Genetic modifications and adaptations of viral Gag-CA that render HIV-1 macaque-tropic.
Abstract
Human immunodeficiency virus type 1 (HIV-1) is tropic for humans and replicates in virtually none of the other animal species. While various animal models to mimic the conflict between HIV-1 and human hosts have been proposed, nonhuman primates (NHPs) are thought to be most suitable from a purely scientific point of view for the HIV-1/AIDS model studies. Because NHPs are resistant to HIV-1, remodeling the HIV-1 genome is required to validate the productive infection of NHPs. Two types have been reported as retrofitted viruses, that is, SHIVs and HIV-1 derivatives. SHIVs are SIVs (simian immunodeficiency viruses) that carry a small portion of the HIV-1 genome, whereas HIV-1 derivatives are HIV-1 with a minimal sequence/genome modification. SHIVs have been successfully used for studies specifically targeting HIV-1 Pol-RT (reverse transcriptase) and Env proteins. HIV-1 derivatives can induce AIDS in NHPs under certain conditions. More importantly, HIV-1 derivatives contribute to elucidating the HIV-1 adaptation and virus-host interaction through analyzing the process of acquiring replication capacity and pathogenicity in restrictive hosts distinct from natural hosts. In this chapter, we summarize NHP model studies on HIV-1/AIDS using SIV, SHIV, or HIV-1 derivatives and discuss the significance of HIV-1 derivatives toward understanding the HIV-1 biology.
Keywords
- HIV-1
- macaque-tropic HIV-1
- SIV
- SHIV
- animal model
- adaptation
- replication
- pathogenesis
1. Introduction
HIV-1 belongs to a subfamily
One of the important biological features of HIV-1 is to specifically adapt itself to replication in humans, exhibiting a narrow host range virtually only to humans. Thus, no appropriate experimental animals that are susceptible to authentic HIV-1 infection and pathogenesis are currently available. Unadulterated HIV-1 clones can establish spreading infection in humanized mice (mice reconstituted with human hematopoietic cells), although they are not pathogenic to humanized mice. HIV-1-infected humanized mice are useful for basic and clinical studies such as those on determination of the
2. The emergence of HIV-1 and its narrow host range
HIV-1 exhibits a narrow host range and cannot replicate in macaque cells as described above. The excellent study using SHIV clones first demonstrated that HIV-1 replication in macaque cells is blocked at the post-entry step [19]. Results obtained in the study indicated that Gag-Pol and Vif derived from SIVmac are most likely to be necessary for viral replication in macaque cells [19]. Several years later, intrinsic restriction factors that potently inhibit HIV-1 replication in macaque cells (APOBEC3 protein family, TRIM5 protein family, and tetherin) were identified one after another [20, 21, 22, 23]. APOBEC3 proteins have cytidine deaminase activity, and its major function is to introduce lethal mutations into the HIV-1 genome. TRIM5 proteins target incoming viral cores and perturb the reverse transcription step of HIV-1 replication. Tetherin suppresses virus budding by tethering progeny virions at the plasma membrane as its name suggests. HIV-1 Vif, Gag-CA, and Vpu can antagonize APOBEC3 proteins, TRIM5 proteins, and tetherin in human cells, respectively, but not at all in macaque cells. The actions of these intrinsic restriction factors explain really well why HIV-1 cannot replicate in macaque cells.
