CD34+ stem cells, the research described above shows that they are able to infect the more differentiated progenitor cells. As the cells differentiate from the CD34+ stem cell, the HIV-1 receptor and coreceptor profiles become altered and enhance HIV-1 infection. Thus, the virus infects progenitor cells as they differentiate down the myeloid lineage in the BM and in the blood. Research surrounding this line of investigation has come from examining cells from patients as well as through development of derivative cell lines. As described here the KG-1, TF-1, and HL-60 cell lines have all been used to understand at which stage of the myeloid cell lineage HIV-1 may be able to infect. This has resulted in understanding this is restricted primarily by the levels of CD4 and CXCR4 or CCR5 on the cells. Given this it appears that HIV-1 can infect cells as early as the pluripotent myeloid precursor (Figure 2). Because of these models there has been extensive work to examine drug toxicities, regulation of HIV-1 infection, and understanding of how HIV-1 may affect hematopoiesis. However, due to ART making HIV-1 infection a more chronic condition and the theory that one of the main reservoirs may involve the myeloid lineage of cells, including the promyelomonocytic cells of the bone marrow. Hence, this cellular compartment has now taken on a renewed interest. This is evident in the use of the OM-10.1 cell line model for mechanistic studies concerning HIV-1 latency as well as testing of latency reactivators on the various cell lines derived from this lineage of cells. It is the role of the myeloid precursor cells during the course of chronic infection that will be one of the major focal points of future research studies. The use of the TF-1 and HL-60 cells especially, will be very useful with respect to answering questions focused on determining when do these cells transverse the vascular endothelium at an increased rate. Do these infected bone marrow–derived cells traffic to end organs? Do they contribute to the increase in activated monocytes observed in the blood that link to HIV-1-associated neurocognitive impairment? Are these promyelomonocytic cells in the bone marrow infected by cell-free HIV-1 or through cell-to-cell contact with other cells? Are the viruses that infect these cells more dependent on CXCR4 or CCR5 and is there genetic variability more related to a reservoir virus that was generated early in infection and has remained or has continually developed over time in infected patients? These are a few questions that these cell lines will help to answer as research in this field advances.


1 - Zhao X, Sun NC, Witt MD, Keller M, Niihara Y. Changing pattern of AIDS: a bone marrow study. Am J Clin Pathol. 2004; 121(3): 393–401.
2 - Isgro A, Aiuti A, Leti W, Gramiccioni C, Esposito A, Mezzaroma I, Aiuti F. Immunodysregulation of HIV disease at bone marrow level. Autoimmun Rev. 2005; 4(8): 486–490.
3 - Lee CI, Cowan MJ, Kohn DB, Tarantal AF. Simian immunodeficiency virus infection of hematopoietic stem cells and bone marrow stromal cells. J Acquir Immune Defic Syndr. 2004; 36(1): 553–561.
4 - Moses AV, Williams S, Heneveld ML, Strussenberg J, Rarick M, Loveless M, Bagby G, Nelson JA. Human immunodeficiency virus infection of bone marrow endothelium reduces induction of stromal hematopoietic growth factors. Blood. 1996; 87(3): 919–925.
5 - Bahner I, Kearns K, Coutinho S, Leonard EH, Kohn DB. Infection of human marrow stroma by human immunodeficiency virus-1 (HIV-1) is both required and sufficient for HIV-1-induced hematopoietic suppression in vitro: demonstration by gene modification of primary human stroma. Blood. 1997; 90(5): 1787–1798.
6 - Durand CM, Ghiaur G, Siliciano JD, Rabi SA, Eisele EE, Salgado M, Shan L, Lai JF, Zhang H, Margolick J, Jones RJ, Gallant JE, Ambinder RF, Siliciano RF. HIV-1 DNA is detected in bone marrow populations containing CD4+ T cells but is not found in purified CD34+ hematopoietic progenitor cells in most patients on antiretroviral therapy. J Infect Dis. 2012; 205(6): 1014–1018. DOI: 10.1093/infdis/jir884
7 - Bordoni V, Bibas M, Abbate I, Viola D, Rozera G, Agrati C, Rinaldi A, Amendola A, Ammassari A, Capobianchi MR, Martini F. Bone marrow CD34+ progenitor cells may harbour HIV-DNA even in successfully treated patients. Clin Microbiol Infect. 2015; 21(3): 290 e295–298. DOI: 10.1016/j.cmi.2014.11.003
8 - Moses A, Nelson J, Bagby GCJr. The influence of human immunodeficiency virus-1 on hematopoiesis. Blood. 1998; 91(5): 1479–1495.
9 - Alexaki A, Wigdahl B. HIV-1 infection of bone marrow hematopoietic progenitor cells and their role in trafficking and viral dissemination. PLoS Pathog. 2008; 4(12): e1000215. DOI: 10.1371/journal.ppat.1000215
10 - Steinberg HN, Crumpacker CS, Chatis PA. In vitro suppression of normal human bone marrow progenitor cells by human immunodeficiency virus. J Virol. 1991; 65(4): 1765–1769.
11 - Kitano K, Abboud CN, Ryan DH, Quan SG, Baldwin GC, Golde DW. Macrophage-active colony-stimulating factors enhance human immunodeficiency virus type 1 infection in bone marrow stem cells. Blood. 1991; 77(8): 1699–1705.
12 - Folks TM, Justement J, Kinter A, Schnittman S, Orenstein J, Poli G, Fauci AS. Characterization of a promonocyte clone chronically infected with HIV and inducible by 13-phorbol-12-myristate acetate. J Immunol. 1988; 140(4): 1117–1122.
13 - Ruiz ME, Cicala C, Arthos J, Kinter A, Catanzaro AT, Adelsberger J, Holmes KL, Cohen OJ, Fauci AS. Peripheral blood-derived CD34+ progenitor cells: CXC chemokine receptor 4 and CC chemokine receptor 5 expression and infection by HIV. J Immunol. 1998; 161(8): 4169–4176.
14 - Weichold FF, Zella D, Barabitskaja O, Maciejewski JP, Dunn DE, Sloand EM, Young NS. Neither human immunodeficiency virus-1 (HIV-1) nor HIV-2 infects most-primitive human hematopoietic stem cells as assessed in long-term bone marrow cultures. Blood. 1998; 91(3): 907–915.
15 - Shen H, Cheng T, Preffer FI, Dombkowski D, Tomasson MH, Golan DE, Yang O, Hofmann W, Sodroski JG, Luster AD, Scadden DT. Intrinsic human immunodeficiency virus type 1 resistance of hematopoietic stem cells despite coreceptor expression. J Virol. 1999; 73(1): 728–737.
16 - Zhang Z, Fu J, Zhao Q, He Y, Jin L, Zhang H, Yao J, Zhang L, Wang FS. Differential restoration of myeloid and plasmacytoid dendritic cells in HIV-1-infected children after treatment with highly active antiretroviral therapy. J Immunol. 2006; 176(9): 5644–5651.
17 - Strazza M, Pirrone V, Wigdahl B, Nonnemacher MR. Breaking down the barrier: the effects of HIV-1 on the blood-brain barrier. Brain Res. 2011; 1399: 96–115. DOI: 10.1016/j.brainres.2011.05.015
18 - Atluri VS, Hidalgo M, Samikkannu T, Kurapati KR, Jayant RD, Sagar V, Nair MP. Effect of human immunodeficiency virus on blood-brain barrier integrity and function: an update. Front Cell Neurosci. 2015; 9: 212. DOI: 10.3389/fncel.2015.00212
19 - Bordoni V, Bibas M, Viola D, Sacchi A, Agrati C, Castelli G, Ammassari A, Amendola A, Abbate I, Martini F. Chronic HIV-infected patients show an impaired dendritic cells differentiation of bone marrow CD34(+) cells. J Acquir Immune Defic Syndr. 2013; 64(4): 342–344. DOI: 10.1097/QAI.0b013e3182a40ff7
20 - Weissman IL. Translating stem and progenitor cell biology to the clinic: barriers and opportunities. Science. 2000; 287(5457): 1442–1446.
