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Coreceptor use in nonhuman primate models of HIV infection


SIV or SHIV infection of nonhuman primates (NHP) has been used to investigate the impact of coreceptor usage on the composition and dynamics of the CD4+ T cell compartment, mechanisms of disease induction and development of clinical syndrome. As the entire course of infection can be followed, with frequent access to tissue compartments, infection of rhesus macaques with CCR5-tropic SHIVs further allows for study of HIV-1 coreceptor switch after intravenous and mucosal inoculation, with longitudinal and systemic analysis to determine the timing, anatomical sites and cause for the change in envelope glycoprotein and coreceptor preference. Here, we review our current understanding of coreceptor use in NHPs and their impact on the pathobiological characteristics of the infection, and discuss recent advances in NHP studies to uncover the underlying selective pressures for the change in coreceptor preference in vivo.


Animal models have always been considered powerful tools for studying the modality of transmission and pathogenesis of human diseases, and for testing the efficacy of novel drugs and vaccines. They afford opportunities to closely monitor the natural course of the disease, with frequent sampling of blood and tissue compartments that are not easily amenable or accessible in humans. Besides their use in elucidating the pathogenic mechanisms of disease, appropriate animal challenge models play key roles in basic vaccine discovery, potentially providing valuable information on the immunogenicity and efficacy of vaccine concepts, and advancing candidate vaccines into human clinical trials.

The challenge in establishing animal models for HIV-1, however, is that the virus does not replicate in most animal species tested [1]. The exceptions are chimpanzee and gibbon apes [2, 3], but experimental HIV-1 infection of chimpanzees is typically non-pathogenic, with only rare animals developing AIDS-like symptoms after prolonged incubation period [46]. Furthermore, these apes are endangered and costly to maintain, limiting their use for research purpose [7]. The AIDS pandemic originally arose as a consequence of zoonotic transmission of simian immunodeficiency viruses (SIVs) from African non-human primate (NHP) species to humans [8]. Phylogenetic analyses indicated that HIV-1 and HIV-2 emerged following transmissions of SIVcpz from chimpanzee and SIVsmm from sooty mangabeys (SM), respectively [9, 10]. The similarities between SIV and HIV with respect to genomic structure and biological features renders infection of various macaque species with SIVs, or with chimeric viruses containing both SIV and HIV sequences (SHIVs), the most relevant animal models to study HIV-1 infection and AIDS.

SIV infection of African and Asian monkeys and coreceptor usage

Over 40 distinct SIVs are found naturally in African NHPs [11]. Infection of natural hosts such as SMs, African green monkeys (AGMs) and mandrillis with SIVs is typically nonpathogenic despite sustained high levels of virus replication [1215]. Development of AIDS has only been observed in one SM and in one mandrill, after 18-year-incubation, a period exceeding the normal lifespan of wild primates [16, 17]. SIVcpz, the precursor for HIV-1, however, is pathogenic in free-ranging chimpanzees. Infected chimps in the wild were 10-16 times more likely to die in any year than those who remained uninfected [18], challenging the prevailing notion that all natural SIV infections are non-pathogenic. In contrast to most natural infections, accidental or experimental transmission of SIVs from SMs to Asian non-natural NHP hosts such as rhesus macaques resulted in progressive infection and AIDS-like symptoms, giving rise to SIVmac [19]. Indeed, Indian rhesus macaques (IndRMs; Macaca mulatta) infected with SIVmac and chimeras encoding the HIV-1 envelope or reverse transcriptase are the best characterized and most widely used animal models of AIDS [20]. Although the tempo of virus replication and disease progression in SIV infected IndRMs is significantly accelerated compared to human HIV infection, the pathobiology and clinical symptoms of SIV and HIV infection are remarkably similar [21]. Considerable efforts have been made to understand the similarities and differences between pathogenic and non-progressive SIV infections, with the hope of uncovering new host defenses that will guide conventional AIDS vaccine development. But with a decrease in availability of IndRM, alternative models of pathogenic infection, such as Chinese RMs, cynomolgus macaques (Macaca fascicularis), and pigtailed macaques (PTMs, Macaca nemestrina) are also being developed [20, 22]. While SIVmac and SHIV infection in Chinese RMs and cynomolgus macaques appear to be more attenuated [23], PTMs are more susceptible, with cases of AIDS reported after experimental infection with SIVsmm, SIVagm, SIVlhoest from l’hoest monkeys, and SIVsun from sun-tailed monkeys [2426]. The absence of the TRIM5α restriction factor that blocks infection by inactivating incoming capsids in PTMs explains the higher susceptibility of these NHPs to different SIVs [2730].

Similar to HIV-1, most SIV strains use CCR5 as their primary coreceptor [3133], despite a paucity of CD4+CCR5+ T cells in the natural hosts [34]. The notable exception is the red capped mangabey. Due to a high frequency of a 24 bp deletion in the CCR5 gene, SIVrcm uses CCR2, a chemokine that is expressed at low levels on CD4+ T cells but at higher levels on macrophages, for entry [35]. Nonetheless, the coreceptor usage profile of SIV is broader than that of HIV-1 in coreceptor-transfected cell lines [36, 37] and PBMCs [38]. Among those reported to be used by SIV, some as efficiently as CCR5, are chemokine receptors that include CCR3, CCR4, CCR8, CXCR6/STRL33/Bonzo, various G-protein coupled receptors (ChemR23, GPR1, GPR15/Bob, RDC1, APJ), and the formyl peptide receptor FPRL1. Whether these alternative coreceptor pathways play a role in SIV infection and pathogenesis in vivo remains to be fully elucidated, but two recent reports provide some insights. In a study to examine the dynamics of in vivo replication of the CCR2- and macrophage-tropic SIVrcm in PTMs, expansion of coreceptor usage to CCR4 was observed, and this was associated with selective depletion of memory CD4+ T cells [39]. More recently, a novel 2 base pair deletion (Δ2) in the sooty mangabey CCR5 gene that resulted in a truncated CCR5 molecule has been identified. This mutant protein is not expressed on the cell surface and does not support SIV entry in vitro [40]. But SIV prevalence was only moderately lower in homozygous CCR5Δ2 mutant animals compared to heterozygous and wild type animals, and plasma viral loads were moderately reduced (0.48 log10) in CCR5Δ2 infected animals compared with wild type animals, demonstrating that CCR5-independent entry pathways are used by SIVsmm in naturally infected SMs.

In contrast to HIV-1, however, CXCR4 usage by SIVs in models of nonpathogenic and pathogenic infection is rarely observed. Only an isolate obtained from mandrills (SIVmnd; [41]) and one from AGM (SIVagm.sab; [42]) were found to use this coreceptor in addition to CCR5 for entry, and expansion to CXCR4-use was documented in two studies of SIVsm/SIVmac infection. In examination of six SIV seropositive SMs with AIDS-defining CD4+ T cell levels, variants with expanded coreceptor usage that included CXCR4 and CCR8 were identified in two mangabeys [43]. Emergence of the multitropic (R5/X4/R8) variants coincided with severe CD4 decline in the blood, lymph nodes and gut-associated lymphoid tissue (GALT), but the infected mangabeys remained clinically healthy for >8 years. Sequence comparison of the multitropic SIVsmm variants to viruses isolated prior to the change in coreceptor preference shows amino acid substitutions and insertions in the V3 loop that increase the overall net positive charge of this envelope region. But genetic studies to demonstrate that these changes in the V3 loop of SIVsmm are sufficient to confer expansion to CXCR4 and CCR8 use are lacking. Expansion to CXCR4 usage has also been reported in a SIVmac239 infected macaque [44, 45]. Compared to the inoculating virus, the lymph node derived variant (SIVmac155T3) has a 10-fold reduction in CCR5 use that is accompanied by acquisition of CXCR4 utilization. Infection of RMs with SIVmac155T3 resulted in rapid and profound circulating and lymph node CD4+ T cell loss [46], similar to observations made in X4 SHIV infected rhesus monkeys (see below). SIVmac155T3 harbors 22 amino acid differences in the envelope glycoprotein compared to the inoculating virus, SIVmac239, including five substitutions and one insertion in the V3 loop [44], but the genetic determinant for expansion to CXCR4 use of this virus remains to be determined.

