Open access peer-reviewed chapter
Abstract
Tuberculosis (TB) and HIV/AIDS infection are one of the most ubiquitous and deadliest communicable diseases in the world. They cause millions of deaths each year and are recognized as major threats for public health worldwide. The corresponding pathogens (Mycobacterium tuberculosis and HIV) share overlapping epidemiology—they affect low-income countries and place an immense burden on their feeble health care systems. Over the last decades, the natural history of both diseases has changed; in addition to devastating single HIV and TB infections, the coinfection with both pathogens has emerged and has spread in pandemic scale. When present as dual infection in an individual, Mycobacterium tuberculosis and HIV potentiate each other and kill in cooperation the host. TB is the leading cause of death in HIV-positive patients and in turn HIV infection is the strongest risk factor for the development of new or reactivation of dormant TB disease. Both pathogens (as single or dual infection) provoke a robust immune response in the infected host but the immune system does not achieve to eliminate the infectious agent(s). The failure of immune defense results in vulnerable immune balance between the micro- and the macroorganism and often ends up in a fatal outcome.
Keywords
- Tuberculosis
- HIV
- immunity
- co-infection
1. Introduction
Human immunodeficiency virus (HIV) and tuberculosis (TB) represent, respectively, the first and the second leading cause of death from infectious disease in the world. Both are responsible for approximately 3 million deaths annually [1].
Either HIV or TB, when present as a single infection, irreversibly affects and exhausts the immune system of the infected person. Moreover, if they simultaneously coexist in an individual (coinfection), they act in synergy to deteriorate the defense mechanisms of the host’s immunity and to accelerate the fatal scenario.
In this chapter, we will review current knowledge of innate and adaptive immune responses against TB and HIV infections. We will discuss in detail the immunological basis behind the dual threat of TB/HIV coinfection.
2. Epidemiology
2.1. Epidemiology of HIV pandemic
HIV infection is a viral disease that affects host immune system and makes the host strongly susceptible to opportunistic infections. It spreads among human population via sexual contact, sharing needles during drug injection, transfusion of contaminated blood products, or during births from HIV-infected women.
Since the late 20th century, HIV infection has become a global pandemic and a major challenge for public health authorities at the national and international levels. At the end of 2013, 35 million people were living with HIV worldwide [2]. During the same year, approximately 2.1 million people were newly infected with HIV. Sub-Saharan Africa is the most affected region in the world—almost 70% of the prevalent and the new HIV-positive cases are diagnosed there. The socio-economic status of the countries in the core of HIV pandemic determines the low number of infected people currently on adequate antiretroviral therapy (only 36% of overall cases).
2.2. Epidemiology of tuberculosis
Tuberculosis (TB) is an infectious disease caused by bacterial species grouped in
The World Health Organization (WHO) recognizes TB as “a global public health emergency” and “one of the world’s deadliest communicable diseases” [1]. At least one-third of the world population (approx. 2 billion people) is currently infected with latent mycobacteria and has a risk, although low (5–10%), to develop an active disease during the life course [1]. In 2013, 9 million new TB cases occurred worldwide (TB incidence: 126 cases per 100,000 population) and the prevalent cases were 11 million (TB prevalence: 159 cases per 100,000 population). Despite the efforts at the international, national, and regional level and the significant progress in the detection and management of TB infection, still the incidence, prevalence, and mortality rate of TB are unacceptably high.
2.3. Epidemiology of TB/HIV coinfection
People living with HIV have 26–31 times higher risk to develop active TB than the normal population [1]. Both diseases are epidemiologically and biologically connected—TB is the leading cause of death in HIV-positive patients and in turn HIV infection exacerbates the gravity of TB. Due to the global circulation of HIV, the incidence of TB —an infection previously thought to be almost eliminated at least in developed countries—is still high in both developing and high-income countries. HIV disrupts the host immune system through significant depletion of CD4+ lymphocytes, a mechanism that readily facilitates the reactivation of latent TB to an active disease. Therefore, HIV is the strongest risk factor for the development of new or the reactivation of dormant TB disease, including multidrug-resistant TB, an infection resistant to at least two of the first choice drugs for TB treatment, isoniazid and rifampicin. HIV infection predisposes TB-infected patients to antibiotic (rifampicin) resistance through gastrointestinal malabsorption of TB medications [4]. On the other hand,
As one-third of the total world population is currently infected with latent
WHO recommends regular screening of TB for all people living with HIV at every visit to a health care specialist [7]. WHO also recommends that routine HIV testing should be offered to all patients with presumptive and diagnosed TB, as well as to partners of known HIV-positive TB patients.
In addition to the increase in TB incidence, the worldwide HIV pandemic changed the average age of TB-infected people. In contrast to normal populations where TB is most prevalent among elderly people, in regions with significant number of HIV-positive cases, the most affected age by TB is the reproductive age (20–45 years). This leads to the consecutive increase in the number of TB-infected children [8].
3. Immunology of tuberculosis
3.1. The first date
Primary infection with
In most cases, the non-immune mechanisms do not allow the development of the infectious process. If infection occurs, the immune system in the lungs activates the first-line innate defense and then, several weeks later, an adaptive anti-mycobacterial immune response is activated. The strong immune response against
3.2. Innate immunity
The early stages of TB infection consist of inhalation of tubercle bacilli and initial encounter between the immune system and the pathogen. Alveolar macrophages and sometimes nonprofessional phagocytic cells (alveolar epithelial cells) are the first to recognize
If bacteria survive bactericidal macrophage action, they can multiply intracellularly to destroy the infected macrophage and to release attractants for monocyte and dendritic cells accumulation. The attracted monocytes will differentiate into macrophages that in turn can recognize new
Macrophages and dendritic cells bind
The interaction between
3.3. Cell-mediated immunity
A fundamental characteristic of
The matured dendritic cells move to the regional lymph nodes where they initiate specific cell immune response by presenting the ingested mycobacterial antigens to the naïve T cells. Dendritic cells are a primary target for
The concentration of macrophages, T-lymphocytes, dendritic cells, and other immune and lung cells (epithelial, giant multinuclear Langerhans’ cells, plasma cells, neutrophils, fibroblasts) in the place of infection is known as granuloma. The process of granuloma formation limits the spread of
Both human and animal granulomas contain giant multinuclear Langerhans’ cells produced after the fusion of macrophages [18, 19]. In these cells, tubercle bacilli cannot multiply and survive successfully.