21 - Gage FH. Mammalian neural stem cells. Science. 2000; 287(5457): 1433–1438.
22 - Williams RJ, Clarke E, Blair A, Evely R, Hale G, Waldmann H, Brookes S, Pamphilon DH. Impact on T-cell depletion and CD34+ cell recovery using humanised CD52 monoclonal antibody (CAMPATH-1H) in BM and PSBC collections; comparison with CAMPATH-1M and CAMPATH-1G. Cytotherapy. 2000; 2(1): 5–14.
23 - Kim H, Whartenby KA, Georgantas RW3rd, Wingard J, Civin CI. Human CD34+ hematopoietic stem/progenitor cells express high levels of FLIP and are resistant to Fas-mediated apoptosis. Stem Cells. 2002; 20(2): 174–182.
24 - Nabors LK, Wang LD, Wagers AJ, Kansas GS. Overlapping roles for endothelial selectins in murine hematopoietic stem/progenitor cell homing to bone marrow. Exp Hematol. 2013; 41(7): 588–596. DOI: 10.1016/j.exphem.2013.02.014
25 - Hardy CL, Minguell JJ. Cellular interactions in hemopoietic progenitor cell homing: a review. Scanning Microsc. 1993; 7(1): 333–341.
26 - Oxley SM, Sackstein R. Detection of an L-selectin ligand on a hematopoietic progenitor cell line. Blood. 1994; 84(10): 3299–3306.
27 - Andrews RG, Bryant EM, Bartelmez SH, Muirhead DY, Knitter GH, Bensinger W, Strong DM, Bernstein ID. CD34+ marrow cells, devoid of T and B lymphocytes, reconstitute stable lymphopoiesis and myelopoiesis in lethally irradiated allogeneic baboons. Blood. 1992; 80(7): 1693–1701.
28 - Aiuti A, Turchetto L, Cota M, Cipponi A, Brambilla A, Arcelloni C, Paroni R, Vicenzi E, Bordignon C, Poli G. Human CD34(+) cells express CXCR4 and its ligand stromal cell-derived factor-1. Implications for infection by T-cell tropic human immunodeficiency virus. Blood. 1999; 94(1): 62–73.
29 - Uchida N, Fleming WH, Alpern EJ, Weissman IL. Heterogeneity of hematopoietic stem cells. Curr Opin Immunol. 1993; 5(2): 177–184.
30 - Zauli G, Re MC, Davis B, Sen L, Visani G, Gugliotta L, Furlini G, La Placa M. Impaired in vitro growth of purified (CD34+) hematopoietic progenitors in human immunodeficiency virus-1 seropositive thrombocytopenic individuals. Blood. 1992; 79(10): 2680–2687.
31 - Lofsness K. Hematography plus: an instructional program in morphologic alterations of blood cells. Minneapolis, MN: Regents of the University of Minnesota; 2000.
32 - Carr JM, Ramshaw HS, Li P, Burrell CJ. CD34+ cells and their derivatives contain mRNA for CD4 and human immunodeficiency virus (HIV) co-receptors and are susceptible to infection with M- and T-tropic HIV. J Gen Virol. 1998; 79 (Pt 1): 71–75.
33 - Reems JA, Torok-Storb B. Cell cycle and functional differences between CD34+/CD38hi and CD34+/38lo human marrow cells after in vitro cytokine exposure. Blood. 1995; 85(6): 1480–1487.
34 - Koka PS, Jamieson BD, Brooks DG, Zack JA. Human immunodeficiency virus type 1-induced hematopoietic inhibition is independent of productive infection of progenitor cells in vivo. J Virol. 1999; 73(11): 9089–9097.
35 - Marandin A, Katz A, Oksenhendler E, Tulliez M, Picard F, Vainchenker W, Louache F. Loss of primitive hematopoietic progenitors in patients with human immunodeficiency virus infection. Blood. 1996; 88(12): 4568–4578.
36 - Metcalf D. Lineage commitment and maturation in hematopoietic cells: the case for extrinsic regulation. Blood. 1998; 92(2): 345–347; discussion 352.
37 - Valledor AF, Borras FE, Cullell-Young M, Celada A. Transcription factors that regulate monocyte/macrophage differentiation. J Leukoc Biol. 1998; 63(4): 405–417.
38 - Bond HM, Bonelli P, Mesuraca M, Agosti V, Masone C, Cuomo C, Nistico A, Tassone P, Tuccillo F, Cecco L, Iacopino L, Barbieri V, Cerra M, Costanzo FS, Morrone G, Venuta S. Identification by differential display of transcripts regulated during hematopoietic differentiation. Stem Cells. 1998; 16(2): 136–143.
39 - Ogawa M. Differentiation and proliferation of hematopoietic stem cells. Blood. 1993; 81(11): 2844–2853.
40 - Yona S, Kim KW, Wolf Y, Mildner A, Varol D, Breker M, Strauss-Ayali D, Viukov S, Guilliams M, Misharin A, Hume DA, Perlman H, Malissen B, Zelzer E, Jung S. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity. 2013; 38(1): 79–91. DOI: 10.1016/j.immuni.2012.12.001
41 - Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008; 8(12): 958–969. DOI: 10.1038/nri2448
42 - Lopez M, Fleisher T, deShazo RD. Use and interpretation of diagnostic immunologic laboratory tests. Jama. 1992; 268(20): 2970–2990.
43 - Hamilton JA. Colony stimulating factors, cytokines and monocyte-macrophages-some controversies. Immunol Today. 1993; 14(1): 18–24.
44 - Fabian I, Shapira E, Gadish M, Kletter Y, Nagler A, Flidel O, Slavin S. Effects of human interleukin 3, macrophage and granulocyte-macrophage colony-stimulating factor on monocyte function following autologous bone marrow transplantation. Leuk Res. 1992; 16(6–7): 703–709.
45 - Young DA, Lowe LD, Clark SC. Comparison of the effects of IL-3, granulocyte-macrophage colony-stimulating factor, and macrophage colony-stimulating factor in supporting monocyte differentiation in culture. Analysis of macrophage antibody-dependent cellular cytotoxicity. J Immunol. 1990; 145(2): 607–615.
46 - Meuret G, Hoffmann G. Monocyte kinetic studies in normal and disease states. Br J Haematol. 1973; 24(3): 275–285.
47 - Meuret G, Batara E, Furste HO. Monocytopoiesis in normal man: pool size, proliferation activity and DNA synthesis time of promonocytes. Acta Haematol. 1975; 54(5): 261–270.
48 - Whitelaw DM, Batho HF. The distribution of monocytes in the rat. Cell Tissue Kinet. 1972; 5(3): 215–225.
49 - Ganz T, Lehrer RI. Defensins. Pharmacol Ther. 1995; 66(2): 191–205.
50 - Naito M. Macrophage heterogeneity in development and differentiation. Arch Histol Cytol. 1993; 56(4): 331–351.
51 - Thomas WE. Brain macrophages: evaluation of microglia and their functions. Brain Res Brain Res Rev. 1992; 17(1): 61–74.
52 - Salmon JK, Armstrong CA, Ansel JC. The skin as an immune organ. West J Med. 1994; 160(2): 146–152.
53 - Weiser B, Burger H, Campbell P, Donelan S, Mladenovic J. HIV type 1 RNA expression in bone marrows of patients with a spectrum of disease. AIDS Res Hum Retroviruses. 1996; 12(16): 1551–1558.
54 - von Laer D, Hufert FT, Fenner TE, Schwander S, Dietrich M, Schmitz H, Kern P. CD34+ hematopoietic progenitor cells are not a major reservoir of the human immunodeficiency virus. Blood. 1990; 76(7): 1281–1286.
55 - Fauci AS. Host factors and the pathogenesis of HIV-induced disease. Nature. 1996; 384(6609): 529–534.