Impact of coreceptor usage on SIV and SHIV infection of Asian macaques

Because the differences in SIV and HIV-1 protein structures might limit the utility of the SIV/macaque model to study the impact of genetic variations on disease outcome, SHIVs containing both SIV and HIV sequences have been engineered. The use of SHIVs that express the envelopes of diverse HIV-1 strains as inoculating viruses increases the relevance of NHP models, as the impact of HIV-1 envelope-determined properties such as coreceptor usage on viral transmission, persistence and pathogenesis can be assessed [47]. Furthermore, pathogenic envelope SHIVs could facilitate direct clinical analysis of HIV-1 Env-based candidate vaccines. Since most HIV-1 transmissions are initiated with R5 viruses, pathogenic and mucosally transmissible R5 SHIVs would be the preferred tools to assess and advance these vaccine concepts. For these reasons, R5, dual-tropic as well as X4 clade B [4855], clade C [5660], clade A and clade E SHIVs [61, 62] have been constructed and assessed for cell and tissue tropism, viral persistence, anti-viral immune responses and disease progression in NHPs. These SHIV constructs do not readily induce disease in RMs. But through serial in vivo passages and adaptation, several X4 [63, 64], dual-tropic [65, 66], and R5 [54, 67] subtype B envelope SHIVs that induce AIDS have been generated. R5 subtype C SHIVs that are highly replication-competent and mucosally-transmissible have also be obtained and are being tested for pathogenicity [68]. Interestingly, while dual-tropic SHIVs can use both CCR5 and CXCR4 efficiently on coreceptor-transfected cell lines, they use almost exclusively CXCR4 to enter and spread in cultured rhesus peripheral blood mononuclear cells and macrophages [38, 69, 70].

The most extensively studied SHIVs thus far use the CXCR4 coreceptor. X4 SHIVs can be transmitted intravenously (i.v.), as well as intrarectally (i.r.) or intravaginally (ivag) in RMs, demonstrating that there is no intrinsic barrier to mucosal transmission and amplification of X4 viruses. The clinical course of X4 SHIV infection in NHPs, however, differs dramatically from that of macaques infected with SIV and R5 SHIVs. Rapid and severe depletion of CXCR4+ target T cells in the peripheral blood, thymus and secondary lymphoid tissues was observed in X4 SHIV infected animals, with high sustained viremia and progression to disease in 12-30 weeks [6365, 71, 72]. Similar to observations made in RMs infected with X4 SIVmac155T3 [46], CXCR4+ naive CD4+ T cells that are enriched in secondary lymph nodes were selectively depleted early in X4 SHIV infected monkeys, with elimination of central memory CD4+ T cells during post-acute infection [70, 73]. Despite the severe and irreversible loss of CD4+ T cell populations, plasma viral load remained high in the inoculated rhesus monkeys, sustained by infected tissue macrophages [74]. However, while HIV-1 macrophage infection is generally associated with CCR5 use [75], acquisition of macrophage tropism by X4 SHIV in late-stage infected macaques is not accompanied by a change in coreceptor usage [76]. In a study that followed the evolution of HIV-1 envelope over time in PT macaques infected with X4 SHIVs [77], most isolates were also found to maintain CXCR4 use. The exception was an envelope protein obtained from the cerebral spinal fluid of an infected macaque that developed severe CD4+ T cell loss and AIDS. This brain-derived Env was found to use CXCR4 very inefficiently, but was able to use CCR2b, and to a lesser extent CCR3, STRL33 and APJ to infect cells. Furthermore, this envelope protein did not use CCR5, but mediate infection of macrophages. Thus, even though CXCR4 is very rarely used by SIV, it functions as an efficient receptor for SHIVs in macaques.

In contrast to X4 SHIV, R5 SHIV infected IndRMs experienced a variable but detectable plasma viremia, with some developing a rapid progressor clinical course. Furthermore, acute pathogenic R5 SHIV infection, similar to HIV or SIV infection [46, 7883], results in a more gradual and moderate loss of CD4+ T cells in peripheral blood and secondary lymphoid tissues, but dramatic depletion of CD4+ effector memory T cells that reside in extra-lymphoid immune effector sites such as the gut, lung and genital tract [54, 67, 68]. Thus, differential target cell selectivity of the two viruses [46, 70], coupled with the difference in tissue distribution of the CD4+ target T cell subsets within the host [73, 84, 85], largely explains the distinct pattern and sites of CD4+ T cell depletion in RMs infected with X4 or R5 viruses. That this process is inextricably linked to coreceptor usage was further demonstrated in a study using isogenic SHIVs that differ only in the gp120 V3 loop sequences and in coreceptor preference [73]. Infection of RMs with pathogenic SIVs and SHIVs of different coreceptor usage, therefore, recapitulates key features of HIV infection and pathogenesis in humans: R5 SIV/SHIV infection induces a disease course that is more similar to that which occurs during most human infections with HIV-1, while X4 SIV/SHIV infection reproduces the precipitous peripheral CD4+ T cell decline observed in patients infected with X4 HIV-1 isolates or in late stage disease concomitant with the emergence of X4 virus. Coreceptor directed targeting results in dramatically different changes in the CD4 T cell subset composition of X4 and R5 SIV/SHIV infected animals, explaining the distinctive clinical courses induced by each virus.

Coreceptor switch in R5 SHIV infected rapid progressor macaques

In ~50% of HIV-1 subtype-B infected individuals, the coreceptor usage of the virus changes from a preference for CCR5 to a preference for CXCR4 over the course of infection [86]. As noted above, expansion or switch to CXCR4 use is rarely observed in SIV infection of RMs, but several cases of tropism switch have been reported in R5 SHIV infection. Coreceptor switching was documented during infection of RMs inoculated with R5 SHIVSF162P3N by the intravenous [87, 88] and the intrarectal route [89]. The IV and mucosally infected macaques in which X4 virus evolved and emerged are rapid progressors (RPs) that experienced high set-point viral loads, undetectable or transient anti-viral antibody response, and progression to AIDS within 3-6 months post-infection. Viruses recovered from one of three RPs inoculated with the CCR5-tropic SHIVAd8 lineage viruses were also shown to acquire the capacity to use CXCR4 [54]. Although rare, rapid disease progression has also been reported in HIV-1 infected individuals [9093], many of whom were found to harbor X4 viruses [94, 95]. In contrast, while approximately 20% of SIVmac/SIVsm infected RMs become RPs, R5-to-X4 switching has not been documented in these rapid progressing macaques [96, 97]. As coreceptor usage by SIV is broader than that for HIV-1, these findings lend further support to the notion that the use of other seven-transmembrane receptor(s) besides CCR5 and CXCR4 may indeed be relevant for SIV infection in vivo.

Consistent with findings in HIV-1 infected individuals that acquire X4 viruses [98100], sequence changes in the V3 loop of envelope gp120 that increased the net charge of this region determine the phenotypic change from R5-to-X4 in R5 SHIV infected macaques [54, 8789]. These include insertions of basic amino acids upstream of the GPGR crown of the V3 loop, as well as replacement of the serine residue at position 11 of the V3 loop with positively charged amino acids, suggesting that evolution pathways to acquisition of CXCR4 use overlap in the two hosts. Similar envelope changes during disease progression in HIV-infected humans and SHIV-infected macaques have previously been reported, indicative of common selection pressures [101, 102]. With regard to coreceptor switch, the observation that the envelope V3 loop sequences required for tropism switch in RP macaques are similar to those in infected humans who usually have developed neutralizing antibodies is noteworthy, since it argues that humoral immunity may not be a main selection pressure for change in coreceptor preference. Additionally, the V3 loop sequence mutations that resulted in tropism switch in R5 SHIVSF162P3N infected RP macaques differed from those required to confer expanded CXCR4 use to the parental SF162 envelope in tissue culture systems [103105], implying that the selective pressures for X4 virus evolution differed in vivo and in vitro. Because both systems lack antiviral antibody response, this selection factor also cannot explain the difference in sequence change required for adaption of the SF162 envelope to function with CXCR4 in vivo and in vitro. Besides humoral immunity, changes in target cell populations during the course of infection has also been proposed as playing a role in driving coreceptor switching [106, 107]. Thus, it is conceivable that the need to escape this selection pressure, while maintaining viral fitness and efficient coreceptor usage on diverse tissue cells of the monkey host, accounts for the difference in sequence requirement for tropism switch in vivo and in tissue culture systems. However, X4 virus emergence in R5 SHIV infected RP macaque occurs at a time when peripheral CD4+ T cell count is >200 per microliter blood, suggesting that CD4+ target T cell limitation is also not a main selection pressure for change in coreceptor preference. A lack of correlation between the percentage of peripheral CCR5+CD4+ target T cells or CCR5 genotype with development of CXCR4-using viruses in HIV-1 infected individuals had also been reported [108, 109]. Further studies in this animal model of coreceptor switch therefore may uncover novel selective pressures that lead to the evolution of CXCR4-using HIV variants in some infected individuals.