Neutrophils are important for early control of acute bacterial infection [20] as they immediately migrate to the place of mycobacterial infection and start bacterial phagocytosis [21]. Infected neutrophils produce IL-8 and TNF for activation of alveolar macrophages and limitation of the infection [22].
Both CD4+ and CD8+[23] contribute to the stimulation of macrophages and lysis of chronically infected macrophages (via INF-gamma action). The principal role in cell-mediated immunity against tuberculosis is played by CD4
CD8+ cells play an important role in IFN-gamma release, cell lysis and bacterial killing [27]. Some CD8+ lymphocytes may also recognize surface antigens presented by Class I MHC molecules—MHC class I-restricted cytotoxic T-lymphocytes (CTL). They are able to eliminate infected macrophages and also to kill intracellular bacteria via production of granulysin (a cytolytic and proinflammatory substance) [28].
Other immune cells—CD1 restricted T cells, γ/δ-T cells, and cytotoxic T-cells—also protect lung tissue against tuberculosis. T cells of type γ/δ are the first line of defense against microbial antigens and the connection between innate and adaptive immune response [29]. They have cytotoxic activity and may present mycobacterial antigens to CD8+ and CD4+ lymphocytes. In response to IL-23 secreted from infected dendritic cells, the γ/δ-Т cells start to release IL-17 for accumulation of additional immune cells in the place of infection.
Activated macrophages represent higher phagocytic activity against extracellular mycobacteria. On the base of T-lymphocyte stimulation, two types of macrophages are known: classically activated macrophages (САМ) and alternatively activated macrophages (ААM). During the immune response against tubercle bacilli, activation of macrophages by T-lymphocytes is achieved mainly through release of IFN-gamma and other Th-1 cytokines. The Th-1 cytokines (INF-gamma, TNF-alpha, IL-1beta) induce САМ to kill tubercle bacilli via production of nitric oxide synthetase (iNOS). This enzyme catalyzes synthesis of nitric oxide (NO), a powerful antimicrobial substance. The Th-2 cytokines (IL-4 and IL-13) activate ААM to produce anti-inflammatory cytokines and arginase. They both compete for arginine utilization with iNOS [30]. The increased arginase activity stimulates tissue repair but at the same time restricts bacterial killing [31].
3.4. Humoral immunity
In addition to cell-mediated immunity, humoral immune response plays a major role in TB infection control. The formed antibodies cannot transfer immunity but have an opsoning role and facilitate the phagocytosis by the macrophages and the cytotoxic function of T-lymphocytes [33]. Besides their antibody synthetic function [34], B-lymphocytes can present mycobacterial antigens to T cells [35]. They stimulate proliferation and differentiation of T-lymphocytes by the production of different cytokines. Specific effector B1-cells secrete Th1-cytokines—IFN-gamma and IL-12—while B2-cells secrete IL-4, typical for Th2-cells. Furthermore, activated B cells can produce IL-6 for T cell stimulation and IL-10 for inhibition of dendritic cells and macrophages.
3.5. Latent tuberculosis
The late stage of TB infection represents a prolonged (in many cases lifelong) suppression of mycobacterial cells as a result of the dynamic balance between the pathogen and the host immunity.
4. Immunology of HIV
4.1. Entry through the mucosal barrier
The principal route of HIV entry into the human body is through the mucosal epithelial surfaces (mainly genital or rectal). The virus prefers to infect immune cells expressing CD4+ receptors on their surface—CD4+ helper T cells, macrophages, and dendritic cells—all present in activated state in the mucosal lymphoid tissues.
HIV crosses the intact epithelial layers via interaction with dendritic cells and/or CD4+ helper T cells. The CD4+ receptor of these cells recognizes the viral envelope glycoprotein 120 (gp120) and causes its conformational change. This makes possible the binding with one of the auxiliary co-receptors: CCR5 or CXCR4. The second binding allows viral glycoprotein 41 (gp41) to integrate within the cell membrane and viral genome to access the host cytoplasm.
After entry into the cell, viral RNA—under the action of reverse transcriptase and integrase—turns into double-strand DNA and integrates into the host DNA. The integrated copy of HIV nucleic acid (named provirus) can stay in latent form for years and can become active at any time to complete the viral life cycle and produce new virions.
The principal target for HIV is the activated CD4+ T-lymphocyte expressing CCR5 or CXCR4 co-receptor. The high number of CD4+ T cells (especially memory CD4+CCR5+ T-lymphocytes) in the mucosa is ideal for HIV replication [37]. In contrast, mucosal dendritic cells do not express CD4+ or CCR5 receptors [38] but they do express other receptors that successfully recognize HIV envelope proteins—dendritic cell-specific intercellular adhesion molecule grabbing nonintegrins (DC-SIGN) and langerin [39].