56 - Harbol AW, Liesveld JL, Simpson-Haidaris PJ, Abboud CN. Mechanisms of cytopenia in human immunodeficiency virus infection. Blood Rev. 1994; 8(4): 241–251.
57 - Scadden DT, Zon LI, Groopman JE. Pathophysiology and management of HIV-associated hematologic disorders. Blood. 1989; 74(5): 1455–1463.
58 - Mir N, Costello C, Luckit J, Lindley R. HIV-disease and bone marrow changes: a study of 60 cases. Eur J Haematol. 1989; 42(4): 339–343.
59 - Kulkosky J, Bouhamdan M, Geist A, Nunnari G, Phinney DG, Pomerantz RJ. Pathogenesis of HIV-1 infection within bone marrow cells. Leuk Lymphoma. 2000; 37(5–6): 497–515.
60 - Sun NC, Shapshak P, Lachant NA, Hsu MY, Sieger L, Schmid P, Beall G, Imagawa DT. Bone marrow examination in patients with AIDS and AIDS-related complex (ARC). Morphologic and in situ hybridization studies. Am J Clin Pathol. 1989; 92(5): 589–594.
61 - Calenda V, Sebahoun G, Chermann JC. Modulation of normal human erythropoietic progenitor cells in longterm liquid cultures after HIV-1 infection. AIDS Res Hum Retroviruses. 1992; 8(1): 61–67.
62 - Cen D, Zauli G, Szarnicki R, Davis BR. Effect of different human immunodeficiency virus type-1 (HIV-1) isolates on long-term bone marrow haemopoiesis. Br J Haematol. 1993; 85(3): 596–602.
63 - Davis BR, Zauli G. Effect of human immunodeficiency virus infection on haematopoiesis. Baillieres Clin Haematol. 1995; 8(1): 113–130.
64 - Molina JM, Scadden DT, Byrn R, Dinarello CA, Groopman JE. Production of tumor necrosis factor alpha and interleukin 1 beta by monocytic cells infected with human immunodeficiency virus. J Clin Invest. 1989; 84(3): 733–737.
65 - Sugiura K, Oyaizu N, Pahwa R, Kalyanaraman VS, Pahwa S. Effect of human immunodeficiency virus-1 envelope glycoprotein on in vitro hematopoiesis of umbilical cord blood. Blood. 1992; 80(6): 1463–1469.
66 - Louache F, Henri A, Bettaieb A, Oksenhendler E, Raguin G, Tulliez M, Vainchenker W. Role of human immunodeficiency virus replication in defective in vitro growth of hematopoietic progenitors. Blood. 1992; 80(12): 2991–2999.
67 - Accornero P, Radrizzani M, Delia D, Gerosa F, Kurrle R, Colombo MP. Differential susceptibility to HIV-GP120- sensitized apoptosis in CD4+ T-cell clones with different T-helper phenotypes: role of CD95/CD95L interactions. Blood. 1997; 89(2): 558–569.
68 - Mondal D, Agrawal KC. Effect of HIV type 1 Tat protein on butyric acid-induced differentiation in a hematopoietic progenitor cell line. AIDS Res Hum Retroviruses. 1996; 12(16): 1529–1536.
69 - Calenda V, Graber P, Delamarter JF, Chermann JC. Involvement of HIV nef protein in abnormal hematopoiesis in AIDS: in vitro study on bone marrow progenitor cells. Eur J Haematol. 1994; 52(2): 103–107.
70 - Zauli G, Vitale M, Re MC, Furlini G, Zamai L, Falcieri E, Gibellini D, Visani G, Davis BR, Capitani S, et al. In vitro exposure to human immunodeficiency virus type 1 induces apoptotic cell death of the factor-dependent TF- 1 hematopoietic cell line. Blood. 1994; 83(1): 167–175.
71 - Re MC, Furlini G, Zauli G, La Placa M. Human immunodeficiency virus type 1 (HIV-1) and human hematopoietic progenitor cells. Arch Virol. 1994; 137(1–2): 1–23.
72 - Esser R, Glienke W, von Briesen H, Rubsamen-Waigmann H, Andreesen R. Differential regulation of proinflammatory and hematopoietic cytokines in human macrophages after infection with human immunodeficiency virus. Blood. 1996; 88(9): 3474–3481.
73 - McLemore ML, Grewal S, Liu F, Archambault A, Poursine-Laurent J, Haug J, Link DC. STAT-3 activation is required for normal G-CSF-dependent proliferation and granulocytic differentiation. Immunity. 2001; 14(2): 193–204.
74 - Haq R, Halupa A, Beattie BK, Mason JM, Zanke BW, Barber DL. Regulation of erythropoietin-induced STAT serine phosphorylation by distinct mitogen-activated protein kinases. J Biol Chem. 2002; 277(19): 17359–17366.
75 - Hubel K, Dale DC, Liles WC. Therapeutic use of cytokines to modulate phagocyte function for the treatment of infectious diseases: current status of granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, macrophage colony-stimulating factor, and interferon-gamma. J Infect Dis. 2002; 185(10): 1490–1501.
76 - Harrison DE, Astle CM, Lerner C. Number and continuous proliferative pattern of transplanted primitive immunohematopoietic stem cells. Proc Natl Acad Sci U S A. 1988; 85(3): 822–826.
77 - Morrison SJ, Wandycz AM, Akashi K, Globerson A, Weissman IL. The aging of hematopoietic stem cells. Nat Med. 1996; 2(9): 1011–1016.
78 - Youn BS, Mantel C, Broxmeyer HE. Chemokines, chemokine receptors and hematopoiesis. Immunol Rev. 2000; 177: 150–174.
79 - Kumar N. Bone marrow class []. 2012. Available from: [Accessed: 2016-12-28]
80 - Gill V, Shattock RJ, Freeman AR, Robinson G, Griffin GE, Gordon-Smith EC, Gibson FM. Macrophages are the major target cell for HIV infection in long-term marrow culture and demonstrate dual susceptibility to lymphocytotropic and monocytotropic strains of HIV-1. Br J Haematol. 1996; 93(1): 30–37.
81 - Chelucci C, Hassan HJ, Locardi C, Bulgarini D, Pelosi E, Mariani G, Testa U, Federico M, Valtieri M, Peschle C. In vitro human immunodeficiency virus-1 infection of purified hematopoietic progenitors in single-cell culture. Blood. 1995; 85(5): 1181–1187.
82 - Molina JM, Scadden DT, Sakaguchi M, Fuller B, Woon A, Groopman JE. Lack of evidence for infection of or effect on growth of hematopoietic progenitor cells after in vivo or in vitro exposure to human immunodeficiency virus. Blood. 1990; 76(12): 2476–2482.
83 - Neal TF, Holland HK, Baum CM, Villinger F, Ansari AA, Saral R, Wingard JR, Fleming WH. CD34+ progenitor cells from asymptomatic patients are not a major reservoir for human immunodeficiency virus-1. Blood. 1995; 86(5): 1749–1756.
84 - Davis BR, Schwartz DH, Marx JC, Johnson CE, Berry JM, Lyding J, Merigan TC, Zander A. Absent or rare human immunodeficiency virus infection of bone marrow stem/progenitor cells in vivo. J Virol. 1991; 65(4): 1985–1990.
85 - Kaczmarski RS, Davison F, Blair E, Sutherland S, Moxham J, McManus T, Mufti GJ. Detection of HIV in haemopoietic progenitors. Br J Haematol. 1992; 82(4): 764–769.
86 - Stanley SK, Kessler SW, Justement JS, Schnittman SM, Greenhouse JJ, Brown CC, Musongela L, Musey K, Kapita B, Fauci AS. CD34+ bone marrow cells are infected with HIV in a subset of seropositive individuals. J Immunol. 1992; 149(2): 689–697.
87 - Muench MO, Roncarolo MG, Rosnet O, Birnbaum D, Namikawa R. Colony-forming cells expressing high levels of CD34 are the main targets for granulocyte colony-stimulating factor and macrophage colony-stimulating factor in the human fetal liver. Exp Hematol. 1997; 25(4): 277–287.
