Virus Subtype-Specific Features of Natural Simian Immunodeficiency Virus SIV
            <sub>smm</sub>
            Infection in Sooty Mangabeys

Apetrei, Cristian; Gautam, Rajeev; Sumpter, Beth; Carter, Anders C.; Gaufin, Thaidra; Staprans, Silvija I.; Else, James G.; Barnes, Mary; Cao, Robert; Garg, Seema; Milush, Jeffrey M.; Sodora, Donald L.; Pandrea, Ivona; Silvestri, Guido

doi:10.1128/jvi.00281-07

Cited by 64 publications

(48 citation statements)

References 65 publications

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“…Acquisition of CXCR4-mediated tropism for naïve CD4 ϩ T cells is strongly linked to accelerated CD4 ϩ T cell loss in HIVinfected humans, so it is uncertain whether the additional coreceptors used by these CXCR4-tropic SIVsmm Envs contribute further to disrupted CD4 ϩ T cell homeostasis. In contrast, we did not see distinct alternative coreceptor use or smCXCR4-mediated entry by isolates derived from SM naturally infected with subtype 5 SIVsmm isolates, which display more moderate levels of CD4 ϩ T cell loss (1). Thus, CD4 ϩ T cell loss in subtype 5 SIVsmm-infected SM is likely due to factors other than expanded tropism by the virus, at least for the coreceptors tested here.…”

Section: Discussioncontrasting

confidence: 46%

Cloning and Analysis of Sooty Mangabey Alternative Coreceptors That Support Simian Immunodeficiency Virus SIVsmm Entry Independently of CCR5

Elliott

Riddick

Francella

et al. 2012

J Virol

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Natural host sooty mangabeys (SM) infected with simian immunodeficiency virus SIVsmm do not develop AIDS despite high viremia. SM and other natural hosts express very low levels of CCR5 on CD4 ؉ T cells, and we recently showed that SIVsmm infection and robust replication occur in vivo in SM genetically lacking CCR5, indicating the use of additional entry pathways. SIVsmm uses several alternative coreceptors of human origin in vitro, but which molecules of SM origin support entry is unknown. We cloned a panel of putative coreceptors from SM and tested their ability to mediate infection, in conjunction with smCD4, by pseudotypes carrying Envs from multiple SIVsmm subtypes. smCXCR6 supported efficient infection by all SIVsmm isolates with entry levels comparable to those for smCCR5, and smGPR15 enabled entry by all isolates at modest levels. smGPR1 and smAPJ supported low and variable entry, whereas smCCR2b, smCCR3, smCCR4, smCCR8, and smCXCR4 were not used by most isolates. In contrast, SIVsmm from rare infected SM with profound CD4 ؉ T cell loss, previously reported to have expanded use of human coreceptors, including CXCR4, used smCXCR4, smCXCR6, and smCCR5 efficiently and also exhibited robust entry through smCCR3, smCCR8, smGPR1, smGPR15, and smAPJ. Entry was similar with both known alleles of smCD4. These alternative coreceptors, particularly smCXCR6 and smGPR15, may support virus replication in SM that have restricted CCR5 expression as well as SM genetically lacking CCR5. Defining expression of these molecules on SM CD4 ؉ subsets may delineate distinct natural host target cell populations capable of supporting SIVsmm replication without CD4 ؉ T cell loss. HIV-1 infection of humans and simian immunodeficiency virus SIVmac infection of non-natural host rhesus macaques (RM) result in high viral loads, peripheral CD4 ϩ T cell loss, and progression to AIDS. In contrast, SIVsmm infection of natural host sooty mangabeys (SM) rarely leads to peripheral CD4 ϩ T cell loss or disease despite viral loads comparable to those measured in non-natural hosts. Identifying the mechanisms responsible for the different outcomes of infection in natural hosts compared with non-natural simian or recent human hosts has become a central focus of efforts to understand AIDS pathogenesis. Although many models of natural host infection exist, SIVsmm is unique because cross-species transmission of SIVsmm from SM to humans and RM gave rise to pathogenic HIV-2 and SIVmac, respectively (2, 28). Similarly, experimental transmission of SIVsmm from infected SM hosts results in AIDS in non-natural host RM (40). While the factors regulating pathogenic versus nonpathogenic outcomes of infection are complex and not fully understood (9), comparison of infected SM with RM recently revealed differential targeting of CD4 ϩ T cell subsets (45). Thus, an understanding of SIVsmm cellular tropism may identify cells in natural host SM that maintain viral replication without leading to CD4 ϩ T cell depletion or AIDS.Classically, SIVsmm was thought to exclus...

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Section: Discussioncontrasting

confidence: 46%

Cloning and Analysis of Sooty Mangabey Alternative Coreceptors That Support Simian Immunodeficiency Virus SIVsmm Entry Independently of CCR5

Elliott

Riddick

Francella

et al. 2012

J Virol

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“…An important common feature of SIV infection in natural hosts is that these animals consistently show levels of immune activation that are significantly lower than those observed in HIV-infected humans or SIV-infected RMs (13,14,(16)(17)(18)(19)(20)(32)(33)(34). In SMs, perhaps the most well-characterized model of natural SIV hosts, it was shown that chronic SIV infection is associated with (a) low levels of CD4 + and CD8 + T cell activation and proliferation in both peripheral blood and lymph nodes (14,(16)(17)(18); (b) no signs of increased levels of T cell apoptosis either in vivo or in vitro (17,(35)(36); (c) absence of the cell-cycle dysregulation associated with pathogenic HIV/SIV infections (37-39); and (d) preserved function of the T cell regenerative compartment, i.e., bone marrow, thymus, and lymph nodes (17,40).…”