Phenotypic characteristics of switch variants in R5 SHIV infected rhesus macaques

Similar to observations made in humans [110112], the evolutionary process in infected macaques transitions through dual-tropic variants capable of using both coreceptors, albeit with reduced efficiency compared to the inoculating R5 virus and the final X4 variant [113]. The findings that SIVmac155T3 as well as the multitropic R5/X4/R8 SIVsmm variants still function with the CCR5 coreceptor while expanding their coreceptor utilization further illustrate the role of transitional intermediates in the pathway to coreceptor switch in NHPs. Furthermore, more than one R5-to-X4 evolutionary pathways were identified in some R5 SHIV infected RP macaques, giving rise to distinct X4 and dual-tropic variants which had a preference for CCR5 coreceptor (dual-R tropic) or a preference for CXCR4 coreceptor (dual-X tropic) [89, 114]. Further characterization of these R5X4 intermediate viruses should provide a better understanding of the costs and benefits associated with switch in vivo, and properties of the transitional intermediates that allow them to eventually outgrow and amplify.

Akin to HIV-1 infection in humans [115], the emerging dual-tropic and X4 viruses are highly susceptible to antibody neutralization compared to the early or co-existing R5 viruses, in particular to soluble CD4 (sCD4) and anti-V3 loop antibodies. In this regard, varying frequencies of X4 viruses have been reported throughout the course of HIV-1 natural infection [116], but their dominance is seen only towards the end stage of disease. These findings, coupled with the observation that dual-tropic and X4 virus evolution is observed in R5 SHIV infected RP macaques with undetectable antiviral antibody responses, lend support to the notion that X4 emergence is the result, rather than the cause, of immune failure [117119]. Thus, while antiviral antibody response may not be a main driving force for R5-to-X4 evolution, it is a major obstacle to X4 emergence and expansion. Interestingly, and consistent with reports for HIV-1 [120, 121], V3 sequence changes that confer CXCR4 usage are also sufficient to determine increase sCD4 sensitivity of the virus [113], suggesting that the early steps in the R5-to-X4 evolution process in the RP macaques may require the same conformation changes that renders the virus neutralization sensitive. Higher sensitivity of viruses to neutralization with sCD4 and anti-V3 loop antibodies implies greater exposure of the CD4 and chemokine receptor binding sites that are usually sequestered away from the humoral immune response [122124], indicative of a more “open” and less constrained envelope conformation. As envelope structural constraints have been suggested to limit the pathways available for coreceptor switching [110, 125, 126], it is tempting to speculate that an “open” and less constrained envelope conformation would be more accommodating for mutational changes that are required for tropism switch, but which usually come with costs to the virus because of fitness loss. Studies to monitor precisely the events surrounding coreceptor switch in the R5 SHIV infected RP macaques may provide insights into the driving forces for the virus to undergo a conformation change that exposes its receptor and coreceptor binding sites.

Secondary lymphoid tissues are the sites of X4 virus evolution and emergence

Frequent samplings and tissue data are very limiting for HIV-1 infection of humans, highlighting the usefulness of the R5 SHIV monkey model in providing a detailed picture of the dynamics and anatomic sites of viral tropism change. In this regard, frequent and extensive samplings of lymphoid and nonlymphoid organs in R5 SHIVSF162P3N infected RP macaques revealed different tempo and tissue localization of the emerging dual-tropic and X4 variants [89, 113]. X4 viruses are poorly represented in the gut but are detectable in secondary lymphoid tissues such as the axillary, Iliac, and inguinal lymph nodes at the time of switch. This contrasts with dual-tropic viruses, which were easier to detect and had a much wider distribution, establishing infection in peripheral as well as mucosal lymphoid tissues. The greater representation and presence of the dual-tropic viruses in multiple tissue sites compared to the X4 virus indicated dominance and generalized dissemination of the former virus, and suggested that the dual-tropic switch event took place earlier than the X4 switch. Moreover, analysis of tissue samples collected at a time point that happened to capture a localized switch event in one infected RP macaque showed emergence of X4 viruses first in the inguinal lymph node [89]. Interestingly, in a study that examined envelope evolution in DKO-hu-HSC mice infected with the CCR5-tropic isolate HIV-1JRCSF, variants that could use CXCR4 in addition to CCR5 emerged in one mouse, and V3 sequences indicative of CXCR4-use were compartmentalized in the mesenteric lymph node [127]. As indicated above, CXCR4+CD4+ naïve T cells that are preferential targets for X4 viruses in acute infection are enriched in peripheral blood and secondary lymphoid tissues. Compartmentalization of these preferred targets for X4 viruses in peripheral lymph nodes, therefore, contribute to the regional evolution and selection of X4 viruses at these sites. Evolution and localization of X4 viruses that are neutralization sensitive in secondary lymphoid tissues which are not frequently sampled, together with the fact that immune selection against HIV appears to continue until late in infection [118, 128], could explain the observation of X4 emergence only in a subset of patients progressing to AIDS.

Concluding remarks

SIV and SHIV infection of RMs provide experimentally attractive models to study the impact of coreceptor usage on viral replication, CD4 T cell depletion and disease. Recent development of a simian model of coreceptor switching, based on the infection of rhesus macaques with pathogenic R5 SHIV isolates, further broadens the use of NHPs to study coreceptor switch following intravenous and mucosal infection. The conditions, phenotypic characteristics as well as envelope V3 sequences required for coreceptor switch in R5 SHIV infected macaques overlap with those reported in HIV-1 infected individuals, supporting the use of this model to study the mechanistic basis and selective forces for HIV-1 coreceptor switching in vivo. While this phenomenon has so far been documented only in a small number of R5 SHIV infected RPs who fail to mount or sustain virus-specific antibody response, studies of these animals are still important, for they allow examination of the process of a generalized switch uncomplicated by the selection pressure of antiviral immune responses. It remains to be determined how broadly findings in the SHIV-rhesus model of coreceptor switch relate to HIV infection of humans. Moreover, although humoral immune pressure may not be a main factor in driving coreceptor switch in the RP macaques, its presence could nevertheless shape or dictate the pathway of R5-to-X4 evolution. Variations in host genetic factors such as MHC, APOBEC and TRIM5 family of proteins [129131] could also play roles in restricting the mutational pathways to coreceptor switch in vivo. Thus, the model could be improved by examining the process of coreceptor switching in genetically-defined R5 SHIV infected rhesus monkeys that have developed a neutralizing antibody response, to discern the impact of innate and adaptive immune selection forces on the evolutionary pathways available for tropism switch.


  1. 1.

    Gardner MB, Luciw PA: Animal models of AIDS. FASEB J. 1989, 3: 2593-2606.

  2. 2.

    Alter HJ, Eichberg JW, Masur H, Saxinger WC, Gallo R, Macher AM, Lane HC, Fauci AS: Transmission of HTLV-III infection from human plasma to chimpanzees: an animal model for AIDS. Science. 1984, 226: 549-552. 10.1126/science.6093251.

  3. 3.

    Lusso P, Markham PD, Ranki A, Earl P, Moss B, Dorner F, Gallo RC, Krohn KJ: Cell-mediated immune response toward viral envelope and core antigens in gibbon apes (Hylobates lar) chronically infected with human immunodeficiency virus-1. J Immunol. 1988, 141: 2467-2473.

  4. 4.

    Davis IC, Girard M, Fultz PN: Loss of CD4+ T cells in human immunodeficiency virus type 1-infected chimpanzees is associated with increased lymphocyte apoptosis. J Virol. 1998, 72: 4623-4632.

  5. 5.

    Novembre FJ, de Rosayro J, Nidtha S, O'Neil SP, Gibson TR, Evans-Strickfaden T, Hart CE, McClure HM: Rapid CD4(+) T-cell loss induced by human immunodeficiency virus type 1(NC) in uninfected and previously infected chimpanzees. J Virol. 2001, 75: 1533-1539. 10.1128/JVI.75.3.1533-1539.2001.