88 - Kaushal S, La Russa VF, Gartner S, Kessler S, Perfetto S, Yu Z, Ritchey DW, Xu J, Perera P, Kim J, Reid T, Mayers DL, St Louis D, Mosca JD. Exposure of human CD34+ cells to human immunodeficiency virus type 1 does not influence their expansion and proliferation of hematopoietic progenitors in vitro. Blood. 1996; 88(1): 130–137.
89 - Folks TM, Kessler SW, Orenstein JM, Justement JS, Jaffe ES, Fauci AS. Infection and replication of HIV-1 in purified progenitor cells of normal human bone marrow. Science. 1988; 242(4880): 919–922.
90 - Sloand EM, Young NS, Kumar P, Weichold FF, Sato T, Maciejewski JP. Role of Fas ligand and receptor in the mechanism of T-cell depletion in acquired immunodeficiency syndrome: effect on CD4+ lymphocyte depletion and human immunodeficiency virus replication. Blood. 1997; 89(4): 1357–1363.
91 - De Luca A, Teofili L, Antinori A, Iovino MS, Mencarini P, Visconti E, Tamburrini E, Leone G, Ortona L. Haemopoietic CD34+ progenitor cells are not infected by HIV-1 in vivo but show impaired clonogenesis. Br J Haematol. 1993; 85(1): 20–24.
92 - Zauli G, Vitale M, Gibellini D, Capitani S. Inhibition of purified CD34+ hematopoietic progenitor cells by human immunodeficiency virus 1 or gp120 mediated by endogenous transforming growth factor beta 1. J Exp Med. 1996; 183(1): 99–108.
93 - Re MC, Zauli G, Gibellini D, Furlini G, Ramazzotti E, Monari P, Ranieri S, Capitani S, La Placa M. Uninfected haematopoietic progenitor (CD34+) cells purified from the bone marrow of AIDS patients are committed to apoptotic cell death in culture. AIDS. 1993; 7(8): 1049–1055.
94 - Louache F, Debili N, Marandin A, Coulombel L, Vainchenker W. Expression of CD4 by human hematopoietic progenitors. Blood. 1994; 84(10): 3344–3355.
95 - Deichmann M, Kronenwett R, Haas R. Expression of the human immunodeficiency virus type-1 coreceptors CXCR-4 (fusin, LESTR) and CKR-5 in CD34+ hematopoietic progenitor cells. Blood. 1997; 89(10): 3522–3528.
96 - Schols D, Struyf S, Van Damme J, Este JA, Henson G, De Clercq E. Inhibition of T-tropic HIV strains by selective antagonization of the chemokine receptor CXCR4. J Exp Med. 1997; 186(8): 1383–1388.
97 - Huisman MT, Smit JW, Crommentuyn KM, Zelcer N, Wiltshire HR, Beijnen JH, Schinkel AH. Multidrug resistance protein 2 (MRP2) transports HIV protease inhibitors, and transport can be enhanced by other drugs. AIDS. 2002; 16(17): 2295–2301.
98 - Kim RB, Fromm MF, Wandel C, Leake B, Wood AJ, Roden DM, Wilkinson GR. The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors. J Clin Invest. 1998; 101(2): 289–294. 10.1172/JCI1269
99 - Hughes ES, Bell JE, Simmonds P. Investigation of the dynamics of the spread of human immunodeficiency virus to brain and other tissues by evolutionary analysis of sequences from the p17gag and env genes. J Virol. 1997; 71(2): 1272–1280.
100 - Lane TE, Buchmeier MJ, Watry DD, Jakubowski DB, Fox HS. Serial passage of microglial SIV results in selection of homogeneous env quasispecies in the brain. Virology. 1995; 212(2): 458–465.
101 - Power C, McArthur JC, Johnson RT, Griffin DE, Glass JD, Perryman S, Chesebro B. Demented and nondemented patients with AIDS differ in brain-derived human immunodeficiency virus type 1 envelope sequences. J Virol. 1994; 68(7): 4643–4649.
102 - Power C, McArthur JC, Johnson RT, Griffin DE, Glass JD, Dewey R, Chesebro B. Distinct HIV-1 env sequences are associated with neurotropism and neurovirulence. Curr Top Microbiol Immunol. 1995; 202: 89–104.
103 - Strizki JM, Albright AV, Sheng H, O'Connor M, Perrin L, Gonzalez-Scarano F. Infection of primary human microglia and monocyte-derived macrophages with human immunodeficiency virus type 1 isolates: evidence of differential tropism. J Virol. 1996; 70(11): 7654–7662.
104 - Gartner S. HIV infection and dementia. Science. 2000; 287(5453): 602–604.
105 - Liu Y, Tang XP, McArthur JC, Scott J, Gartner S. Analysis of human immunodeficiency virus type 1 gp160 sequences from a patient with HIV dementia: evidence for monocyte trafficking into brain. J Neurovirol. 2000; 6 Suppl 1: S70–81.
106 - Williams KC, Corey S, Westmoreland SV, Pauley D, Knight H, deBakker C, Alvarez X, Lackner AA. Perivascular macrophages are the primary cell type productively infected by simian immunodeficiency virus in the brains of macaques: implications for the neuropathogenesis of AIDS. J Exp Med. 2001; 193(8): 905–915.
107 - Fischer-Smith T, Croul S, Sverstiuk AE, Capini C, L’Heureux D, Regulier EG, Richardson MW, Amini S, Morgello S, Khalili K, Rappaport J. CNS invasion by CD14+/CD16+ peripheral blood-derived monocytes in HIV dementia: perivascular accumulation and reservoir of HIV infection. J Neurovirol. 2001; 7(6): 528–541.
108 - Koeffler HP, Golde DW. Acute myelogenous leukemia: a human cell line responsive to colony-stimulating activity. Science. 1978; 200(4346): 1153–1154.
109 - Koeffler HP, Golde DW. Human myeloid leukemia cell lines: a review. Blood. 1980; 56(3): 344–350.
110 - Hulette BC, Rowden G, Ryan CA, Lawson CM, Dawes SM, Ridder GM, Gerberick GF. Cytokine induction of a human acute myelogenous leukemia cell line (KG-1) to a CD1a+ dendritic cell phenotype. Arch Dermatol Res. 2001; 293(3): 147–158.
111 - Hooper WC, Abraham RT, Ashendel CL, Woloschak GE. Differential responsiveness to phorbol esters correlates with differential expression of protein kinase C in KG-1 and KG-1a human myeloid leukemia cells. Biochim Biophys Acta. 1989; 1013(1): 47–54.
112 - Kiss Z, Deli E, Shoji M, Koeffler HP, Pettit GR, Vogler WR, Kuo JF. Differential effects of various protein kinase C activators on protein phosphorylation in human acute myeloblastic leukemia cell line KG-1 and its phorbol ester-resistant subline KG-1a. Cancer Res. 1987; 47(5): 1302–1307.
113 - Vignoli M, Furlini G, Re MC, Ramazzotti E, La Placa M. Modulation of CD4, CXCR-4, and CCR-5 makes human hematopoietic progenitor cell lines infected with human herpesvirus-6 susceptible to human immunodeficiency virus type 1. J Hematother Stem Cell Res. 2000; 9(1): 39–45. DOI: 10.1089/152581600319603
114 - Furlini G, Vignoli M, Ramazzotti E, Re MC, Visani G, La P. A concurrent human herpesvirus-6 infection renders two human hematopoietic progenitor (TF-1 and KG-1) cell lines susceptible to human immunodeficiency virus type-1. Blood. 1996; 87(11): 4737–4745.
115 - Re MC, Vignoli M, Furlini G, Ramazzotti E, Maldini C, La Placa M. In a human lymphomyeloid progenitor cell line (KG-1) HIV-1 gp120 binds to chemokine-receptors CXC-R4 and CCR5, only in the presence of CD4. New Microbiol. 1999; 22(4): 365–368.