While HIV-1 replication is completely blocked in macaques, HIV-1 has been shown to have emerged through the repeated cross-species transmissions of various SIVs from their natural hosts to the new hosts and the viral recombination/adaptation in transmitted hosts (Figure 2) [20, 24, 25]. In brief, SIVmon/mus/gsn, which parasitize Mona monkey, Mustached monkey, and Greater spot-nosed monkey as natural hosts, respectively, and SIVrcm from Red-capped mangabey co-infected chimpanzees by cross-species transmissions. SIVcpz arose by their recombination in chimpanzees and resulted in the elimination of
3. SIV/SHIV clones and nonhuman primate models
Taking the strict human tropism of HIV-1 into consideration, researchers have made every effort to generate appropriate model study systems for the HIV-1/AIDS research by selecting viruses, selecting host animals, genetically altering viruses, and/or genetically altering host animals [10, 11, 12, 13, 14, 15, 16, 17, 18]. A wide variety of animal species from mice to primates and of lentivirus species have been proposed for the surrogate models and extensively tested for their usability and for their scientific value. Among these, NHP models using primate immunodeficiency viruses (SIVmac and SHIV) (Figure 1) are most suitable for the HIV-1/AIDS research from various points of view, such as pathogenic outcome and robust immune responses [13, 17, 28]. Due to the close similarity in genetic background and physiological status, researchers have plenty and successful experience in the NHP system to carry out various basic research on viruses and/or to do translational research to develop drugs, vaccines, and other interventions [10, 11, 12, 13, 14, 15, 16, 17, 18]. Of the three macaque species (rhesus, cynomolgus, and pigtailed macaques) frequently used for experimental virus infections, the pigtailed and rhesus macaques are known to be most susceptible and resistant to the SIV infection, respectively. Pigtailed macaques genetically lack the restriction of TRIM5alpha against viruses
To construct a novel class of infectious molecular clones carrying the HIV-1 genes that replicate in macaque cells, two different approaches have been taken. One is the SHIV (Figure 1), that is, a virus clone constructed in the background of SIVmac genome, and another is the HIV-1 derivative, that is, a variant HIV-1 clone with a minimal sequence modification in the context of HIV-1 genome [29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44]. While the former virus clones commonly have been designated SHIV [31], the latter clones have been variously called as HIV-1 derivative [34], stHIV-1 [33], HIV-1mt [39], HSIV [40], or HIV-1rmt [43]. Research on the SHIV preceded study on the HIV-1 derivative. As for SHIVs, it is reasonable to construct clones carrying the HIV-1 genes/domain sequences that are not determinants for its species tropism. Even if the chimeric constructs mainly consist of SIVmac sequences/genes, the activity and/or function of the inserted HIV-1 genes in the replication cycle can be readily assessed individually or combinedly
4. HIV-1 derivative clones
It has been well-recognized and generalized that the restriction of viral replication occurs at the entry step on the cell surface and/or at some intracellular stage(s) [84]. As clarified by our early studies, the HIV-1 species tropism is determined at the early post-entry phase, within the viral DNA synthesis event [19, 29]. The viral determinants for the tropism were predicted to be Gag-CA and Vif as described above. To generate a novel class of HIV-1 that can replicate in macaque cells, it was necessary to genetically modify the two viral genomic regions. We first checked whether a small portion of
In order to improve the replication ability in macaque cells of NL-DT5R, and also to construct CCR5-tropic clones, we altered virus genomes in a stepwise manner by the sequence/structure-guided mutagenesis and by virus adaptation in cells (Figure 3). NL-DT5R was found to be rather sensitive, if not completely, to cellular restriction factors TRIM5 and APOBEC3 proteins [91]. First, we replaced the loop domain of HIV-1 Gag-CA between helices 6 and 7 with the corresponding site of SIVmac (MN4-5S in Figure 3A) [39, 92] to increase resistance to TRIM5, and then randomly modify the viral genome by the adaptation in macaque cells and structure-guided mutagenesis (MN4-Rh-3 in Figure 3A) [42, 87]. CCR5-tropic MN5Rh-3 that carries the
Finally, the growth potential of CXCR4-tropic and CCR5-tropic HIV-1rmt clones was examined in rhesus macaques [44]. Both clones grew comparably well in rhesus PBMCs. When inoculated into rhesus macaques, the two virus clones certainly initiated productive infection (peak viremia ~105 copies/mL and ~ 104 copies/mL for CXCR4- and CCR5-tropic viruses, respectively). However, virus production gradually became undetectable for all the animals tested (5–6- and 3–4-weeks post-infection for CXCR4- and CCR5-tropic viruses, respectively), indicating that the virus replication level at the initial phase was insufficient for viral persistence [44]. The peak level of virus production was significantly low relative to that by SIVmac. On one hand, Hatziioannou et al. have reported that they successfully generated a pathogenic molecular clone (stHIV-A19) upon infection to CD8+ cell-depleted pigtailed macaques [93, 94]. The molecular clone stHIV-A19 was obtained from a pathogenic viral swarm by repeated animal-to-animal (CD8+ cell-depleted pigtailed macaque) virus passage [94]. The virus level in the animal is maintained to be high only with the depletion treatment, being consistent with the appearance of AIDS. Clearly, this is the first study to describe the HIV-1 derivative molecular clone that can cause AIDS in animals.