Section: Natural Siv Infections Are Characterized By Low Immune Activmentioning

confidence: 99%

“…Figure 1 summarizes the key differences and similarities between nonpathogenic SIV infection of natural hosts and LTNPs. In a recent survey of 110 naturally SIV-infected SMs housed at the Yerkes National Primate Research Center, we found a mean viral load of 170,000 ± 205,000 copies/ml of plasma and a mean CD4 + T cell count of 1,067 ± 589 cells/mm 3 (19,20). This typical phenotype of natural SIV hosts - high CD4 + T cell counts despite high viral loads - is very different from the observation that in both HIV-infected individuals and experimentally SIVmac-infected RMs, high levels of virus replication predict faster disease progression (21)(22)(23).…”

Section: Basic Features Of Natural Siv Infectionmentioning

confidence: 99%

Understanding the benign nature of SIV infection in natural hosts

et al. 2007

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In striking contrast to HIV infection, natural SIV infection of African nonhuman primates is asymptomatic and usually does not induce significant CD4 + T cell depletion despite high levels of virus replication. Recently, significant progress has been made in understanding the mechanisms underlying the remarkable difference in infection outcome between natural and nonnatural HIV/ SIV hosts. These advances include the identification of limited immune activation as a key factor protecting natural SIV hosts from AIDS and the discovery of low CC chemokine receptor 5 expression on CD4 + T cells as a specific and consistent immunologic feature in these animals. Further elucidation of the pathways by which the differences in immune activation between natural and nonnatural hosts are manifest holds promise for the design of novel therapeutic approaches to HIV infection.Nonstandard abbreviations used: AGM, African green monkey; CCR5, CC chemokine receptor 5; CXCR4, CXC chemokine receptor 4; LTNP, long-term nonprogressor; MALT, mucosa-associated lymphoid tissue; NHP, nonhuman primate; RM, rhesus macaque; SM, sooty mangabey.

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“…It has been noted that the genetic diversity of naturally circulating SIVsmm strains is roughly comparable to the diversity of the HIV-1 M group (1), and the predictive utility of SIV heterologous-challenge models rests in part on this observation. However, SIVsmm in sooty mangabeys represents a far more ancient lineage than HIV-1 in humans: the global diversity of the current HIV-1 epidemic harks back to a common ancestor about a century ago (43,89), while SIVsmm origins in sooty mangabey go back many millennia (90).…”

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confidence: 99%

Distinct Evolutionary Pressures Underlie Diversity in Simian Immunodeficiency Virus and Human Immunodeficiency Virus Lineages

Fischer

Apetrei

Santiago

et al. 2012

J Virol

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iSimian immunodeficiency virus (SIV) infection of rhesus macaques causes immune depletion and disease closely resembling human AIDS and is well recognized as the most relevant animal model for the human disease. Experimental investigations of viral pathogenesis and vaccine protection primarily involve a limited set of related viruses originating in sooty mangabeys (SIVsmm). The diversity of human immunodeficiency virus type 1 (HIV-1) has evolved in humans in about a century; in contrast, SIV isolates used in the macaque model evolved in sooty mangabeys over millennia. To investigate the possible consequences of such different evolutionary histories for selection pressures and observed diversity in SIVsmm and HIV-1, we isolated, sequenced, and analyzed 20 independent isolates of SIVsmm, including representatives of 7 distinct clades of viruses isolated from natural infection. We found SIVsmm diversity to be lower overall than HIV-1 M group diversity. Reduced positive selection (i.e., less diversifying evolution) was evident in extended regions of SIVsmm proteins, most notably in Gag p27 and Env gp120. In addition, the relative diversities of proteins in the two lineages were distinct: SIVsmm Env and Gag were much less diverse than their HIV-1 counterparts. This may be explained by lower SIV-directed immune activity in mangabeys relative to HIV-1-directed immunity in humans. These findings add an additional layer of complexity to the interpretation and, potentially, to the predictive utility of the SIV/macaque model, and they highlight the unique features of human and simian lentiviral evolution that inform studies of pathogenesis and strategies for AIDS vaccine design.

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Virus Subtype-Specific Features of Natural Simian Immunodeficiency Virus SIV _smm Infection in Sooty Mangabeys

Cited by 64 publications

References 65 publications

Cloning and Analysis of Sooty Mangabey Alternative Coreceptors That Support Simian Immunodeficiency Virus SIVsmm Entry Independently of CCR5

Cloning and Analysis of Sooty Mangabey Alternative Coreceptors That Support Simian Immunodeficiency Virus SIVsmm Entry Independently of CCR5

Understanding the benign nature of SIV infection in natural hosts

Distinct Evolutionary Pressures Underlie Diversity in Simian Immunodeficiency Virus and Human Immunodeficiency Virus Lineages

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Virus Subtype-Specific Features of Natural Simian Immunodeficiency Virus SIV smm Infection in Sooty Mangabeys

Cited by 64 publications

References 65 publications

Cloning and Analysis of Sooty Mangabey Alternative Coreceptors That Support Simian Immunodeficiency Virus SIVsmm Entry Independently of CCR5

Cloning and Analysis of Sooty Mangabey Alternative Coreceptors That Support Simian Immunodeficiency Virus SIVsmm Entry Independently of CCR5

Understanding the benign nature of SIV infection in natural hosts

Distinct Evolutionary Pressures Underlie Diversity in Simian Immunodeficiency Virus and Human Immunodeficiency Virus Lineages

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Product

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Virus Subtype-Specific Features of Natural Simian Immunodeficiency Virus SIV _smm Infection in Sooty Mangabeys