116 - Sakagami H, Kishino K, Kobayashi M, Hashimoto K, Iida S, Shimetani A, Nakamura Y, Takahashi K, Ikarashi T, Fukamachi H, Satoh K, Nakashima H, Shimizu T, Takeda K, Watanabe S, Nakamura W. Selective antibacterial and apoptosis-modulating activities of mastic. In Vivo. 2009; 23(2): 215–223.
117 - Erice A, Balfour HHJr, Myers DE, Leske VL, Sannerud KJ, Kuebelbeck V, Irvin JD, Uckun FM. Anti-human immunodeficiency virus type 1 activity of an anti-CD4 immunoconjugate containing pokeweed antiviral protein. Antimicrob Agents Chemother. 1993; 37(4): 835–838.
118 - Kitamura T, Tange T, Terasawa T, Chiba S, Kuwaki T, Miyagawa K, Piao YF, Miyazono K, Urabe A, Takaku F. Establishment and characterization of a unique human cell line that proliferates dependently on GM-CSF, IL-3, or erythropoietin. J Cell Physiol. 1989; 140(2): 323–334. DOI: 10.1002/jcp.1041400219
119 - Kitamura T, Tojo A, Kuwaki T, Chiba S, Miyazono K, Urabe A, Takaku F. Identification and analysis of human erythropoietin receptors on a factor-dependent cell line, TF-1. Blood. 1989; 73(2): 375–380.
120 - Hu X, Moscinski LC, Hill BJ, Chen Q, Wu J, Fisher AB, Zuckerman KS. Characterization of a unique factor independent variant derived from human factor-dependent TF-1 cells: a transformed event. Leuk Res. 1998; 22(9): 817–826.
121 - Cremer I, Vieillard V, De Maeyer E. Interferon-beta-induced human immunodeficiency virus resistance in CD34(+) human hematopoietic progenitor cells: correlation with a down- regulation of CCR-5 expression. Virology. 1999; 253(2): 241–249.
122 - Suzu S, Harada H, Matsumoto T, Okada S. HIV-1 Nef interferes with M-CSF receptor signaling through Hck activation and inhibits M-CSF bioactivities. Blood. 2005; 105(8): 3230–3237. DOI: 10.1182/blood-2004-06-2084
123 - Zhang MY, Harhaj EW, Bell L, Sun SC, Miller BA. Bcl-3 expression and nuclear translocation are induced by granulocyte-macrophage colony-stimulating factor and erythropoietin in proliferating human erythroid precursors. Blood. 1998; 92(4): 1225–1234.
124 - Briggs SD, Scholtz B, Jacque JM, Swingler S, Stevenson M, Smithgall TE. HIV-1 Nef promotes survival of myeloid cells by a Stat3-dependent pathway. J Biol Chem. 2001; 276(27): 25605–25611. DOI: 10.1074/jbc.M103244200
125 - Furlini G, Re MC, Vignoli M, Ramazzotti E, Monari P, La Placa M. The lack of susceptibility to HIV-1 infection in human hematopoietic progenitor TF-1 cell line correlates with the absence of LFA-1 (CD11a) surface adhesion molecule. New Microbiol. 1995; 18(1): 59–67.
126 - Quiterio S, Grant C, Hogan TH, Krebs FC, Wigdahl B. C/EBP- and Tat-mediated activation of the HIV-1 LTR in CD34+ hematopoietic progenitor cells. Biomed Pharmacother. 2003; 57(1): 49–56.
127 - Alexaki A, Quiterio SJ, Liu Y, Irish B, Kilareski E, Nonnemacher MR, Wigdahl B. PMA-induced differentiation of a bone marrow progenitor cell line activates HIV-1 LTR-driven transcription. DNA Cell Biol. 2007; 26(6): 387–394. DOI: 10.1089/dna.2006.0542
128 - Alexaki A, Quiterio SJ, Nonnemacher MR, Shah S, Liu Y, Banerjee A, Li L, Passic S, Pirrone V, Kilareski E, Petrovas C, Wigdahl B. Modeling Bone Marrow Progenitor Cell Differentiation and Susceptibility to HIV-1 Infection. MOJ immunology. 2014; 1(2): 00009–00009. DOI: 10.15406/moji.2014.01.00009
129 - Collins SJ, Gallo RC, Gallagher RE. Continuous growth and differentiation of human myeloid leukaemic cells in suspension culture. Nature. 1977; 270(5635): 347–349.
130 - Gallagher R, Collins S, Trujillo J, McCredie K, Ahearn M, Tsai S, Metzgar R, Aulakh G, Ting R, Ruscetti F, Gallo R. Characterization of the continuous, differentiating myeloid cell line (HL-60) from a patient with acute promyelocytic leukemia. Blood. 1979; 54(3): 713–733.
131 - Collins SJ, Ruscetti FW, Gallagher RE, Gallo RC. Terminal differentiation of human promyelocytic leukemia cells induced by dimethyl sulfoxide and other polar compounds. Proc Natl Acad Sci U S A. 1978; 75(5): 2458–2462.
132 - Lotem J, Sachs L. Regulation of normal differentiation in mouse and human myeloid leukemic cells by phorbol esters and the mechanism of tumor promotion. Proc Natl Acad Sci U S A. 1979; 76(10): 5158–5162.
133 - Fibach E, Peled T, Treves A, Kornberg A, Rachmilewitz EA. Modulation of the maturation of human leukemic promyelocytes (HL-60) to granulocytes or macrophages. Leuk Res. 1982; 6(6): 781–790.
134 - Dayton ET, Perussia B, Trinchieri G. Correlation between differentiation, expression of monocyte-specific antigens, and cytotoxic functions in human promyelocytic cell lines treated with leukocyte-conditioned medium. J Immunol. 1983; 130(3): 1120–1128.
135 - McCarthy DM, San Miguel JF, Freake HC, Green PM, Zola H, Catovsky D, Goldman JM. 1,25-dihydroxyvitamin D3 inhibits proliferation of human promyelocytic leukaemia (HL60) cells and induces monocyte-macrophage differentiation in HL60 and normal human bone marrow cells. Leuk Res. 1983; 7(1): 51–55.
136 - Newburger PE, Chovaniec ME, Greenberger JS, Cohen HJ. Functional changes in human leukemic cell line HL- 60. A model for myeloid differentiation. J Cell Biol. 1979; 82(2): 315–322.
137 - Rovera G, Santoli D, Damsky C. Human promyelocytic leukemia cells in culture differentiate into macrophagelike cells when treated with a phorbol diester. Proc Natl Acad Sci U S A. 1979; 76(6): 2779–2783.
138 - Butera ST, Perez VL, Wu BY, Nabel GJ, Folks TM. Oscillation of the human immunodeficiency virus surface receptor is regulated by the state of viral activation in a CD4+ cell model of chronic infection. J Virol. 1991; 65(9): 4645–4653.
139 - Ushijima H, Kunisada T, Ami Y, Tsuchie H, Takahashi I, Klocking HP, Muller WE. Characterization of human immunodeficiency virus-1-infected cells of myeloid-monocytic lineage (ML-1, HL-60, THP-1, U-937). J Acquir Immune Defic Syndr. 1992; 5(10): 1001–1004.
140 - Semmel M, Macho A, Morozov V, Coulaud D, Alileche A, Plaisance S, Aguilar J, Jasmin C. Replication of human immunodeficiency virus in HL-60 cells. Res Virol. 1992; 143(4): 249–258.
141 - Ushijima H, Abe T. Human immunodeficiency virus infection in central nervous system and myeloid-monocytic lineage. Acta Paediatr Jpn. 1992; 34(3): 371–376.
142 - Ushijima H, Dairaku M, Honma H, Yamaguchi K, Shimizu H, Tsuchie H, Abe K, Yamamoto A, Hoshino H, Muller WE. Human immunodeficiency virus infection in cells of myeloid-monocytic lineage. Microbiol Immunol. 1991; 35(6): 487–492.
143 - Kitano K, Baldwin GC, Raines MA, Golde DW. Differentiating agents facilitate infection of myeloid leukemia cell lines by monocytotropic HIV-1 strains. Blood. 1990; 76(10): 1980–1988.