4.2. HIV expansion
Early after the entry of HIV, the primary infected T-lymphocytes attract and activate other immune cells to expand the initial place of infection. The infected local site starts to grow until the detachment of the infected cells. Thus, the virus disseminates from the mucosal surfaces to the regional lymph nodes (usually in 10 days after the infection) and then throughout the body. The virus can be detected in all lymphoid organs but the highest number of viral particles concentrates in the mucosal lymphoid tissues (such as gastro-intestinal associated lymphoid tissue). Dendritic cells in lymph nodes and mucosal lymphoid tissues present the HIV antigens to naïve B cells and T cells, prompting them to differentiate and activate. In these first stages, the viral load is significant and CD4+ T cells count starts to decline rapidly.
In many cases, the early events of viral expansion (acute stage) are not clinically manifested. In some people, influenza-like or mononucleosis-like symptoms may occur several weeks after the exposure to infection but they are not specific and often misdiagnosed.
4.3. T cell-mediated immune response during HIV latency
Several months after the initial infection, a precise balance between the virus and the immune response (both cell-mediated and humoral) is established. Host immune system (especially CD8+ lymphocytes) succeeds to control viral replication at some degree but the elimination of target CD4+ population continues. This represents the chronic (latent) phase in HIV infection, clinically manifested with decreased viral load and appearance of specific anti-HIV antibodies in the blood of infected individuals.
Although the major characteristic of HIV infection is the depletion of CD4+ T cells, other lymphocyte types are also affected. HIV notably influences naïve T cells (both CD4 T naïve cells and CD8 T naïve cells) during the asymptomatic phase of the infection [40]. Any T cell-mediated immune response requires new naïve T cells and their depletion results in progressively compromised immunity. The reduction in naïve T cell counts is probably due to decreased thymic output and increased T cell turnover in HIV-positive patients [41]. Furthermore, during HIV asymptomatic phase, the overall CD8+ count remains the same as before infection but significant alteration in the ratio memory/naïve CD8+ cells occurs, the normal predominance of naïve CD8+ is replaced by the domination of memory cells (in many patients, the compartment of CD8+ memory cells represents more than 80% of all CD8+ circulating cells) [40].
The cellular immune response mediated by CD8+ cytotoxic T-lymphocytes (CTLs) plays a crucial role in HIV infection [42]. The precursor CTLs recognize viral antigens expressed on the surface of presenting cells. They become active with the help of IL-2, IFN-gamma, and TNF-alpha (produced from CD4+ T cells) and can directly eliminate infected CD4+ lymphocytes via secretion of perforin (a cytolytic protein) and granzymes (serine proteases). The increased ability to secrete perforin is specific for CD8+ T cells from small group HIV-positive individuals who maintain HIV replication in undetectable levels (elite controllers) [43] and who do not progress immunologically towards AIDS in the absence of antiretroviral treatment.
Simultaneously with the host response, the virus starts a mutation process to escape CD8+ recognition by changing epitopes and to correct the present viral variant. At this moment, a balance between host elimination and replication of new HIV variants is established. However, CD8+ immune response, as well as humoral response, strongly needs CD4+ T helpers and gradually with CD4+ depletion, the CD8+ control fails to maintain the viremia.
The loss of effective antiviral response leads to a constant stimulation and repeated activation of HIV specific CD8+ T cells. This chronic activation soon exhausts the pool of CD8+ lymphocytes together with CD4+ T cell one.
The elevated activation is characteristic not only for CD8+ and CD4+ T cells, but also for B cells, NK cells, and monocytes. In HIV-seropositive patients, even in early stages of infection, high levels of proinflammatory cytokines (TNF-alpha, IL-6 and IL-1β) and chemokines (MIP-1alpha, MIP-1beta and RANTES) are detected [37].
The HIV life cycle is closely related to the extent of immune system activation. Activation of the immune cells enhances the entry of HIV into the cytoplasm because the auxiliary co-receptors are upregulated under immune stimulation [44]. It also increases the level of provirus transcription together with the normal cellular transcription [45]. The exhausted CD8+ T cells diminish secretion of immune-stimulatory cytokines, slow down proliferation and suspend killing of infected cells [46]. HIV infection stimulates upregulation of CD8+ inhibitory receptors (Programmed Death-1 (PD-1), T cell immunoglobulin, and mucin-domain-containing molecule-3 (Tim-3) [47,48]) that downregulate CD8+ immune response and maintain T cell tolerance.
4.4. Humoral immune response against HIV
The humoral immune response against HIV is mediated by specific anti-HIV antibodies produced from B-lymphocytes several weeks to several months after the initial infection. HIV cannot replicate into B-lymphocytes but influences their activation and apoptosis. Unmatured B-lymphocytes differentiate under the action of Th1 cytokines (IL-4, IL-5, IL-6, IL-10, TGF-beta) into plasma cells producing large amounts of binding and virus-neutralizing antibodies. Antibodies target free viral particles in the HIV-positive blood and a small quantity of them can also eliminate infected cells.
HIV specific antibodies recognize viral envelope (envelope proteins gp120 and gp41) and protect host cells from viral entry, but the virus successfully escapes the antibodies’ binding via continual mutations. Memory B cells constantly produce new variants of antibodies and soon become exhausted.
4.5. AIDS
The latent phase can last several years (usually up to ten) and terminates finally with the development of AIDS and death. In the final stage, HIV infection completely exhausts the host immune system and especially the CD4+ T cell pool. AIDS is immunologically diagnosed by a CD4+ count less than 200 per µL or/and clinically by the occurrence of opportunistic HIV-related diseases.