  6. 6.

    O'Neil SP, Novembre FJ, Hill AB, Suwyn C, Hart CE, Evans-Strickfaden T, Anderson DC, deRosayro J, Herndon JG, Saucier M, McClure HM: Progressive infection in a subset of HIV-1-positive chimpanzees. J Infect Dis. 2000, 182: 1051-1062.

  7. 7.

    Conlee KM: Chimpanzees in research and testing worldwide: Overview, oversight and applicable laws. AATEX. 2007, 14: 111-118.

  8. 8.

    Hahn BH, Shaw GM, De Cock KM, Sharp PM: AIDS as a zoonosis: scientific and public health implications. Science. 2000, 287: 607-614. 10.1126/science.287.5453.607.

  9. 9.

    Gao F, Bailes E, Robertson DL, Chen Y, Rodenburg CM, Michael SF, Cummins LB, Arthur LO, Peeters M, Shaw GM: Origin of HIV-1 in the chimpanzee Pan troglodytes troglodytes. Nature. 1999, 397: 436-441. 10.1038/17130.

  10. 10.

    Hirsch VM, Olmsted RA, Murphey-Corb M, Purcell RH, Johnson PR: An African primate lentivirus (SIVsm) closely related to HIV-2. Nature. 1989, 339: 389-392. 10.1038/339389a0.

  11. 11.

    VandeWoude S, Apetrei C: Going wild: lessons from naturally occurring T-lymphotropic lentiviruses. Clin Microbiol Rev. 2006, 19: 728-762. 10.1128/CMR.00009-06.

  12. 12.

    Paiardini M, Pandrea I, Apetrei C, Silvestri G: Lessons learned from the natural hosts of HIV-related viruses. Annu Rev Med. 2009, 60: 485-495. 10.1146/

  13. 13.

    Pandrea I, Silvestri G, Apetrei C: AIDS in african nonhuman primate hosts of SIVs: a new paradigm of SIV infection. Curr HIV Res. 2009, 7: 57-72. 10.2174/157016209787048456.

  14. 14.

    Silvestri G: Immunity in natural SIV infections. J Intern Med. 2009, 265: 97-109. 10.1111/j.1365-2796.2008.02049.x.

  15. 15.

    Sodora DL, Allan JS, Apetrei C, Brenchley JM, Douek DC, Else JG, Estes JD, Hahn BH, Hirsch VM, Kaur A: Toward an AIDS vaccine: lessons from natural simian immunodeficiency virus infections of African nonhuman primate hosts. Nat Med. 2009, 15: 861-865. 10.1038/nm.2013.

  16. 16.

    Ling B, Apetrei C, Pandrea I, Veazey RS, Lackner AA, Gormus B, Marx PA: Classic AIDS in a sooty mangabey after an 18-year natural infection. J Virol. 2004, 78: 8902-8908. 10.1128/JVI.78.16.8902-8908.2004.

  17. 17.

    Pandrea I, Onanga R, Kornfeld C, Rouquet P, Bourry O, Clifford S, Telfer PT, Abernethy K, White LT, Ngari P: High levels of SIVmnd-1 replication in chronically infected Mandrillus sphinx. Virology. 2003, 317: 119-127. 10.1016/j.virol.2003.08.015.

  18. 18.

    Keele BF, Jones JH, Terio KA, Estes JD, Rudicell RS, Wilson ML, Li Y, Learn GH, Beasley TM, Schumacher-Stankey J: Increased mortality and AIDS-like immunopathology in wild chimpanzees infected with SIVcpz. Nature. 2009, 460: 515-519. 10.1038/nature08200.

  19. 19.

    Gardner MB: Simian AIDS: an historical perspective. J Med Primatol. 2003, 32: 180-186. 10.1034/j.1600-0684.2003.00023.x.

  20. 20.

    Staprans SI, Feinberg MB: The roles of nonhuman primates in the preclinical evaluation of candidate AIDS vaccines. Expert Rev Vaccines. 2004, 3: S5-32. 10.1586/14760584.3.4.S5.

  21. 21.

    Hirsch VM, Lifson JD: Simian immunodeficiency virus infection of monkeys as a model system for the study of AIDS pathogenesis, treatment, and prevention. Adv Pharmacol. 2000, 49: 437-477. full_text.

  22. 22.

    Hu SL: Non-human primate models for AIDS vaccine research. Curr Drug Targets Infect Disord. 2005, 5: 193-201. 10.2174/1568005054201508.

  23. 23.

    Reimann KA, Parker RA, Seaman MS, Beaudry K, Beddall M, Peterson L, Williams KC, Veazey RS, Montefiori DC, Mascola JR: Pathogenicity of simian-human immunodeficiency virus SHIV-89.6P and SIVmac is attenuated in cynomolgus macaques and associated with early T-lymphocyte responses. J Virol. 2005, 79: 8878-8885. 10.1128/JVI.79.14.8878-8885.2005.

  24. 24.

    Beer BE, Brown CR, Whitted S, Goldstein S, Goeken R, Plishka R, Buckler-White A, Hirsch VM: Immunodeficiency in the absence of high viral load in pig-tailed macaques infected with Simian immunodeficiency virus SIVsun or SIVlhoest. J Virol. 2005, 79: 14044-14056. 10.1128/JVI.79.22.14044-14056.2005.

  25. 25.

    Hirsch VM, Dapolito G, Johnson PR, Elkins WR, London WT, Montali RJ, Goldstein S, Brown C: Induction of AIDS by simian immunodeficiency virus from an African green monkey: species-specific variation in pathogenicity correlates with the extent of in vivo replication. J Virol. 1995, 69: 955-967.

  26. 26.

    Fultz PN, McClure HM, Anderson DC, Switzer WM: Identification and biologic characterization of an acutely lethal variant of simian immunodeficiency virus from sooty mangabeys (SIV/SMM). AIDS Res Hum Retroviruses. 1989, 5: 397-409. 10.1089/aid.1989.5.397.

  27. 27.

    Brennan G, Kozyrev Y, Kodama T, Hu SL: Novel TRIM5 isoforms expressed by Macaca nemestrina. J Virol. 2007, 81: 12210-12217. 10.1128/JVI.02499-06.

  28. 28.

    Newman RM, Hall L, Kirmaier A, Pozzi LA, Pery E, Farzan M, O'Neil SP, Johnson W: Evolution of a TRIM5-CypA splice isoform in old world monkeys. PLoS Pathog. 2008, 4: e1000003-10.1371/journal.ppat.1000003.

  29. 29.

    Virgen CA, Kratovac Z, Bieniasz PD, Hatziioannou T: Independent genesis of chimeric TRIM5-cyclophilin proteins in two primate species. Proc Natl Acad Sci U S A. 2008, 105: 3563-3568. 10.1073/pnas.0709258105.

  30. 30.

    Wilson SJ, Webb BL, Ylinen LM, Verschoor E, Heeney JL, Towers GJ: Independent evolution of an antiviral TRIMCyp in rhesus macaques. Proc Natl Acad Sci U S A. 2008, 105: 3557-3562. 10.1073/pnas.0709003105.

  31. 31.

    Berger EA: HIV entry and tropism: the chemokine receptor connection. AIDS. 1997, 11 (Suppl A): S3-16.

  32. 32.

    Doms RW, Peiper SC: Unwelcomed guests with master keys: how HIV uses chemokine receptors for cellular entry. Virology. 1997, 235: 179-190. 10.1006/viro.1997.8703.

  33. 33.

    Moore JP, Trkola A, Dragic T: Co-receptors for HIV-1 entry. Curr Opin Immunol. 1997, 9: 551-562. 10.1016/S0952-7915(97)80110-0.

  34. 34.

    Pandrea I, Apetrei C, Gordon S, Barbercheck J, Dufour J, Bohm R, Sumpter B, Roques P, Marx PA, Hirsch VM: Paucity of CD4+CCR5+ T cells is a typical feature of natural SIV hosts. Blood. 2007, 109: 1069-1076. 10.1182/blood-2006-05-024364.

  35. 35.