144 - Beider K, Begin M, Abraham M, Wald H, Weiss ID, Wald O, Pikarsky E, Zeira E, Eizenberg O, Galun E, Hardan I, Engelhard D, Nagler A, Peled A. CXCR4 antagonist 4F-benzoyl-TN14003 inhibits leukemia and multiple myeloma tumor growth. Exp Hematol. 2011; 39(3): 282–292. DOI: 10.1016/j.exphem.2010.11.010
145 - Zoughlami Y, Voermans C, Brussen K, van Dort KA, Kootstra NA, Maussang D, Smit MJ, Hordijk PL, van Hennik PB. Regulation of CXCR4 conformation by the small GTPase Rac1: implications for HIV infection. Blood. 2012; 119(9): 2024–2032. DOI: 10.1182/blood-2011-06-364828
146 - Beltran JA, Pallur A, Chang SL. HIV-1 gp120 up-regulation of the mu opioid receptor in TPA-differentiated HL- 60 cells. Int Immunopharmacol. 2006; 6(9): 1459–1467. DOI: 10.1016/j.intimp.2006.04.018
147 - Garin A, Pellet P, Deterre P, Debre P, Combadiere C. Cloning and functional characterization of the human fractalkine receptor promoter regions. Biochem J. 2002; 368(Pt 3): 753–760. DOI: 10.1042/BJ20020951
148 - Foti M, Phelouzat MA, Holm A, Rasmusson BJ, Carpentier JL. p56Lck anchors CD4 to distinct microdomains on microvilli. Proc Natl Acad Sci U S A. 2002; 99(4): 2008–2013. DOI: 10.1073/pnas.042689099
149 - Kijowski J, Baj-Krzyworzeka M, Majka M, Reca R, Marquez LA, Christofidou-Solomidou M, Janowska- Wieczorek A, Ratajczak MZ. The SDF-1-CXCR4 axis stimulates VEGF secretion and activates integrins but does not affect proliferation and survival in lymphohematopoietic cells. Stem Cells. 2001; 19(5): 453–466. DOI: 10.1634/stemcells.19-5-453
150 - Gupta SK, Pillarisetti K, Thomas RA, Aiyar N. Pharmacological evidence for complex and multiple site interaction of CXCR4 with SDF-1alpha: implications for development of selective CXCR4 antagonists. Immunol Lett. 2001; 78(1): 29–34.
151 - Di Marzio P, Tse J, Landau NR. Chemokine receptor regulation and HIV type 1 tropism in monocyte-macrophages. AIDS Res Hum Retroviruses. 1998; 14(2): 129–138. DOI: 10.1089/aid.1998.14.129
152 - Horuk R, Hesselgesser J, Zhou Y, Faulds D, Halks-Miller M, Harvey S, Taub D, Samson M, Parmentier M, Rucker J, Doranz BJ, Doms RW. The CC chemokine I-309 inhibits CCR8-dependent infection by diverse HIV-1 strains. J Biol Chem. 1998; 273(1): 386–391.
153 - Roberts BD, Butera ST. Changes in CXC-chemokine receptor-4 expression during HIV-1 replication are independent of CD4 modulations. AIDS. 1997; 11(15): 1886–1888.
154 - Davis CB, Dikic I, Unutmaz D, Hill CM, Arthos J, Siani MA, Thompson DA, Schlessinger J, Littman DR. Signal transduction due to HIV-1 envelope interactions with chemokine receptors CXCR4 or CCR5. J Exp Med. 1997; 186(10): 1793–1798.
155 - Dhawan S, Puri RK, Kumar A, Duplan H, Masson JM, Aggarwal BB. Human immunodeficiency virus-1-tat protein induces the cell surface expression of endothelial leukocyte adhesion molecule-1, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1 in human endothelial cells. Blood. 1997; 90(4): 1535–1544.
156 - Pimentel-Muinos FX, Lopez-Guerrero JA, Fresno M, Alonso MA. CD4 gene transcription is transiently repressed during differentiation of myeloid cells to macrophage-like cells. Eur J Biochem. 1992; 207(1): 321–325.
157 - Schlesinger M, Bar-Shavit Z, Hadar R, Rabinowitz R. Modulation of the expression of CD4 on HL-60 cells by exposure to 1,25-dihydroxyvitamin D3. Immunol Lett. 1989; 22(4): 307–311.
158 - Faltynek CR, Finch LR, Miller P, Overton WR. Treatment with recombinant IFN-gamma decreases cell surface CD4 levels on peripheral blood monocytes and on myelomonocyte cell lines. J Immunol. 1989; 142(2): 500–508.
159 - Firestein GS, Reifler D, Richman D, Gruber HE. Rapid and reversible modulation of T4 (CD4) on monocytoid cells by phorbol myristate acetate: effect on HIV susceptibility. Cell Immunol. 1988; 113(1): 63–69.
160 - Venkataraman N, Cole AL, Ruchala P, Waring AJ, Lehrer RI, Stuchlik O, Pohl J, Cole AM. Reawakening retrocyclins: ancestral human defensins active against HIV-1. PLoS Biol. 2009; 7(4): e95. DOI: 10.1371/journal.pbio.1000095
161 - Imai K, Okamoto T. Transcriptional repression of human immunodeficiency virus type 1 by AP-4. J Biol Chem. 2006; 281(18): 12495–12505. DOI: 10.1074/jbc.M511773200
162 - Ng TB, Lam SK, Fong WP. A homodimeric sporamin-type trypsin inhibitor with antiproliferative, HIV reverse transcriptase-inhibitory and antifungal activities from wampee (Clausena lansium) seeds. Biol Chem. 2003; 384(2): 289–293. DOI: 10.1515/BC.2003.032
163 - Okamoto M, Wang X, Debyser Z, De Clercq E, Baba M. Establishment of an in vitro assay system mimicking human immunodeficiency virus type 1-induced neural cell death and evaluation of inhibitors thereof. J Virol Methods. 2003; 108(2): 195–203.
164 - Suffredini IB, Varella D, de Oliviera AA, Younes RN. In vitro anti-HIV and antitumor evaluation of Amazonian plants belonging to the Apocynaceae family. Phytomedicine. 2002; 9(2): 175. DOI: 10.1078/0944-7113-00109
165 - Kulkosky J, Culnan DM, Roman J, Dornadula G, Schnell M, Boyd MR, Pomerantz RJ. Prostratin: activation of latent HIV-1 expression suggests a potential inductive adjuvant therapy for HAART. Blood. 2001; 98(10): 3006–3015.
166 - Ikezoe T, Daar ES, Hisatake J, Taguchi H, Koeffler HP. HIV-1 protease inhibitors decrease proliferation and induce differentiation of human myelocytic leukemia cells. Blood. 2000; 96(10): 3553–3559.
167 - Critchfield JW, Ho O, Roberts BD, Van Lint C, Verdin E, Butera ST. Isoquinolinesulphonamide derivatives inhibit transcriptional elongation of human immunodeficiency virus type 1 RNA in a promyelocytic model of latency. Antivir Chem Chemother. 1999; 10(5): 275–284.
168 - Critchfield JW, Coligan JE, Folks TM, Butera ST. Casein kinase II is a selective target of HIV-1 transcriptional inhibitors. Proc Natl Acad Sci U S A. 1997; 94(12): 6110–6115.
169 - Butera ST, Roberts BD, Folks TM. Ligand passing by the p75 tumour necrosis factor receptor enhances HIV-1 activation. Cytokine. 1996; 8(10): 745–750. DOI: 10.1006/cyto.1996.0099
170 - Kira T, Hashimoto K, Baba M, Okamoto T, Shigeta S. 2-Glycineamide-5-chlorophenyl 2-pyrryl ketone, a nonbenzodiazepin Tat antagonist, is effective against acute and chronic HIV-1 infections in vitro. Antiviral Res. 1996; 32(2): 55–62.