5. Adaptation of macaque-tropic HIV-1 derivatives to macaque cells/individuals
Macaque-tropic HIV-1 derivatives are useful not only for the establishment of HIV-1-macaque infection models but also serve as model systems to investigate the inherent HIV-1 property, the high mutation/adaptation abilities. It is because one can analyze how HIV-1 adapts to replication-restrictive environments imposed by macaque cells. Studies on the adaptation process, for example, what mutations emerged in the genome of macaque-tropic HIV-1 derivatives in macaques as a new host and how the mutations altered the activity/function of viral proteins, would provide pivotal insights into determinants related to HIV-1 replication and pathogenesis. As described earlier, evading the potent restriction from intrinsic factors such as APOBEC3 and TRIM5 proteins in macaque cells was essential for the generation of macaque-tropic HIV-1 clones. The restriction from APOBEC3 proteins can be overcome by the replacement of the entire
Clones | Gag-CA | Genetic modifications | Adaptive mutations | References |
---|---|---|---|---|
stHIV-1(SCA) (Figure 4) | SCA | Gag containing SIVmac239 Gag-CA (1 to 204 amino acids) | Gag (K110I, A208V, and P371L) | [33] |
HIV-1NL4–3/HIV-1HXB2/GFP (NHG) | LNEIEa | Gag-CA (M10L, I91N, A92E, M96I, and G116E) | [97] | |
HIV-1rmt (Figure 4) | LSDQ | Gag-CA containing a loop between helices 4 and 5/a loop between helices 6 and 7 loop from SIVmac239, and amino acid substitutions (M94L, R98S, and G114Q) | Structure-guided Gag-CA mutation (Q110D) based on an adaptive mutation (Gag-CA G114E) | [43, 87, 96] |
Adaptation experiments of our prototype macaque-tropic HIV-1 derivatives NL-DT5R and NL-DT562 in macaque cells led to the identification of a novel genomic region that can determine the Vif expression level. Initially, we found replication-enhancing adaptive mutations within integrase (Pol-IN) C-terminal domain (CTD) that frequently and reproducibly emerged during independent adaptation experiments (Table 2) [88, 104, 105]. Extensive virological and sequence analyses of these adaptive mutations showed: 1) viral growth potential can be altered by naturally occurring synonymous single-nucleotide mutations (nsSNMs) within the region surrounding identified adaptive mutations, 2) these identified nsSNMs result in variations in Vif expression levels, and thus, 3) variations in viral replication by the nsSNMs occur dependently on both Vif and APOBEC3G expression levels. Moreover, we found that changes in Vif expression levels were due to the effect of these nsSNMs on the splicing efficiency at the splicing acceptor 1 (SA1) within
Clones | Cells or animals used for adaptation | Adaptive mutations | Effects | References | |
---|---|---|---|---|---|
Regions | Mutations | ||||
NL-DT5R (Figure 3) | Cynomolgus HSC-F cells | Pol-IN | V234I | Optimization of vial mRNA production through modification of splicing efficiency at splicing acceptor 1 | [88, 104, 105] |
Env-gp120 (C4) | E427K | Enhancement of CD4 binding ability | [88, 106] | ||
Rhesus HSR5.4S1 cells | Pol-IN | F223Y | Same as the Pol-IN V234I mutation | [88, 104, 105] | |
NL-DT562 (Figure 3) | Cynomolgus HSC-F cells | Pol-IN | N222K | Same as the Pol-IN V234I mutation | [88, 104, 105] |
Env-gp120 (V3)a | S304G | Increase in the interaction with CCR5 | [88, 107] | ||
Rhesus HSR5.4S1 cells | Pol-IN | N222K | Same as the Pol-IN V234I mutation | [88, 104, 105] | |
Env-gp120 (V3)b | S304G | See the identical mutation above | [88, 107] | ||
G310R | Increase in the species-specific interaction with macaque CD4 and CCR5 | [88, 108] | |||
stHIV-1 carrying | Pig-tailed macaques | Env-gp120 (V3) | Deletion of four amino acids (313TTGD316) | Association with coreceptor switch | [93] |
Vpu | One amino acid (I) insertion at position 15 and one amino acid substitution (V21G) | Antagonization to pig-tailed macaque tetherin | [93] | ||
stHIV-1-A19 | Pig-tailed macaques | Gag-CA | H87P, T107I, and I91A | Resistance to interferon alpha-inducible restriction factor Mx2 | [94] |
As expected, we found numerous growth-enhancing mutations in the Env proteins of the viral clones that were obtained from adaptation experiments in macaque cells using NL-DT5R/NL-DT562 (Table 2). Our