    Chen Z, Kwon D, Jin Z, Monard S, Telfer P, Jones MS, Lu CY, Aguilar RF, Ho DD, Marx PA: Natural infection of a homozygous delta24 CCR5 red-capped mangabey with an R2b-tropic simian immunodeficiency virus. J Exp Med. 1998, 188: 2057-2065. 10.1084/jem.188.11.2057.

  36. 36.

    Doms RW: Chemokine receptors and HIV entry. AIDS. 2001, 15 (Suppl 1): S34-35. 10.1097/00002030-200102001-00051.

  37. 37.

    Marx PA, Chen Z: The function of simian chemokine receptors in the replication of SIV. Semin Immunol. 1998, 10: 215-223. 10.1006/smim.1998.0135.

  38. 38.

    Zhang Y, Lou B, Lal RB, Gettie A, Marx PA, Moore JP: Use of inhibitors to evaluate coreceptor usage by simian and simian/human immunodeficiency viruses and human immunodeficiency virus type 2 in primary cells. J Virol. 2000, 74: 6893-6910. 10.1128/JVI.74.15.6893-6910.2000.

  39. 39.

    Gautam R, Gaufin T, Butler I, Gautam A, Barnes M, Mandell D, Pattison M, Tatum C, Macfarland J, Monjure C: Simian immunodeficiency virus SIVrcm, a unique CCR2-tropic virus, selectively depletes memory CD4+ T cells in pigtailed macaques through expanded coreceptor usage in vivo. J Virol. 2009, 83: 7894-7908. 10.1128/JVI.00444-09.

  40. 40.

    Riddick NE, Hermann EA, Loftin LM, Elliott ST, Wey WC, Cervasi B, Taaffe J, Engram JC, Li B, Else JG: A novel CCR5 mutation common in sooty mangabeys reveals SIVsmm infection of CCR5-null natural hosts and efficient alternative coreceptor use in vivo. PLoS Pathog. 2010, 6: e1001064-10.1371/journal.ppat.1001064.

  41. 41.

    Schols D, De Clercq E: The simian immunodeficiency virus mnd(GB-1) strain uses CXCR4, not CCR5, as coreceptor for entry in human cells. J Gen Virol. 1998, 79 (Pt 9): 2203-2205.

  42. 42.

    Pandrea I, Kornfeld C, Ploquin MJ, Apetrei C, Faye A, Rouquet P, Roques P, Simon F, Barre-Sinoussi F, Muller-Trutwin MC, Diop OM: Impact of viral factors on very early in vivo replication profiles in simian immunodeficiency virus SIVagm-infected African green monkeys. J Virol. 2005, 79: 6249-6259. 10.1128/JVI.79.10.6249-6259.2005.

  43. 43.

    Milush JM, Reeves JD, Gordon SN, Zhou D, Muthukumar A, Kosub DA, Chacko E, Giavedoni LD, Ibegbu CC, Cole KS: Virally induced CD4+ T cell depletion is not sufficient to induce AIDS in a natural host. J Immunol. 2007, 179: 3047-3056.

  44. 44.

    Means RE, Matthews T, Hoxie JA, Malim MH, Kodama T, Desrosiers RC: Ability of the V3 loop of simian immunodeficiency virus to serve as a target for antibody-mediated neutralization: correlation of neutralization sensitivity, growth in macrophages, and decreased dependence on CD4. J Virol. 2001, 75: 3903-3915. 10.1128/JVI.75.8.3903-3915.2001.

  45. 45.

    Kodama T, Mori K, Kawahara T, Ringler DJ, Desrosiers RC: Analysis of simian immunodeficiency virus sequence variation in tissues of rhesus macaques with simian AIDS. J Virol. 1993, 67: 6522-6534.

  46. 46.

    Picker LJ, Hagen SI, Lum R, Reed-Inderbitzin EF, Daly LM, Sylwester AW, Walker JM, Siess DC, Piatak M, Wang C: Insufficient production and tissue delivery of CD4+ memory T cells in rapidly progressive simian immunodeficiency virus infection. J Exp Med. 2004, 200: 1299-1314. 10.1084/jem.20041049.

  47. 47.

    Bogers WM, Cheng-Mayer C, Montelaro RC: Developments in preclinical AIDS vaccine efficacy models. Aids. 2000, 14 (Suppl 3): S141-151.

  48. 48.

    Ranjbar S, Jones S, Stott EJ, Almond N: The construction and evaluation of SIV/HIV chimeras that express the envelope of European HIV type 1 isolates. AIDS Res Hum Retroviruses. 1997, 13: 797-800. 10.1089/aid.1997.13.797.

  49. 49.

    Kuwata T, Shioda T, Igarashi T, Ido E, Ibuki K, Enose Y, Stahl-Hennig C, Hunsmann G, Miura T, Hayami M: Chimeric viruses between SIVmac and various HIV-1 isolates have biological properties that are similar to those of the parental HIV-1. Aids. 1996, 10: 1331-1337. 10.1097/00002030-199610000-00004.

  50. 50.

    Li J, Lord CI, Haseltine W, Letvin NL, Sodroski J: Infection of cynomolgus monkeys with a chimeric HIV-1/SIVmac virus that expresses the HIV-1 envelope glycoproteins. J Acquir Immune Defic Syndr. 1992, 5: 639-646.

  51. 51.

    Luciw PA, Pratt-Lowe E, Shaw KE, Levy JA, Cheng-Mayer C: Persistent infection of rhesus macaques with T-cell-line-tropic and macrophage-tropic clones of simian/human immunodeficiency viruses (SHIV). Proc Natl Acad Sci U S A. 1995, 92: 7490-7494. 10.1073/pnas.92.16.7490.

  52. 52.

    Pal R, Taylor B, Foulke JS, Woodward R, Merges M, Praschunus R, Gibson A, Reitz M: Characterization of a simian human immunodeficiency virus encoding the envelope gene from the CCR5-tropic HIV-1 Ba-L. J Acquir Immune Defic Syndr. 2003, 33: 300-307.

  53. 53.

    Shibata R, Kawamura M, Sakai H, Hayami M, Ishimoto A, Adachi A: Generation of a chimeric human and simian immunodeficiency virus infectious to monkey peripheral blood mononuclear cells. J Virol. 1991, 65: 3514-3520.

  54. 54.

    Nishimura Y, Shingai M, Willey R, Sadjadpour R, Lee WR, Brown CR, Brenchley JM, Buckler-White A, Petros R, Eckhaus M: Generation of the Pathogenic R5-Tropic SHIVAd8 by Serial Passaging in Rhesus Macaques. J Virol. 2010

  55. 55.

    Matsuda K, Inaba K, Fukazawa Y, Matsuyama M, Ibuki K, Horiike M, Saito N, Hayami M, Igarashi T, Miura T: In vivo analysis of a new R5 tropic SHIV generated from the highly pathogenic SHIV-KS661, a derivative of SHIV-89.6. Virology. 2010, 399: 134-143. 10.1016/j.virol.2010.01.008.

  56. 56.

    Cayabyab M, Rohne D, Pollakis G, Mische C, Messele T, Abebe A, Etemad-Moghadam B, Yang P, Henson S, Axthelm M: Rapid CD4+ T-lymphocyte depletion in rhesus monkeys infected with a simian-human immunodeficiency virus expressing the envelope glycoproteins of a primary dual-tropic Ethiopian Clade C HIV type 1 isolate. AIDS Res Hum Retroviruses. 2004, 20: 27-40. 10.1089/088922204322749477.

  57. 57.

    Chen Z, Huang Y, Zhao X, Skulsky E, Lin D, Ip J, Gettie A, Ho DD: Enhanced infectivity of an R5-tropic simian/human immunodeficiency virus carrying human immunodeficiency virus type 1 subtype C envelope after serial passages in pig-tailed macaques (Macaca nemestrina). J Virol. 2000, 74: 6501-6510. 10.1128/JVI.74.14.6501-6510.2000.

  58. 58.

    Ndung'u T, Lu Y, Renjifo B, Touzjian N, Kushner N, Pena-Cruz V, Novitsky VA, Lee TH, Essex M: Infectious simian/human immunodeficiency virus with human immunodeficiency virus type 1 subtype C from an African isolate: rhesus macaque model. J Virol. 2001, 75: 11417-11425.

  59. 59.

