CD4-Like Immunological Function by CD4 − T Cells in Multiple Natural Hosts of Simian Immunodeficiency Virus

Self Cite

Simian immunodeficiency virus (SIV) infection in African nonhuman primate (NHP) natural hosts is usuallynonpathogenic, despite high levels of virus replication. We have previously shown that chronic SIV infection in sooty mangabeys (SMs) and African green monkeys (AGMs) is associated with low levels of immune activation and bystander T cell apoptosis. To compare these features with those observed in another natural host, the mandrill (MND), we conducted a cross-sectional survey of the 23 SIV-infected and 25 uninfected MNDs from the only semifree colony of mandrills available worldwide. Viral loads (VLs) were determined and phenotypic and functional analysis of peripheral blood-and lymph node-derived lymphocytes was performed. We found that mandrills chronically infected with SIVmnd-1 or SIVmnd-2 have similar levels of viral replication, and we observed a trend toward lower CD4 ؉ T cell counts in chronically SIVmnd-2-infected MNDs than SIVmnd-1-infected MNDs. No correlation between CD4؉ T cell counts and VLs in SIV-infected MNDs could be established. Of note, the levels of T cell activation, proliferation, and apoptosis were comparable between SIVmnd-1-and SIVmnd-2-infected MNDs and to those observed in uninfected animals, with the only exception being an increase in tumor necrosis factor alpha-producing CD8 ؉ T cells in SIVmnd-2-infected MNDs. Overall, these findings recapitulate previous observations in SIV-infected SMs and AGMs and lend further evidence to the hypothesis that low levels of immune activation protect natural SIV hosts from disease progression.

mentioning

confidence: 99%

“…ϩ T cells from virusmediated killing (1,4,33,37,67). Regardless of their molecular mechanisms, these adaptations underlining the benign course of SIV infection in natural hosts most likely occurred over millennia (65).…”

mentioning

confidence: 99%

Immunovirological Analyses of Chronically Simian Immunodeficiency Virus SIVmnd-1- and SIVmnd-2-Infected Mandrills (Mandrillus sphinx)

Apetrei

Sumpter

Souquière

et al. 2011

Self Cite

“…The SM model of SIV infection is of keen interest given the ability of natural hosts to avoid disease despite robust viral replication. Although multiple mechanisms likely contribute to this resistance, including distinct immune activation patterns and CD4-negative T helper cell function (3,9,41,56,61), entry coreceptor use by immunodeficiency viruses defines viral target cell tropism and can be an important determinant of CD4 ϩ T cell loss. Acquisition of CXCR4 use by HIV-1 parallels rapid CD4 ϩ T cell decline as HIV-1 gains the ability to infect CXCR4-expressing naïve T cells (6,7,31).…”

Section: Discussionmentioning

confidence: 99%

“…Multiple complex and nonexclusive mechanisms are likely involved in protecting SM and other natural hosts both from CD4 ϩ T cell loss in most individuals and from disease in the few animals where CD4 ϩ T cell depletion does occur (3,8,9,41,45,56,57,61), Thus, both the target cells spared from infection and those supporting replication are critical to understanding the nature of infection and pathogenesis (26). Future studies are needed to define CXCR6 and GPR15 coreceptor expression patterns on SM CD4 ϩ cell subsets, the relationship between alternative coreceptor and CCR5 expression, and how alternative coreceptors are regulated.…”

Section: Discussionmentioning

confidence: 99%

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

Elliott

Riddick

Francella

et al. 2012

Self Cite

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...

“…For example, uninfected AGMs have intrinsically low levels of CD4 ϩ T cells (17,18), and furthermore, their helper cells downregulate CD4 expression as they enter the memory pool, thus protecting the central-memory CD4 ϩ T cells from virus-mediated killing (34,35).…”

mentioning

confidence: 99%

Factors Associated with Siman Immunodeficiency Virus Transmission in a Natural African Nonhuman Primate Host in the Wild

Jasinska

Feyertag

et al. 2014

Self Cite

African green monkeys (AGMs) are naturally infected with simian immunodeficiency virus (SIV) at high prevalence levels and do not progress to AIDS. Sexual transmission is the main transmission route in AGM, while mother-to-infant transmission (MTIT) is negligible. We investigated SIV transmission in wild AGMs to assess whether or not high SIV prevalence is due to differences in mucosal permissivity to SIV (i.e., whether the genetic bottleneck of viral transmission reported in humans and macaques is also observed in AGMs in the wild). We tested 121 sabaeus AGMs (Chlorocebus sabaeus) from the Gambia and found that 53 were SIV infected (44%). By combining serology and viral load quantitation, we identified 4 acutely infected AGMs, in which we assessed the diversity of the quasispecies by single-genome amplification (SGA) and documented that a single virus variant established the infections. We thus show that natural SIV transmission in the wild is associated with a genetic bottleneck similar to that described for mucosal human immunodeficiency virus (HIV) transmission in humans. Flow cytometry assessment of the immune cell populations did not identify major differences between infected and uninfected AGM. The expression of the SIV coreceptor CCR5 on CD4 ؉ T cells dramatically increased in adults, being higher in infected than in uninfected infant and juvenile AGMs. Thus, the limited SIV MTIT in natural hosts appears to be due to low target cell availability in newborns and infants, which supports HIV MTIT prevention strategies aimed at limiting the target cells at mucosal sites. Combined, (i) the extremely high prevalence in sexually active AGMs, (ii) the very efficient SIV transmission in the wild, and (iii) the existence of a fraction of multiparous females that remain uninfected in spite of massive exposure to SIV identify wild AGMs as an acceptable model of exposed, uninfected individuals. IMPORTANCEWe report an extensive analysis of the natural history of SIVagm infection in its sabaeus monkey host, the African green monkey species endemic to West Africa. Virtually no study has investigated the natural history of SIV infection in the wild. The novelty of our approach is that we report for the first time that SIV infection has no discernible impact on the major immune cell populations in natural hosts, thus confirming the nonpathogenic nature of SIV infection in the wild. We also focused on the correlates of SIV transmission, and we report, also for the first time, that SIV transmission in the wild is characterized by a major genetic bottleneck, similar to that described for HIV-1 transmission in humans. Finally, we report here that the restriction of target cell availability is a major correlate of the lack of SIV transmission to the offspring in natural hosts of SIVs.