5. Immunology of TB/HIV coinfection
5.1. HIV impact on TB infection
TB is the leading opportunistic infection and major cause of death in HIV-seropositive people. There is some evidence that both HIV-negative and HIV-positive persons have the same chance to be infected with TB [49]. In contrast, other studies have found that already existing HIV infection increased the risk of newly acquired TB [50, 51] and relapse of dormant
Existing data outlines two main hypotheses how HIV influences the course of TB infection: 1. HIV manipulates bactericidal activity of macrophages against
HIV impairs macrophages in HIV-positive patients turning them more susceptible to
HIV manifests its presence by gradual depletion of CD4+ T cells, a main feature of HIV infection and clinical sign for progression towards AIDS. The low CD4+ cell count makes the host more susceptible to tubercle bacilli as the immune system cannot establish an efficient cell-mediated immune response. The risk of reactivation of latent TB, acquirement of new TB infection, and/or of dissemination of TB towards extra pulmonary locations increases with the decrease of CD4+ cell count; patients with CD4+ counts >350 cells/µL have unaltered clinical and radiographic presentation as HIV seronegative patients, while patients with CD4+ counts <350 cells/µL have atypical chest X-ray findings and frequent extra pulmonary TB. HIV-positive patients in South Africa with CD4+ counts <200 cells/µL are more susceptible to
The insufficient CD4+ T number fails to control granuloma formation and maintenance, therefore leading to higher incidence of extra pulmonary TB and enlarged risk of reactivation of latent infection in HIV-positive patients. Caseous necrotic granulomas—typical for single TB infection—are rare in TB/HIV coinfected patients. Despite the same number of granulomas and acid-fast stained bacilli in TB infected and TB/HIV coinfected persons [59], granulomas from dual-infected individuals are easy disrupted and infection can readily disseminate into multiple organs to form diffuse lesions [60].
However, HIV influence on TB course may only partially depend on CD4+ depletion, as HIV-positive miners in South Africa had an increased risk (2 to 3 times higher) of developing active TB in the first and second year after HIV seroconversion, when the number of CD4+ T-cell was still high [61]. HIV-positive individuals with preserved CD4+ T cell counts (during an antiretroviral treatment) also have an increased risk of developing TB infection. This suggests that additional immunological changes could happen during HIV infection, making the host more susceptible to TB. Such possible mechanism is the observed uniform distribution of CD8+ T cells within the granuloma, in contrast to the peripheral findings in the single TB infection [62]. HIV also specifically diminishes production of IFN-gamma, IL-2, and IL-12 [63], and suppresses proliferation of TB-specific T cells. Several months after HIV seroconversion, the number of
5.2. TB importance in HIV infection
HIV recognizes immune cells expressing CD4+ glycoprotein on their surface: CD4+ T-cells, macrophages, and dendritic cells. All of these cellular types are involved in TB pathogenesis and immune response. HIV also needs activated immune cells for replication and propagation; such cells are abundantly present during
HIV-positive patients who developed TB have an increased viral load during the acute phase of TB disease [65, 66]. Lung tissue samples from patients with TB have increased HIV viral load when compared to HIV-positive patients without lung disease or plasma samples from the same TB patients [67]. This suggests that a TB-infected lung has elevated local HIV replication in vivo. In addition, HIV replication is activated in TB-infected alveolar macrophages [68], lymphocytes, and CD14+ macrophages of the pleural space [69].
Infection with
Coinfected individuals have increased incidence and death rate of HIV-related opportunistic infections comparing to HIV-positive but TB-negative patients with the same level of immunosuppression (absolute CD4+ count) [71], indicating that
6. Concluding remarks
TB/HIV coinfection represents a leading threat to public health worldwide. Despite the extreme research effort, many aspects of the exceptionally complicated immunology of concurrent TB and HIV infections still need to be elucidated. Diagnosis of HIV/TB coinfection is challenging as both infections have overlapping clinical manifestations, which often lead to late or misdiagnosis. Furthermore, TB and HIV as well the coinfection mostly affect poor and developing regions where competent health care is hardly accessible.
Changes in both innate and adaptive immune response demand well-organized clinical and laboratory studies to understand possible mechanisms by which HIV and TB disrupt in perfect and fatal cooperation the immune system of the host.
Abbreviatons
AAM – Alternatively activated macrophages
AIDS – Acquired immune deficiency syndrome
CAM – Classically activated macrophages
CCL – CC chemokine ligand
CTL – Cytotoxic T-lymphocytes
DC-SIGN – Dendritic cell-specific intercellular adhesion molecule grabbing nonintegrins
HIV – Human immuno deficiency virus
IFN – Interferon
IL – Interleukin
iNOS – Nitric oxide synthetase
MBTC –
MHC – Major histocompatibility complex
MIP – Macrophage inflammatory protein
NK – Natural killer cells
NLR – NOD-like receptors
NO – Nitric oxide
NOD – Nucleotide-binding oligomerization domain
PD-1 – Programmed death-1
RANTES – Regulated on activation, normal T cell expressed and secreted
ROS – Reactive oxygen species
TB – Tuberculosis
TGF – Transforming growth factor
Tim-3 – T cell immunoglobulin and mucin-domain-containing molecule
TLRs – Toll-like receptors
TNF – Tumor necrosis factor
WHO – World Health Organization
References
- 1.
WHO | Global tuberculosis report 2014. World Health Organization; [cited 2015 Jan 15]; Available from: http://www.who.int/tb/publications/global_report/en/. - 2.
WHO | HIV/AIDS. World Health Organization; [cited 2015 Jan 15]; Available from: http://www.who.int/mediacentre/factsheets/fs360/en/. - 3.
Ahmad S. Pathogenesis, immunology, and diagnosis of latent Mycobacterium tuberculosis infection. Clin Dev Immunol [Internet]. 2011 Jan [cited 2015 Jan 15];2011:814943. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3017943&tool=pmcentrez&rendertype=abstract. - 4.
Frieden TR, Sterling T, Pablos-Mendez A, Kilburn JO, Cauthen GM, Dooley SW. The emergence of drug-resistant tuberculosis in New York City. N Engl J Med [Internet]. 1993 Feb 25 [cited 2015 Jan 15];328(8):521–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8381207. - 5.