    Song RJ, Chenine AL, Rasmussen RA, Ruprecht CR, Mirshahidi S, Grisson RD, Xu W, Whitney JB, Goins LM, Ong H: Molecularly cloned SHIV-1157ipd3N4: a highly replication- competent, mucosally transmissible R5 simian-human immunodeficiency virus encoding HIV clade C Env. J Virol. 2006, 80: 8729-8738. 10.1128/JVI.00558-06.

  60. 60.

    Wu Y, Hong K, Chenine AL, Whitney JB, Xu W, Chen Q, Geng Y, Ruprecht RM, Shao Y: Molecular cloning and in vitro evaluation of an infectious simian-human immunodeficiency virus containing env of a primary Chinese HIV-1 subtype C isolate. J Med Primatol. 2005, 34: 101-107. 10.1111/j.1600-0684.2005.00098.x.

  61. 61.

    Himathongkham S, Douglas GC, Fang A, Yu E, Barnett SW, Luciw PA: Species tropism of chimeric SHIV clones containing HIV-1 subtype-A and subtype-E envelope genes. Virology. 2002, 298: 189-199. 10.1006/viro.2002.1454.

  62. 62.

    Himathongkham S, Halpin NS, Li J, Stout MW, Miller CJ, Luciw PA: Simian-human immunodeficiency virus containing a human immunodeficiency virus type 1 subtype-E envelope gene: persistent infection, CD4(+) T-cell depletion, and mucosal membrane transmission in macaques. J Virol. 2000, 74: 7851-7860. 10.1128/JVI.74.17.7851-7860.2000.

  63. 63.

    Luciw PA, Mandell CP, Himathongkham S, Li J, Low TA, Schmidt KA, Shaw KE, Cheng-Mayer C: Fatal immunopathogenesis by SIV/HIV-1 (SHIV) containing a variant form of the HIV-1SF33 env gene in juvenile and newborn rhesus macaques. Virology. 1999, 263: 112-127. 10.1006/viro.1999.9908.

  64. 64.

    Joag SV, Li Z, Foresman L, Stephens EB, Zhao LJ, Adany I, Pinson DM, McClure HM, Narayan O: Chimeric simian/human immunodeficiency virus that causes progressive loss of CD4+ T cells and AIDS in pig-tailed macaques. J Virol. 1996, 70: 3189-3197.

  65. 65.

    Reimann KA, Li JT, Veazey R, Halloran M, Park IW, Karlsson GB, Sodroski J, Letvin NL: A chimeric simian/human immunodeficiency virus expressing a primary patient human immunodeficiency virus type 1 isolate env causes an AIDS-like disease after in vivo passage in rhesus monkeys. J Virol. 1996, 70: 6922-6928.

  66. 66.

    Shibata R, Maldarelli F, Siemon C, Matano T, Parta M, Miller G, Fredrickson T, Martin MA: Infection and pathogenicity of chimeric simian-human immunodeficiency viruses in macaques: determinants of high virus loads and CD4 cell killing. J Infect Dis. 1997, 176: 362-373. 10.1086/514053.

  67. 67.

    Harouse JM, Gettie A, Tan RC, Blanchard J, Cheng-Mayer C: Distinct pathogenic sequela in rhesus macaques infected with CCR5 or CXCR4 utilizing SHIVs. Science. 1999, 284: 816-819. 10.1126/science.284.5415.816.

  68. 68.

    Siddappa NB, Song R, Kramer VG, Chenine AL, Velu V, Ong H, Rasmussen RA, Grisson RD, Wood C, Zhang H: Neutralization-Sensitive R5-Tropic Simian-Human Immunodeficiency Virus SHIV-2873Nip, Which Carries env Isolated from an Infant with a Recent HIV Clade C Infection. J Virol. 2009, 83: 1422-1432. 10.1128/JVI.02066-08.

  69. 69.

    Igarashi T, Imamichi H, Brown CR, Hirsch VM, Martin MA: The emergence and characterization of macrophage-tropic SIV/HIV chimeric viruses (SHIVs) present in CD4+ T cell-depleted rhesus monkeys. J Leukoc Biol. 2003, 74: 772-780. 10.1189/jlb.0503196.

  70. 70.

    Nishimura Y, Igarashi T, Donau OK, Buckler-White A, Buckler C, Lafont BA, Goeken RM, Goldstein S, Hirsch VM, Martin MA: Highly pathogenic SHIVs and SIVs target different CD4+ T cell subsets in rhesus monkeys, explaining their divergent clinical courses. Proc Natl Acad Sci U S A. 2004, 101: 12324-12329. 10.1073/pnas.0404620101.

  71. 71.

    Igarashi T, Endo Y, Englund G, Sadjadpour R, Matano T, Buckler C, Buckler-White A, Plishka R, Theodore T, Shibata R, Martin M: Emergence of a highly pathogenic simian/human immunodeficiency virus in a rhesus macaque treated with anti-CD8 mAb during a primary infection with a nonpathogenic virus. Proc Natl Acad Sci U S A. 1999, 96: 14049-14054. 10.1073/pnas.96.24.14049.

  72. 72.

    Reyes RA, Canfield DR, Esser U, Adamson LA, Brown CR, Cheng-Mayer C, Gardner MB, Harouse JM, Luciw PA: Induction of simian AIDS in infant rhesus macaques infected with CCR5- or CXCR4-utilizing simian-human immunodeficiency viruses is associated with distinct lesions of the thymus. J Virol. 2004, 78: 2121-2130. 10.1128/JVI.78.4.2121-2130.2004.

  73. 73.

    Ho SH, Shek L, Gettie A, Blanchard J, Cheng-Mayer C: V3 loop-determined coreceptor preference dictates the dynamics of CD4+-T-cell loss in simian-human immunodeficiency virus-infected macaques. J Virol. 2005, 79: 12296-12303. 10.1128/JVI.79.19.12296-12303.2005.

  74. 74.

    Igarashi T, Brown CR, Endo Y, Buckler-White A, Plishka R, Bischofberger N, Hirsch V, Martin MA: Macrophage are the principal reservoir and sustain high virus loads in rhesus macaques after the depletion of CD4+ T cells by a highly pathogenic simian immunodeficiency virus/HIV type 1 chimera (SHIV): Implications for HIV-1 infections of humans. Proc Natl Acad Sci U S A. 2001, 98: 658-663. 10.1073/pnas.021551798.

  75. 75.

    Alkhatib G, Combadiere C, Broder CC, Feng Y, Kennedy PE, Murphy PM, Berger EA: CC CKR5: a RANTES, MIP-1alpha, MIP-1beta receptor as a fusion cofactor for macrophage-tropic HIV-1. Science. 1996, 272: 1955-1958. 10.1126/science.272.5270.1955.

  76. 76.

    Igarashi T, Donau OK, Imamichi H, Dumaurier MJ, Sadjadpour R, Plishka RJ, Buckler-White A, Buckler C, Suffredini AF, Lane HC: Macrophage-tropic simian/human immunodeficiency virus chimeras use CXCR4, not CCR5, for infections of rhesus macaque peripheral blood mononuclear cells and alveolar macrophages. J Virol. 2003, 77: 13042-13052. 10.1128/JVI.77.24.13042-13052.2003.

  77. 77.

    Hoffman TL, Stephens EB, Narayan O, Doms RW: HIV type I envelope determinants for use of the CCR2b, CCR3, STRL33, and APJ coreceptors. Proc Natl Acad Sci U S A. 1998, 95: 11360-11365. 10.1073/pnas.95.19.11360.

  78. 78.

    Mattapallil JJ, Smit-McBride Z, McChesney M, Dandekar S: Intestinal intraepithelial lymphocytes are primed for gamma interferon and MIP-1beta expression and display antiviral cytotoxic activity despite severe CD4(+) T-cell depletion in primary simian immunodeficiency virus infection. J Virol. 1998, 72: 6421-6429.

  79. 79.

    Veazey RS, DeMaria M, Chalifoux LV, Shvetz DE, Pauley DR, Knight HL, Rosenzweig M, Johnson RP, Desrosiers RC, Lackner AA: Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. Science. 1998, 280: 427-431. 10.1126/science.280.5362.427.

  80. 80.

    Mattapallil JJ, Douek DC, Hill B, Nishimura Y, Martin M, Roederer M: Massive infection and loss of memory CD4+ T cells in multiple tissues during acute SIV infection. Nature. 2005, 434: 1093-1097. 10.1038/nature03501.