171 - Xu M, Sharma V, Bryans M, Wilkie NM. Identification of a new member of the MNP transcription factor family in differentiated HL60 cells. Biochem Biophys Res Commun. 1996; 226(2): 488–494. DOI: 10.1006/bbrc.1996.1382
172 - Lee MO, Dawson MI, Picard N, Hobbs PD, Pfahl M. A novel class of retinoid antagonists and their mechanism of action. J Biol Chem. 1996; 271(20): 11897–11903.
173 - Mufson RA, Myers C, Turpin JA, Meltzer M. Phorbol ester reduces constitutive nuclear NF kappa B and inhibits HIV-1 production in mature human monocytic cells. J Leukoc Biol. 1992; 52(6): 637–644.
174 - Yasuno T, Ohe T, Takahashi K, Nakamura S, Mashino T. The human immunodeficiency virus-reverse transcriptase inhibition activity of novel pyridine/pyridinium-type fullerene derivatives. Bioorg Med Chem Lett. 2015; 25(16): 3226–3229. DOI: 10.1016/j.bmcl.2015.05.086
175 - Huang SZ, Zhang XJ, Li XY, Kong LM, Jiang HZ, Ma QY, Liu YQ, Hu JM, Zheng YT, Li Y, Zhou J, Zhao YX. Daphnane-type diterpene esters with cytotoxic and anti-HIV-1 activities from Daphne acutiloba Rehd. Phytochemistry. 2012; 75: 99–107. DOI: 10.1016/j.phytochem.2011.11.013
176 - Yanvarev DV, Shirokova EA, Astapova MV, Shram VI, Kukhanova MK, Skoblov YS. 5'-carbamoylphosphonyl-[6-3H]-AZT as a tool for studying metabolic transformations of the nonradioactive counterpart, an inhibitor of HIV replication. Nucleosides Nucleotides Nucleic Acids. 2007; 26(8–9): 897–900. DOI: 10.1080/15257770701505899
177 - Yanvarev DV, Shirokova EA, Astapova MV, Skoblov YS. AZT 5'-Cholinephosphate as an anti-HIV agent: the study of biochemical properties and metabolic transformations using its 32P-labelled counterpart. Nucleosides Nucleotides Nucleic Acids. 2007; 26(1): 23–36. DOI: 10.1080/15257770601052257
178 - Ikezoe T, Bandobashi K, Yang Y, Takeuchi S, Sekiguchi N, Sakai S, Koeffler HP, Taguchi H. HIV-1 protease inhibitor ritonavir potentiates the effect of 1,25-dihydroxyvitamin D3 to induce growth arrest and differentiation of human myeloid leukemia cells via down-regulation of CYP24. Leuk Res. 2006; 30(8): 1005–1011. DOI: 10.1016/j.leukres.2005.12.008
179 - Skoblov Y, Karpenko I, Shirokova E, Popov K, Andronova V, Galegov G, Kukhanova M. Intracellular metabolism and pharmacokinetics of 5'-hydrogenphosphonate of 3'-azido-2',3'-dideoxythymidine, a prodrug of 3'-azido-2',3'-dideoxythymidine. Antiviral Res. 2004; 63(2): 107–113. DOI: 10.1016/j.antiviral.2004.03.001
180 - Nusbaum NJ, Joseph PE. AZT incorporation into mitochondria: study in a human myeloid cell line. DNA Cell Biol. 1996; 15(5): 363–366. DOI: 10.1089/dna.1996.15.363
181 - Nusbaum NJ, Abraham T. Combination antiretroviral chemotherapy: a potential strategy in AIDS-related malignancy. Anticancer Drugs. 1996; 7(1): 109–114.
182 - Balzarini J, Verstuyf A, Hatse S, Goebels J, Sobis H, Vandeputte M, De Clercq E. The human immunodeficiency virus(HIV) inhibitor 9-(2-phosphonylmethoxyethyl)adenine (PMEA) is a strong inducer of differentiation of several tumor cell lines. Int J Cancer. 1995; 61(1): 130–137.
183 - Semmel M, Macho A, Coulaud D, Alileche A, Plaisance S, Aguilar J, Jasmin C. Effect of retinoic acid on HL-60 cells infected with human immunodeficiency virus type 1. Blood. 1994; 84(8): 2480–2488.
184 - Rivas CI, Golde DW, Vera JC, Kolesnick RN. Involvement of the sphingomyelin pathway in autocrine tumor necrosis factor signaling for human immunodeficiency virus production in chronically infected HL-60 cells. Blood. 1994; 83(8): 2191–2197.
185 - Kitano K, Rivas CI, Baldwin GC, Vera JC, Golde DW. Tumor necrosis factor-dependent production of human immunodeficiency virus 1 in chronically infected HL-60 cells. Blood. 1993; 82(9): 2742–2748.
186 - Butera ST, Roberts BD, Leung K, Nabel GJ, Folks TM. Tumor necrosis factor receptor expression and signal transduction in HIV-1-infected cells. AIDS. 1993; 7(7): 911–918.
187 - Franzoso G, Biswas P, Poli G, Carlson LM, Brown KD, Tomita-Yamaguchi M, Fauci AS, Siebenlist UK. A family of serine proteases expressed exclusively in myelo-monocytic cells specifically processes the nuclear factor kappa B subunit p65 in vitro and may impair human immunodeficiency virus replication in these cells. J Exp Med. 1994; 180(4): 1445–1456.
188 - Ushijima H, Kunisada T, Ami Y, Tsuchie H, Takahashi I, Schacke H, Muller WE. Characterization of cells of the myeloid-monocytic lineage (ML-1, HL-60, THP-1, U-937) chronically infected with the human immunodeficiency virus-1. Pathobiology. 1993; 61(3–4): 145–153.
189 - Kunisada T, Sakagami H, Takeda M, Naoe T, Kawazoe Y, Ushijima H, Muller WE, Kitamura T. Effect of lignins on HIV-induced cytopathogenicity and myeloperoxidase activity in human myelogenous leukemic cell lines. Anticancer Res. 1992; 12(6B): 2225–2228.
190 - DiFronzo NL, Pise-Masison CA, Fernandez-Larsson R, Holland CA. Viral determinants of HIV-1 sufficient to extend tropism to macrophages are distinct from the determinants that control the cytopathic phenotype in HL- 60 cells. AIDS. 1997; 11(14): 1681–1688.
191 - Pise-Masison CA, Holland CA. Restricted replication of the HIV-1 T-lymphotropic isolate NL4-3 in HL-60 cells. Virology. 1995; 206(1): 641–645.
192 - Cannon PM, Tenen DG, Feinberg MB, Shin HS, Kim S. Human immunodeficiency virus-1 infection of the human promyelocytic cell line HL-60: high frequency of low-level infection and effect of subsequent cell differentiation. Blood. 1993; 81(2): 437–445.
193 - Pise CA, Newburger PE, Holland CA. Human immunodeficiency virus type 1-infected HL-60 cells are capable of both monocytic and granulocytic differentiation. J Gen Virol. 1992; 73 (Pt 12): 3257–3261. DOI: 10.1099/0022-1317-73-12-3257
194 - Foti M, Cartier L, Piguet V, Lew DP, Carpentier JL, Trono D, Krause KH. The HIV Nef protein alters Ca(2+) signaling in myelomonocytic cells through SH3-mediated protein-protein interactions. J Biol Chem. 1999; 274(49): 34765–34772.