Olczak A, Grąbczewska E. Tuberculosis in HIV-infected patients in the HAART era. HIV AIDS Rev [Internet]. 2010 Jan [cited 2015 Jan 15];9(2):41–4. Available from: http://www.sciencedirect.com/science/article/pii/S1730127010600689. - 6.
Golub JE, Saraceni V, Cavalcante SC, Pacheco AG, Moulton LH, King BS, et al. The impact of antiretroviral therapy and isoniazid preventive therapy on tuberculosis incidence in HIV-infected patients in Rio de Janeiro, Brazil. AIDS [Internet]. 2007 Jul 11 [cited 2015 Jan 15];21(11):1441–8. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3063947&tool=pmcentrez&rendertype=abstract. - 7.
World Health Organization. Guidelines for intensified tuberculosis case-finding and isoniazid preventive therapy for people living with HIV in resource-constrained settings. World Health [Internet]. 2011;01:142. Available from: http://whqlibdoc.who.int/publications/2011/9789241500708_eng.pdf. - 8.
Marais BJ, Rabie H, Cotton MF. TB and HIV in children - advances in prevention and management. Paediatr Respir Rev [Internet]. 2011 Mar [cited 2015 Jan 15];12(1):39–45. Available from: http://www.sciencedirect.com/science/article/pii/S1526054210000709. - 9.
Schwander S, Dheda K. Human lung immunity against Mycobacterium tuberculosis: Insights into pathogenesis and protection. Am J Respir Crit Care Med [Internet]. 2011 Mar 15 [cited 2015 Jan 2];183(6):696–707. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3081283&tool=pmcentrez&rendertype=abstract. - 10.
Andersson M, Lutay N, Hallgren O, Westergren-Thorsson G, Svensson M, Godaly G. Mycobacterium bovis bacilli Calmette-Guerin regulates leukocyte recruitment by modulating alveolar inflammatory responses. Innate Immun [Internet]. 2012 Jun 12 [cited 2015 Jan 15];18(3):531–40. Available from: http://ini.sagepub.com/content/early/2012/01/11/1753425911426591. - 11.
Jo E-K, Yang C-S, Choi CH, Harding C V. Intracellular signalling cascades regulating innate immune responses to Mycobacteria: Branching out from Toll-like receptors. Cell Microbiol [Internet]. 2007 May [cited 2015 Jan 15];9(5):1087–98. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17359235. - 12.
Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell [Internet]. 2006 Feb 24 [cited 2014 Jul 9];124(4):783–801. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16497588. - 13.
Algood HMS, Chan J, Flynn JL. Chemokines and tuberculosis. Cytokine Growth Factor Rev [Internet]. Elsevier; 2003 Dec 12 [cited 2015 Jan 15];14(6):467–77. Available from: http://www.cgfr.co.uk/article/S1359610103000546/fulltext. - 14.
Saunders BM, Cooper AM. Restraining mycobacteria: Role of granulomas in mycobacterial infections. Immunol Cell Biol [Internet]. 2000 Aug [cited 2015 Jan 15];78(4):334–41. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10947857. - 15.
Wolf AJ, Linas B, Trevejo-Nunez GJ, Kincaid E, Tamura T, Takatsu K, et al. Mycobacterium tuberculosis Infects Dendritic Cells with High Frequency and Impairs Their Function In Vivo. J Immunol [Internet]. American Association of Immunologists; 2007 Aug 3 [cited 2014 Nov 28];179(4):2509–19. Available from: http://www.jimmunol.org/content/179/4/2509.full. - 16.
Giacomini E, Iona E, Ferroni L, Miettinen M, Fattorini L, Orefici G, et al. Infection of Human Macrophages and Dendritic Cells with Mycobacterium tuberculosis Induces a Differential Cytokine Gene Expression That Modulates T Cell Response. J Immunol [Internet]. American Association of Immunologists; 2001 Jun 15 [cited 2015 Jan 15];166(12):7033–41. Available from: http://www.jimmunol.org/content/166/12/7033.full. - 17.
Tailleux L, Neyrolles O, Honore-Bouakline S, Perret E, Sanchez F, Abastado J-P, et al. Constrained Intracellular Survival of Mycobacterium tuberculosis in Human Dendritic Cells. J Immunol [Internet]. American Association of Immunologists; 2003 Feb 15 [cited 2015 Jan 15];170(4):1939–48. Available from: http://www.jimmunol.org/content/170/4/1939.full. - 18.
Co DO, Hogan LH, Kim S-I, Sandor M. Mycobacterial granulomas: keys to a long-lasting host-pathogen relationship. Clin Immunol [Internet]. 2004 Nov [cited 2015 Jan 15];113(2):130–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15451467. - 19.
Peyron P, Vaubourgeix J, Poquet Y, Levillain F, Botanch C, Bardou F, et al. Foamy macrophages from tuberculous patients’ granulomas constitute a nutrient-rich reservoir for M. tuberculosis persistence. PLoS Pathog [Internet]. 2008 Nov 11 [cited 2014 Dec 27];4(11):e1000204. Available from: http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1000204. - 20.
Fulton SA, Reba SM, Martin TD, Boom WH. Neutrophil-Mediated Mycobacteriocidal Immunity in the Lung during Mycobacterium bovis BCG Infection in C57BL/6 Mice. Infect Immun [Internet]. 2002 Sep 1 [cited 2015 Jan 15];70(9):5322–7. Available from: http://iai.asm.org/content/70/9/5322.full. - 21.
Lowe DM, Redford PS, Wilkinson RJ, O’Garra A, Martineau AR. Neutrophils in tuberculosis: friend or foe? Trends Immunol [Internet]. 2012 Jan [cited 2015 Jan 9];33(1):14–25. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22094048. - 22.