  81. 81.

    Li Q, Duan L, Estes JD, Ma ZM, Rourke T, Wang Y, Reilly C, Carlis J, Miller CJ, Haase AT: Peak SIV replication in resting memory CD4+ T cells depletes gut lamina propria CD4+ T cells. Nature. 2005, 434: 1148-1152.

  82. 82.

    Brenchley JM, Schacker TW, Ruff LE, Price DA, Taylor JH, Beilman GJ, Nguyen PL, Khoruts A, Larson M, Haase AT, Douek DC: CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J Exp Med. 2004, 200: 749-759. 10.1084/jem.20040874.

  83. 83.

    Mehandru S, Poles MA, Tenner-Racz K, Horowitz A, Hurley A, Hogan C, Boden D, Racz P, Markowitz M: Primary HIV-1 infection is associated with preferential depletion of CD4+ T lymphocytes from effector sites in the gastrointestinal tract. J Exp Med. 2004, 200: 761-770. 10.1084/jem.20041196.

  84. 84.

    Vajdy M, Veazey R, Tham I, deBakker C, Westmoreland S, Neutra M, Lackner A: Early immunologic events in mucosal and systemic lymphoid tissues after intrarectal inoculation with simian immunodeficiency virus. J Infect Dis. 2001, 184: 1007-1014. 10.1086/323615.

  85. 85.

    Veazey RS, Mansfield KG, Tham IC, Carville AC, Shvetz DE, Forand AE, Lackner AA: Dynamics of CCR5 expression by CD4(+) T cells in lymphoid tissues during simian immunodeficiency virus infection. J Virol. 2000, 74: 11001-11007. 10.1128/JVI.74.23.11001-11007.2000.

  86. 86.

    Berger EA, Murphy PM, Farber JM: Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and disease. Annu Rev Immunol. 1999, 17: 657-700. 10.1146/annurev.immunol.17.1.657.

  87. 87.

    Ho SH, Tasca S, Shek L, Li A, Gettie A, Blanchard J, Boden D, Cheng-Mayer C: Coreceptor switch in R5-tropic simian/human immunodeficiency virus-infected macaques. J Virol. 2007, 81: 8621-8633. 10.1128/JVI.00759-07.

  88. 88.

    Ho SH, Trunova N, Gettie A, Blanchard J, Cheng-Mayer C: Different mutational pathways to CXCR4 coreceptor switch of CCR5-using simian-human immunodeficiency virus. J Virol. 2008, 82: 5653-5656. 10.1128/JVI.00145-08.

  89. 89.

    Ren W, Tasca S, Zhuang K, Gettie A, Blanchard J, Cheng-Mayer C: Different tempo and anatomic location of dual-tropic and X4 virus emergence in a model of R5 simian-human immunodeficiency virus infection. J Virol. 2010, 84: 340-351. 10.1128/JVI.01865-09.

  90. 90.

    Ganeshan S, Dickover RE, Korber BT, Bryson YJ, Wolinsky SM: Human immunodeficiency virus type 1 genetic evolution in children with different rates of development of disease. J Virol. 1997, 71: 663-677.

  91. 91.

    Liu SL, Schacker T, Musey L, Shriner D, McElrath MJ, Corey L, Mullins JI: Divergent patterns of progression to AIDS after infection from the same source: human immunodeficiency virus type 1 evolution and antiviral responses. J Virol. 1997, 71: 4284-4295.

  92. 92.

    Michael NL, Brown AE, Voigt RF, Frankel SS, Mascola JR, Brothers KS, Louder M, Birx DL, Cassol SA: Rapid disease progression without seroconversion following primary human immunodeficiency virus type 1 infection--evidence for highly susceptible human hosts. J Infect Dis. 1997, 175: 1352-1359. 10.1086/516467.

  93. 93.

    Montagnier L, Brenner C, Chamaret S, Guetard D, Blanchard A, de Saint Martin J, Poveda JD, Pialoux G, Gougeon ML: Human immunodeficiency virus infection and AIDS in a person with negative serology. J Infect Dis. 1997, 175: 955-959. 10.1086/513999.

  94. 94.

    Kuipers H, Workman C, Dyer W, Geczy A, Sullivan J, Oelrichs R: An HIV-1-infected individual homozygous for the CCR-5 delta32 allele and the SDF-1 3'A allele. AiIDS. 1999, 13: 433-434. 10.1097/00002030-199902250-00025.

  95. 95.

    Michael NL, Nelson JA, KewalRamani VN, Chang G, O'Brien SJ, Mascola JR, Volsky B, Louder M, White GC, Littman DR: Exclusive and persistent use of the entry coreceptor CXCR4 by human immunodeficiency virus type 1 from a subject homozygous for CCR5 delta32. J Virol. 1998, 72: 6040-6047.

  96. 96.

    Hirsch VM, Santra S, Goldstein S, Plishka R, Buckler-White A, Seth A, Ourmanov I, Brown CR, Engle R, Montefiori D: Immune failure in the absence of profound CD4+ T-lymphocyte depletion in simian immunodeficiency virus-infected rapid progressor macaques. J Virol. 2004, 78: 275-284. 10.1128/JVI.78.1.275-284.2004.

  97. 97.

    Brown CR, Czapiga M, Kabat J, Dang Q, Ourmanov I, Nishimura Y, Martin MA, Hirsch VM: Unique pathology in simian immunodeficiency virus-infected rapid progressor macaques is consistent with a pathogenesis distinct from that of classical AIDS. J Virol. 2007, 81: 5594-5606. 10.1128/JVI.00202-07.

  98. 98.

    Cocchi F, DeVico AL, Garzino-Demo A, Cara A, Gallo RC, Lusso P: The V3 domain of the HIV-1 gp120 envelope glycoprotein is critical for chemokine-mediated blockade of infection. Nat Med. 1996, 2: 1244-1247. 10.1038/nm1196-1244.

  99. 99.

    De Jong JJ, De Ronde A, Keulen W, Tersmette M, Goudsmit J: Minimal requirements for the human immunodeficiency virus type 1 V3 domain to support the syncytium-inducing phenotype: analysis by single amino acid substitution. J Virol. 1992, 66: 6777-6780.

  100. 100.

    Fouchier RA, Groenink M, Kootstra NA, Tersmette M, Huisman HG, Miedema F, Schuitemaker H: Phenotype-associated sequence variation in the third variable domain of the human immunodeficiency virus type 1 gp120 molecule. J Virol. 1992, 66: 3183-3187.

  101. 101.

    Hofmann-Lehmann R, Vlasak J, Chenine AL, Li PL, Baba TW, Montefiori DC, McClure HM, Anderson DC, Ruprecht RM: Molecular evolution of human immunodeficiency virus env in humans and monkeys: similar patterns occur during natural disease progression or rapid virus passage. J Virol. 2002, 76: 5278-5284. 10.1128/JVI.76.10.5278-5284.2002.

  102. 102.

    Tso FY, Hoffmann FG, Tully DC, Lemey P, Rasmussen RA, Zhang H, Ruprecht RM, Wood C: A comparative study of HIV-1 clade C env evolution in a Zambian infant with an infected rhesus macaque during disease progression. AIDS. 2009, 23: 1817-1828. 10.1097/QAD.0b013e32832f3da6.

  103. 103.

    Dejucq N, Simmons G, Clapham PR: T-cell line adaptation of human immunodeficiency virus type 1 strain SF162: effects on envelope, vpu and macrophage-tropism. J Gen Virol. 2000, 81: 2899-2904.

  104. 104.

    Harrowe G, Cheng-Mayer C: Amino acid substitutions in the V3 loop are responsible for adaptation to growth in transformed T-cell lines of a primary human immunodeficiency virus type 1. Virology. 1995, 210: 490-494. 10.1006/viro.1995.1367.

  105. 105.

    Kiselyeva Y, Nedellec R, Ramos A, Pastore C, Margolis LB, Mosier DE: Evolution of CXCR4-using human immunodeficiency virus type 1 SF162 is associated with two unique envelope mutations. J Virol. 2007, 81: 3657-3661. 10.1128/JVI.02310-06.

  106. 106.

    Regoes RR, Bonhoeffer S: The HIV coreceptor switch: a population dynamical perspective. Trends Microbiol. 2005, 13: 269-277. 10.1016/j.tim.2005.04.005.