The stHIV-1 clone, which is currently the only AIDS-inducible clone, also has been shown to adapt to CD8-depleted macaque individuals (Table 2) [93, 94]. After the animal-to-animal adaptation using stHIV-1 clones carrying four distinct
6. Conclusion
The infection system consisting of HIV-1 derivative viruses and macaque hosts may sophisticatedly reflect, as an experimental model, the interaction between HIV-1 and its host humans. In an effort to establish HIV-1-infected macaque models, a noteworthy result was obtained that stHIV-1/stHIV-1-A19 could induce AIDS in CD8-depleted pigtailed macaques after some animal-to-animal adaptations. However, this is the only case that showed the pathogenicity of the HIV-1 derivative virus in macaques as fully described above. Furthermore, the viruses were unable to cause the disease in naïve animals. And, it is not clarified yet whether certain viral gene(s) and/or viral genomic region(s) are linked to viral pathogenicity. Totally, based on the experimental results obtained so far, we may predict that the pathogenic viruses such as some SIVs and SHIVs grew quite well at the early infection phase in individuals so as to obtain variations sufficient to persist in host individuals in the presence of strong host antiviral immunity. If the viruses could persist and maintain the critical set-point level in hosts, they might finally cause AIDS and AIDS-related complex. Further experimental studies are required to confirm this perspective.
It should be mentioned here as a virologically critically important matter that through the generation of macaque-tropic HIV-1 derivatives and a series of their infection experiments in macaque cells and individuals, we and others could learn how HIV-1 mutate and adapt itself to restrictive environments. Numerous synonymous and non-synonymous mutational changes in the HIV-1 genome that significantly affect viral replication and pathogenicity have been successfully identified. The identified alterations are closely linked to our understanding as to how HIV-1 replicates in host cells through modulating functional domains/regions/activity of its genome and proteins such as viral RNA splicing and viral proteins’ binding to cellular receptors and to some other replication-relevant cellular factors. Findings obtained using macaque-tropic HIV-1 derivatives have already greatly contributed to and would also play a significant role in understanding the HIV-1 biology.
Acknowledgments
We thank Yayoi Shono (Tokushima University) for experimental assistance. We also thank Kazuko Yoshida (Tokushima University) and Kyoko Inui (Tokushima University) for editorial and administrative assistance.
AA and MN conceived the idea and wrote a draft/the final manuscript. TaK, ND, BQL, and ToK reviewed it and discussed its content. All authors approved submission.
This work was supported in part by JSPS KAKENHI Grant Numbers 21K07042 to MN, 22K07102 to TaK, 21K08491 to ND, and 20K18484 to ToK, and by grants from the Takeda Science Foundation and The Uehara Memorial Foundation to TaK.
Notes/thanks/other declarations
Our recent studies described in this chapter have been done in collaboration with the following researchers: Masaru Yokoyama, Osamu Kotani, Hironori Sato, Kei Miyakawa, and Akihide Ryo (National Institute of Infectious Diseases, Japan). We are indebted to these scientists for their critical contribution to our work. We also thank our all staffs in our department and the other institutions who have supported our work.
Many original articles reporting the scientifically new and important findings could not be cited due to the tremendous numbers of publications and the space limitations. We express our sincere regret over these omissions based on rather subjective considerations.
Abbreviations
human immunodeficiency virus type 1 | |
nonhuman primate | |
acquired immunodeficiency syndrome | |
simian immunodeficiency virus | |
chimeric viruses of SIV and HIV-1 | |
tripartite motif 5 | |
apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3 | |
simian-tropic HIV-1 | |
macaque-tropic HIV-1 | |
pigtailed macaque-tropic HIV-1 | |
rhesus macaque-tropic HIV-1 |
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