Sawant K V, McMurray DN. Guinea pig neutrophils infected with Mycobacterium tuberculosis produce cytokines which activate alveolar macrophages in noncontact cultures. Infect Immun [Internet]. 2007 Apr [cited 2015 Jan 15];75(4):1870–7. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1865707&tool=pmcentrez&rendertype=abstract. - 23.
Segovia-Juarez JL, Ganguli S, Kirschner D. Identifying control mechanisms of granuloma formation during M. tuberculosis infection using an agent-based model. J Theor Biol [Internet]. 2004 Dec 7 [cited 2014 Dec 29];231(3):357–76. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15501468. - 24.
Schluger NW, Rom WN. The host immune response to tuberculosis. Am J Respir Crit Care Med [Internet]. 1998 Mar [cited 2015 Jan 7];157(3 Pt 1):679–91. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9517576. - 25.
Oddo M, Renno T, Attinger A, Bakker T, MacDonald HR, Meylan PR. Fas ligand-induced apoptosis of infected human macrophages reduces the viability of intracellular Mycobacterium tuberculosis. J Immunol [Internet]. 1998 Jun 1 [cited 2015 Jan 15];160(11):5448–54. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9605147. - 26.
Serbina N V., Lazarevic V, Flynn JL. CD4+ T Cells Are Required for the Development of Cytotoxic CD8+ T Cells During Mycobacterium tuberculosis Infection. J Immunol [Internet]. American Association of Immunologists; 2001 Dec 15 [cited 2015 Jan 7];167(12):6991–7000. Available from: http://www.jimmunol.org/content/167/12/6991.full. - 27.
Cho S, Mehra V, Thoma-Uszynski S, Stenger S, Serbina N, Mazzaccaro RJ, et al. Antimicrobial activity of MHC class I-restricted CD8+ T cells in human tuberculosis. Proc Natl Acad Sci U S A [Internet]. 2000 Oct 24 [cited 2015 Jan 15];97(22):12210–5. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=17320&tool=pmcentrez&rendertype=abstract. - 28.
Stenger S, Hanson DA, Teitelbaum R, Dewan P, Niazi KR, Froelich CJ, et al. An antimicrobial activity of cytolytic T cells mediated by granulysin. Science [Internet]. 1998 Oct 2 [cited 2015 Jan 15];282(5386):121–5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9756476. - 29.
Brandes M, Willimann K, Bioley G, Lévy N, Eberl M, Luo M, et al. Cross-presenting human gammadelta T cells induce robust CD8+ alphabeta T cell responses. Proc Natl Acad Sci U S A [Internet]. 2009 Feb 17 [cited 2015 Jan 15];106(7):2307–12. Available from: http://www.pnas.org/content/106/7/2307.full. - 30.
Silva Miranda M, Breiman A, Allain S, Deknuydt F, Altare F. The tuberculous granuloma: An unsuccessful host defence mechanism providing a safety shelter for the bacteria? Clin Dev Immunol [Internet]. 2012 Jan [cited 2015 Jan 10];2012:139127. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3395138&tool=pmcentrez&rendertype=abstract. - 31.
Benoit M, Desnues B, Mege J-L. Macrophage polarization in bacterial infections. J Immunol [Internet]. 2008 Sep 15 [cited 2015 Jan 15];181(6):3733–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18768823. - 32.
Behar SM, Martin CJ, Booty MG, Nishimura T, Zhao X, Gan H-X, et al. Apoptosis is an innate defense function of macrophages against Mycobacterium tuberculosis. Mucosal Immunol [Internet]. 2011 May [cited 2014 Dec 15];4(3):279–87. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3155700&tool=pmcentrez&rendertype=abstract. - 33.
De Vallière S, Abate G, Blazevic A, Heuertz RM, Hoft DF. Enhancement of innate and cell-mediated immunity by antimycobacterial antibodies. Infect Immun [Internet]. 2005 Oct [cited 2015 Jan 15];73(10):6711–20. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1230956&tool=pmcentrez&rendertype=abstract. - 34.
Abebe F, Bjune G. The protective role of antibody responses during Mycobacterium tuberculosis infection. Clin Exp Immunol [Internet]. 2009 Aug [cited 2015 Jan 15];157(2):235–43. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2730849&tool=pmcentrez&rendertype=abstract. - 35.
Maglione PJ, Chan J. How B cells shape the immune response against Mycobacterium tuberculosis. Eur J Immunol [Internet]. 2009 Mar [cited 2014 Dec 30];39(3):676–86. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2760469&tool=pmcentrez&rendertype=abstract. - 36.
Diedrich CR, Flynn JL. HIV-1/mycobacterium tuberculosis coinfection immunology: How does HIV-1 exacerbate tuberculosis? Infect Immun [Internet]. 2011 Apr [cited 2014 Sep 5];79(4):1407–17. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3067569&tool=pmcentrez&rendertype=abstract. - 37.
Appay V, Sauce D. Immune activation and inflammation in HIV-1 infection: Causes and consequences. J Pathol [Internet]. 2008 Jan [cited 2015 Jan 15];214(2):231–41. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18161758. - 38.
Poonia B, Wang X, Veazey RS. Distribution of simian immunodeficiency virus target cells in vaginal tissues of normal rhesus macaques: implications for virus transmission. J Reprod Immunol [Internet]. 2006 Dec [cited 2015 Jan 15];72(1-2):74–84. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16956666. - 39.
Hussain LA, Lehner T. Comparative investigation of Langerhans’ cells and potential receptors for HIV in oral, genitourinary and rectal epithelia. Immunology [Internet]. 1995 Jul [cited 2015 Jan 15];85(3):475–84. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1383923&tool=pmcentrez&rendertype=abstract. - 40.