195 - Tyagi M, Iordanskiy S, Ammosova T, Kumari N, Smith K, Breuer D, Ilatovskiy AV, Kont YS, Ivanov A, Uren A, Kovalskyy D, Petukhov M, Kashanchi F, Nekhai S. Reactivation of latent HIV-1 provirus via targeting protein phosphatase-1. Retrovirology. 2015; 12: 63. DOI: 10.1186/s12977-015-0190-4
196 - Victoriano AF, Imai K, Togami H, Ueno T, Asamitsu K, Suzuki T, Miyata N, Ochiai K, Okamoto T. Novel histone deacetylase inhibitor NCH-51 activates latent HIV-1 gene expression. FEBS Lett. 2011; 585(7): 1103–1111. DOI: 10.1016/j.febslet.2011.03.017
197 - Ueoka R, Komizu Y, Matsumoto Y, Zhong Y, Tanaka R, Yamamoto N. Selective inhibitory effects of hybrid liposomes on the growth of HIV type 1-infected cells in vitro. Bioorg Med Chem Lett. 2008; 18(16): 4578–4580. DOI: 10.1016/j.bmcl.2008.07.030
198 - Qi X, Koya Y, Saitoh T, Saitoh Y, Shimizu S, Ohba K, Yamamoto N, Yamaoka S, Yamamoto N. Efficient induction of HIV-1 replication in latently infected cells through contact with CD4+ T cells: involvement of NF-kappaB activation. Virology. 2007; 361(2): 325–334. DOI: 10.1016/j.virol.2006.11.014
199 - Roberts BD, Fang G, Butera ST. Influence of cell cycle on HIV-1 expression differs among various models of chronic infection. Arch Virol. 1997; 142(6): 1087–1099.
200 - Butera ST, Roberts BD, Lam L, Hodge T, Folks TM. Human immunodeficiency virus type 1 RNA expression by four chronically infected cell lines indicates multiple mechanisms of latency. J Virol. 1994; 68(4): 2726–2730.
201 - Sundstrom C, Nilsson K. Establishment and characterization of a human histiocytic lymphoma cell line (U-937). Int J Cancer. 1976; 17(5): 565–577.
202 - Ralph P, Moore MA, Nilsson K. Lysozyme synthesis by established human and murine histiocytic lymphoma cell lines. J Exp Med. 1976; 143(6): 1528–1533.
203 - Larrick JW, Fischer DG, Anderson SJ, Koren HS. Characterization of a human macrophage-like cell line stimulated in vitro: a model of macrophage functions. J Immunol. 1980; 125(1): 6–12.
204 - Ralph P, Harris PE, Punjabi CJ, Welte K, Litcofsky PB, Ho MK, Rubin BY, Moore MA, Springer TA. Lymphokine inducing “terminal differentiation” of the human monoblast leukemia line U937: a role for gamma interferon. Blood. 1983; 62(6): 1169–1175.
205 - Harris PE, Ralph P, Litcofsky P, Moore MA. Distinct activities of interferon-gamma, lymphokine and cytokine differentiation-inducing factors acting on the human monoblastic leukemia cell line U937. Cancer Res. 1985; 45(1): 9–13.
206 - Tsuchiya S, Kobayashi Y, Goto Y, Okumura H, Nakae S, Konno T, Tada K. Induction of maturation in cultured human monocytic leukemia cells by a phorbol diester. Cancer Res. 1982; 42(4): 1530–1536.
207 - Ralph P, Williams N, Moore MA, Litcofsky PB. Induction of antibody-dependent and nonspecific tumor killing in human monocytic leukemia cells by nonlymphocyte factors and phorbol ester. Cell Immunol. 1982; 71(2): 215–223.
208 - Folks TM, Justement J, Kinter A, Dinarello CA, Fauci AS. Cytokine-induced expression of HIV-1 in a chronically infected promonocyte cell line. Science. 1987; 238(4828): 800–802.
209 - Wang X, Sun B, Mbondji C, Biswas S, Zhao J, Hewlett I. Differences in Activation of HIV-1 Replication by Superinfection With HIV-1 and HIV-2 in U1 Cells. J Cell Physiol. 2016. Epub ahead of print. DOI: 10.1002/jcp.25614
210 - Rao P, Ande A, Sinha N, Kumar A, Kumar S. Effects of cigarette smoke condensate on oxidative stress, apoptotic cell death, and HIV replication in human monocytic cells. PLoS One. 2016; 11(5): e0155791. DOI: 10.1371/journal.pone.0155791
211 - Arenaccio C, Anticoli S, Manfredi F, Chiozzini C, Olivetta E, Federico M. Latent HIV-1 is activated by exosomes from cells infected with either replication-competent or defective HIV-1. Retrovirology. 2015; 12: 87. DOI: 10.1186/s12977-015-0216-y
212 - Barquero AA, Davola ME, Riva DA, Mersich SE, Alche LE. Naturally occurring compounds elicit HIV-1 replication in chronically infected promonocytic cells. BioMed Res Int. 2014; 2014: 989101. DOI: 10.1155/2014/989101
213 - Rasmussen TA, Schmeltz Sogaard O, Brinkmann C, Wightman F, Lewin SR, Melchjorsen J, Dinarello C, Ostergaard L, Tolstrup M. Comparison of HDAC inhibitors in clinical development: effect on HIV production in latently infected cells and T-cell activation. Hum Vaccin Immunother. 2013; 9(5): 993–1001. DOI: 10.4161/hv.23800
214 - Palmisano I, Della Chiara G, D'Ambrosio RL, Huichalaf C, Brambilla P, Corbetta S, Riba M, Piccirillo R, Valente S, Casari G, Mai A, Martinelli Boneschi F, Gabellini D, Poli G, Schiaffino MV. Amino acid starvation induces reactivation of silenced transgenes and latent HIV-1 provirus via down-regulation of histone deacetylase 4 (HDAC4). Proc Natl Acad Sci U S A. 2012; 109(34): E2284–2293. DOI: 10.1073/pnas.1202174109
215 - Hu W, Kaminski R, Yang F, Zhang Y, Cosentino L, Li F, Luo B, Alvarez-Carbonell D, Garcia-Mesa Y, Karn J, Mo X, Khalili K. RNA-directed gene editing specifically eradicates latent and prevents new HIV-1 infection. Proc Natl Acad Sci U S A. 2014; 111(31): 11461–11466. DOI: 10.1073/pnas.1405186111
216 - Chanput W, Mes JJ, Wichers HJ. THP-1 cell line: an in vitro cell model for immune modulation approach. Int Immunopharmacol. 2014; 23(1): 37–45. DOI: 10.1016/j.intimp.2014.08.002
217 - Lund ME, To J, O'Brien BA, Donnelly S. The choice of phorbol 12-myristate 13-acetate differentiation protocol influences the response of THP-1 macrophages to a pro-inflammatory stimulus. J Immunol Methods. 2016; 430: 64–70. DOI: 10.1016/j.jim.2016.01.012
218 - Schildberger A, Rossmanith E, Eichhorn T, Strassl K, Weber V. Monocytes, peripheral blood mononuclear cells, and THP-1 cells exhibit different cytokine expression patterns following stimulation with lipopolysaccharide. Mediators Inflamm. 2013; 2013: 697972. DOI: 10.1155/2013/697972
219 - Sharif O, Bolshakov VN, Raines S, Newham P, Perkins ND. Transcriptional profiling of the LPS induced NF-kappaB response in macrophages. BMC Immunol. 2007; 8: 1. DOI: 10.1186/1471-2172-8-1
220 - Cassol E, Alfano M, Biswas P, Poli G. Monocyte-derived macrophages and myeloid cell lines as targets of HIV-1 replication and persistence. J Leukoc Biol. 2006; 80(5): 1018–1030. DOI: 10.1189/jlb.0306150
221 - Planelles V, Wolschendorf F, Kutsch O. Facts and fiction: cellular models for high throughput screening for HIV- 1 reactivating drugs. Curr HIV Res. 2011; 9(8): 568–578.
222 - Watters SA, Mlcochova P, Gupta RK. Macrophages: the neglected barrier to eradication. Curr Opin Infect Dis. 2013; 26(6): 561–566. DOI: 10.1097/QCO.0000000000000014
223 - Redel L, Le Douce V, Cherrier T, Marban C, Janossy A, Aunis D, Van Lint C, Rohr O, Schwartz C. HIV-1 regulation of latency in the monocyte-macrophage lineage and in CD4+ T lymphocytes. J Leukoc Biol. 2010; 87(4): 575–588. DOI: 10.1189/jlb.0409264