  107. 107.

    Moore JP, Kitchen SG, Pugach P, Zack JA: The CCR5 and CXCR4 coreceptors--central to understanding the transmission and pathogenesis of human immunodeficiency virus type 1 infection. AIDS Res Hum Retroviruses. 2004, 20: 111-126. 10.1089/088922204322749567.

  108. 108.

    van Rij RP, Hazenberg MD, van Benthem BH, Otto SA, Prins M, Miedema F, Schuitemaker H: Early viral load and CD4+ T cell count, but not percentage of CCR5+ or CXCR4+ CD4+ T cells, are associated with R5-to-X4 HIV type 1 virus evolution. AIDS Res Hum Retroviruses. 2003, 19: 389-398. 10.1089/088922203765551737.

  109. 109.

    de Roda Husman AM, Koot M, Cornelissen M, Keet IP, Brouwer M, Broersen SM, Bakker M, Roos MT, Prins M, de Wolf F: Association between CCR5 genotype and the clinical course of HIV-1 infection. Ann Intern Med. 1997, 127: 882-890.

  110. 110.

    Pastore C, Ramos A, Mosier DE: Intrinsic obstacles to human immunodeficiency virus type 1 coreceptor switching. J Virol. 2004, 78: 7565-7574. 10.1128/JVI.78.14.7565-7574.2004.

  111. 111.

    Simmons G, Wilkinson D, Reeves JD, Dittmar MT, Beddows S, Weber J, Carnegie G, Desselberger U, Gray PW, Weiss RA, Clapham PR: Primary, syncytium-inducing human immunodeficiency virus type 1 isolates are dual-tropic and most can use either Lestr or CCR5 as coreceptors for virus entry. J Virol. 1996, 70: 8355-8360.

  112. 112.

    Singh A, Collman RG: Heterogeneous spectrum of coreceptor usage among variants within a dualtropic human immunodeficiency virus type 1 primary-isolate quasispecies. J Virol. 2000, 74: 10229-10235. 10.1128/JVI.74.21.10229-10235.2000.

  113. 113.

    Tasca S, Ho SH, Cheng-Mayer C: R5X4 viruses are evolutionary, functional, and antigenic intermediates in the pathway of a simian-human immunodeficiency virus coreceptor switch. J Virol. 2008, 82: 7089-7099. 10.1128/JVI.00570-08.

  114. 114.

    Shakirzyanova M, Ren W, Zhuang K, Tasca S, Cheng-Mayer C: Fitness disadvantage of the transitional intermediates contributes to the dynamic change in infecting virus population during coreceptor switch in R5 SHIV-infected macaques. Journal of Virology. published ahead of print on 13 October 2010, doi: 10.1128/JVI.01478-10

  115. 115.

    Bunnik EM, Quakkelaar ED, van Nuenen AC, Boeser-Nunnink B, Schuitemaker H: Increased neutralization sensitivity of recently emerged CXCR4-using human immunodeficiency virus type 1 strains compared to coexisting CCR5-using variants from the same patient. J Virol. 2007, 81: 525-531. 10.1128/JVI.01983-06.

  116. 116.

    Shankarappa R, Margolick JB, Gange SJ, Rodrigo AG, Upchurch D, Farzadegan H, Gupta P, Rinaldo CR, Learn GH, He X: Consistent viral evolutionary changes associated with the progression of human immunodeficiency virus type 1 infection. J Virol. 1999, 73: 10489-10502.

  117. 117.

    Casper C, Naver L, Clevestig P, Belfrage E, Leitner T, Albert J, Lindgren S, Ottenblad C, Bohlin AB, Fenyo EM, Ehrnst A: Coreceptor change appears after immune deficiency is established in children infected with different HIV-1 subtypes. AIDS Res Hum Retroviruses. 2002, 18: 343-352. 10.1089/088922202753519124.

  118. 118.

    Riddle TM, Shire NJ, Sherman MS, Franco KF, Sheppard HW, Nelson JA: Sequential turnover of human immunodeficiency virus type 1 env throughout the course of infection. J Virol. 2006, 80: 10591-10599. 10.1128/JVI.00644-06.

  119. 119.

    Nelson J, Riddle T, Shire N, Sherman M, Franco K, Sheppard H: Sequencial Turnover of env Variants and Co-receptor Switching during HIV-1 Chronic Infection. In 14th Conference on Retroviruses and Opportunistic Infections. 2007, Los Angeles, USA

  120. 120.

    Hwang SS, Boyle TJ, Lyerly HK, Cullen BR: Identification of envelope V3 loop as the major determinant of CD4 neutralization sensitivity of HIV-1. Science. 1992, 257: 535-537. 10.1126/science.1636088.

  121. 121.

    O'Brien WA, Chen IS, Ho DD, Daar ES: Mapping genetic determinants for human immunodeficiency virus type 1 resistance to soluble CD4. J Virol. 1992, 66: 3125-3130.

  122. 122.

    Kwong PD, Doyle ML, Casper DJ, Cicala C, Leavitt SA, Majeed S, Steenbeke TD, Venturi M, Chaiken I, Fung M: HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites. Nature. 2002, 420: 678-682. 10.1038/nature01188.

  123. 123.

    Labrijn AF, Poignard P, Raja A, Zwick MB, Delgado K, Franti M, Binley J, Vivona V, Grundner C, Huang CC: Access of antibody molecules to the conserved coreceptor binding site on glycoprotein gp120 is sterically restricted on primary human immunodeficiency virus type 1. J Virol. 2003, 77: 10557-10565. 10.1128/JVI.77.19.10557-10565.2003.

  124. 124.

    Bou-Habib DC, Roderiquez G, Oravecz T, Berman PW, Lusso P, Norcross MA: Cryptic nature of envelope V3 region epitopes protects primary monocytotropic human immunodeficiency virus type 1 from antibody neutralization. J Virol. 1994, 68: 6006-6013.

  125. 125.

    Kuiken CL, de Jong JJ, Baan E, Keulen W, Tersmette M, Goudsmit J: Evolution of the V3 envelope domain in proviral sequences and isolates of human immunodeficiency virus type 1 during transition of the viral biological phenotype. J Virol. 1992, 66: 4622-4627.

  126. 126.

    van't Wout AB, Blaak H, Ran LJ, Brouwer M, Kuiken C, Schuitemaker H: Evolution of syncytium-inducing and non-syncytium-inducing biological virus clones in relation to replication kinetics during the course of human immunodeficiency virus type 1 infection. J Virol. 1998, 72: 5099-5107.

  127. 127.

    Ince WL, Zhang L, Jiang Q, Arrildt K, Su L, Swanstrom R: Evolution of the HIV-1 env gene in the Rag2-/- gammaC-/- humanized mouse model. J Virol. 2010, 84: 2740-2752. 10.1128/JVI.02180-09.

  128. 128.

    Frost SD, Liu Y, Pond SL, Chappey C, Wrin T, Petropoulos CJ, Little SJ, Richman DD: Characterization of human immunodeficiency virus type 1 (HIV-1) envelope variation and neutralizing antibody responses during transmission of HIV-1 subtype B. J Virol. 2005, 79: 6523-6527. 10.1128/JVI.79.10.6523-6527.2005.

  129. 129.

    Goulder PJ, Watkins DI: Impact of MHC class I diversity on immune control of immunodeficiency virus replication. Nat Rev Immunol. 2008, 8: 619-630. 10.1038/nri2357.

  130. 130.

    Stremlau M, Owens CM, Perron MJ, Kiessling M, Autissier P, Sodroski J: The cytoplasmic body component TRIM5alpha restricts HIV-1 infection in Old World monkeys. Nature. 2004, 427: 848-853. 10.1038/nature02343.

  131. 131.

    Sheehy AM, Gaddis NC, Choi JD, Malim MH: Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein. Nature. 2002, 418: 646-650. 10.1038/nature00939.

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This article has been published as part of Journal of Translational Medicine Volume 9 Supplement 1, 2011: Differential use of CCR5 vs. CSCR4 by HIV-1. Pathogenic, Translational and Clinical Open Questions. The full contents of the supplement are available online at

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Correspondence to Cecilia Cheng-Mayer.

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Sina, S.T., Ren, W. & Cheng-Mayer, C. Coreceptor use in nonhuman primate models of HIV infection. J Transl Med 9, S7 (2011).

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