Roederer M, Dubs JG, Anderson MT, Raju PA, Herzenberg LA. CD8 naive T cell counts decrease progressively in HIV-infected adults. J Clin Invest [Internet]. 1995 May [cited 2015 Jan 15];95(5):2061–6. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=295794&tool=pmcentrez&rendertype=abstract. - 41.
Douek DC, Betts MR, Hill BJ, Little SJ, Lempicki R, Metcalf JA, et al. Evidence for Increased T Cell Turnover and Decreased Thymic Output in HIV Infection. J Immunol [Internet]. American Association of Immunologists; 2001 Dec 1 [cited 2015 Jan 15];167(11):6663–8. Available from: http://www.jimmunol.org/content/167/11/6663.full. - 42.
Schmitz JE, Kuroda MJ, Santra S, Sasseville VG, Simon MA, Lifton MA, et al. Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science [Internet]. 1999 Feb 5 [cited 2015 Jan 15];283(5403):857–60. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9933172. - 43.
Hersperger AR, Pereyra F, Nason M, Demers K, Sheth P, Shin LY, et al. Perforin expression directly ex vivo by HIV-specific CD8 T-cells is a correlate of HIV elite control. PLoS Pathog [Internet]. 2010 May 27 [cited 2015 Jan 15];6(5):e1000917. Available from: http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1000917. - 44.
Levy JA. Wiley: HIV and the Pathogenesis of AIDS, 3rd Edition - J. A. Levy [Internet]. [cited 2015 Jan 15]. Available from: http://eu.wiley.com/WileyCDA/WileyTitle/productCd-1555813933.html. - 45.
Cron RQ, Bartz SR, Clausell A, Bort SJ, Klebanoff SJ, Lewis DB. NFAT1 enhances HIV-1 gene expression in primary human CD4 T cells. Clin Immunol [Internet]. 2000 Mar [cited 2015 Jan 15];94(3):179–91. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10692237. - 46.
Wherry EJ, Ahmed R. Memory CD8 T-cell differentiation during viral infection. J Virol [Internet]. 2004 Jun [cited 2015 Jan 15];78(11):5535–45. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=415833&tool=pmcentrez&rendertype=abstract. - 47.
Jin H-T, Anderson AC, Tan WG, West EE, Ha S-J, Araki K, et al. Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection. Proc Natl Acad Sci U S A [Internet]. 2010 Aug 17 [cited 2015 Jan 9];107(33):14733–8. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2930455&tool=pmcentrez&rendertype=abstract. - 48.
Tandon R, Giret MTM, Sengupta D, York VA, Wiznia AA, Rosenberg MG, et al. Age-related expansion of Tim-3 expressing T cells in vertically HIV-1 infected children. PLoS One [Internet]. 2012 Jan [cited 2015 Jan 15];7(9):e45733. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3454343&tool=pmcentrez&rendertype=abstract. - 49.
Whalen CC, Zalwango S, Chiunda A, Malone L, Eisenach K, Joloba M, et al. Secondary attack rate of tuberculosis in urban households in Kampala, Uganda. PLoS One [Internet]. 2011 Jan 14 [cited 2015 Jan 15];6(2):e16137. Available from: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0016137. - 50.
Crampin AC, Mwaungulu JN, Mwaungulu FD, Mwafulirwa DT, Munthali K, Floyd S, et al. Recurrent TB: relapse or reinfection? The effect of HIV in a general population cohort in Malawi. AIDS [Internet]. 2010 Jan 28 [cited 2015 Jan 7];24(3):417–26. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2917772&tool=pmcentrez&rendertype=abstract. - 51.
Sonnenberg P, Murray J, Glynn JR, Shearer S, Kambashi B, Godfrey-Faussett P. HIV-1 and recurrence, relapse, and reinfection of tuberculosis after cure: a cohort study in South African mineworkers. Lancet [Internet]. Elsevier; 2001 Nov 17 [cited 2014 Dec 28];358(9294):1687–93. Available from: http://www.thelancet.com/article/S0140673601067125/fulltext. - 52.
Selwyn PA, Hartel D, Lewis VA, Schoenbaum EE, Vermund SH, Klein RS, et al. A prospective study of the risk of tuberculosis among intravenous drug users with human immunodeficiency virus infection. N Engl J Med [Internet]. 1989 Mar 2 [cited 2015 Jan 15];320(9):545–50. Available from: http://www.ncbi.nlm.nih.gov/pubmed/2915665. - 53.
Patel NR, Swan K, Li X, Tachado SD, Koziel H. Impaired M. tuberculosis-mediated apoptosis in alveolar macrophages from HIV+ persons: Potential role of IL-10 and BCL-3. J Leukoc Biol [Internet]. 2009 Jul [cited 2015 Jan 15];86(1):53–60. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2704623&tool=pmcentrez&rendertype=abstract. - 54.
Rosas-Taraco AG, Arce-Mendoza AY, Caballero-Olín G, Salinas-Carmona MC. Mycobacterium tuberculosis upregulates coreceptors CCR5 and CXCR4 while HIV modulates CD14 favoring concurrent infection. AIDS Res Hum Retroviruses [Internet]. 2006 Jan [cited 2015 Jan 15];22(1):45–51. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16438645. - 55.
Spear GT, Kessler HA, Rothberg L, Phair J, Landay AL. Decreased oxidative burst activity of monocytes from asymptomatic HIV-infected individuals. Clin Immunol Immunopathol [Internet]. 1990 Feb [cited 2015 Jan 15];54(2):184–91. Available from: http://www.ncbi.nlm.nih.gov/pubmed/1688521. - 56.
Patel NR, Zhu J, Tachado SD, Zhang J, Wan Z, Saukkonen J, et al. HIV impairs TNF-alpha mediated macrophage apoptotic response to Mycobacterium tuberculosis. J Immunol [Internet]. 2007 Nov 15 [cited 2014 Dec 23];179(10):6973–80. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17982088. - 57.
Mwandumba HC, Russell DG, Nyirenda MH, Anderson J, White SA, Molyneux ME, et al. Mycobacterium tuberculosis resides in nonacidified vacuoles in endocytically competent alveolar macrophages from patients with tuberculosis and HIV infection. J Immunol [Internet]. 2004 Apr 1 [cited 2015 Jan 15];172(7):4592–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15034077. - 58.
Lawn SD, Myer L, Edwards D, Bekker L-G, Wood R. Short-term and long-term risk of tuberculosis associated with CD4 cell recovery during antiretroviral therapy in South Africa. AIDS [Internet]. 2009 Aug 24 [cited 2015 Jan 15];23(13):1717–25. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3801095&tool=pmcentrez&rendertype=abstract. - 59.
Heyderman RS, Makunike R, Muza T, Odwee M, Kadzirange G, Manyemba J, et al. Pleural tuberculosis in Harare, Zimbabwe: The relationship between human immunodeficiency virus, CD4 lymphocyte count, granuloma formation and disseminated disease. Trop Med Int Health [Internet]. 1998 Jan [cited 2015 Jan 15];3(1):14–20. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9484963. - 60.
De Noronha ALL, Báfica A, Nogueira L, Barral A, Barral-Netto M. Lung granulomas from Mycobacterium tuberculosis/HIV-1 co-infected patients display decreased in situ TNF production. Pathol Res Pract [Internet]. 2008 Jan [cited 2015 Jan 15];204(3):155–61. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18096327. - 61.
Sonnenberg P, Glynn JR, Fielding K, Murray J, Godfrey-Faussett P, Shearer S. How soon after infection with HIV does the risk of tuberculosis start to increase? A retrospective cohort study in South African gold miners. J Infect Dis [Internet]. 2005 Jan 15 [cited 2015 Jan 15];191(2):150–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15609223. - 62.
Shen JY, Barnes PF, Rea TH, Meyer PR. Immunohistology of tuberculous adenitis in symptomatic HIV infection. Clin Exp Immunol [Internet]. 1988 May [cited 2015 Jan 15];72(2):186–9. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1541541&tool=pmcentrez&rendertype=abstract. - 63.
Zhang M, Gong J, Iyer D V, Jones BE, Modlin RL, Barnes PF. T cell cytokine responses in persons with tuberculosis and human immunodeficiency virus infection. J Clin Invest [Internet]. 1994 Dec [cited 2015 Jan 15];94(6):2435–42. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=330075&tool=pmcentrez&rendertype=abstract. - 64.
Geldmacher C, Schuetz A, Ngwenyama N, Casazza JP, Sanga E, Saathoff E, et al. Early depletion of Mycobacterium tuberculosis-specific T helper 1 cell responses after HIV-1 infection. J Infect Dis [Internet]. 2008 Dec 1 [cited 2015 Jan 15];198(11):1590–8. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2650495&tool=pmcentrez&rendertype=abstract. - 65.
Toossi Z, Mayanja-Kizza H, Hirsch CS, Edmonds KL, Spahlinger T, Hom DL, et al. Impact of tuberculosis (TB) on HIV-1 activity in dually infected patients. Clin Exp Immunol [Internet]. 2001 Feb [cited 2015 Jan 15];123(2):233–8. Available from: http://doi.wiley.com/10.1046/j.1365-2249.2001.01401.x. - 66.
Goletti D, Weissman D, Jackson RW, Graham NM, Vlahov D, Klein RS, et al. Effect of Mycobacterium tuberculosis on HIV replication. Role of immune activation. J Immunol [Internet]. 1996 Aug 1 [cited 2015 Jan 15];157(3):1271–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8757635. - 67.
Nakata K, Rom WN, Honda Y, Condos R, Kanegasaki S, Cao Y, et al. Mycobacterium tuberculosis enhances human immunodeficiency virus-1 replication in the lung. Am J Respir Crit Care Med [Internet]. 1997 Mar [cited 2015 Jan 15];155(3):996–1003. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9117038. - 68.
Hoshino Y, Hoshino S, Gold JA, Raju B, Prabhakar S, Pine R, et al. Mechanisms of polymorphonuclear neutrophil-mediated induction of HIV-1 replication in macrophages during pulmonary tuberculosis. J Infect Dis [Internet]. 2007 May 1 [cited 2015 Jan 15];195(9):1303–10. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17396999. - 69.
Lawn SD, Pisell TL, Hirsch CS, Wu M, Butera ST, Toossi Z. Anatomically compartmentalized human immunodeficiency virus replication in HLA-DR+ cells and CD14+ macrophages at the site of pleural tuberculosis coinfection. J Infect Dis [Internet]. 2001 Nov 1 [cited 2015 Jan 15];184(9):1127–33. Available from: http://jid.oxfordjournals.org/content/184/9/1127.long. - 70.
Garrait V, Cadranel J, Esvant H, Herry I, Morinet P, Mayaud C, et al. Tuberculosis generates a microenvironment enhancing the productive infection of local lymphocytes by HIV. J Immunol [Internet]. 1997 Sep 15 [cited 2015 Jan 15];159(6):2824–30. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9300705. - 71.
Whalen C, Horsburgh CR, Hom D, Lahart C, Simberkoff M, Ellner J. Accelerated course of human immunodeficiency virus infection after tuberculosis. Am J Respir Crit Care Med [Internet]. 1995 Jan [cited 2015 Jan 15];151(1):129–35. Available from: http://www.ncbi.nlm.nih.gov/pubmed/7812542.