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Virus subtype-specific features of natural simian immunodeficiency virus SIVsmm infection in sooty mangabeys.

ABSTRACT: Simian immunodeficiency virus (SIV) SIV(smm) naturally infects sooty mangabeys (SMs) and is the source virus of pathogenic infections with human immunodeficiency virus type 2 (HIV-2) and SIV(mac) of humans and macaques, respectively. In previous studies we characterized SIV(smm) diversity in naturally SIV-infected SMs and identified nine different phylogenetic subtypes whose genetic distances are similar to those reported for the different HIV-1 group M subtypes. Here we report that, within the colony of SMs housed at the Yerkes National Primate Research Center, at least four SIV(smm) subtypes cocirculate, with the vast majority of animals infected with SIV(smm) subtype 1, 2, or 3, resulting in the emergence of occasional recombinant forms. While SIV(smm)-infected SMs show a typically nonpathogenic course of infection, we have observed that different SIV(smm) subtypes are in fact associated with specific immunologic features. Notably, while subtypes 1, 2, and 3 are associated with a very benign course of infection and preservation of normal CD4+ T-cell counts, three out of four SMs infected with subtype 5 show a significant depletion of CD4+ T cells. The fact that virus replication in SMs infected with subtype 5 is similar to that in SMs infected with other SIV(smm) subtypes suggests that the subtype 5-associated CD4+ T-cell depletion is unlikely to simply reflect higher levels of virus-mediated direct killing of CD4+ T-cells. Taken together, this systematic analysis of the subtype-specific features of SIV(smm) infection in natural SM hosts identifies subtype-specific differences in the pathogenicity of SIV(smm) infection.

SUBMITTER: Apetrei C

PROVIDER: S-EPMC1951324 | biostudies-literature | 2007 Aug

REPOSITORIES: biostudies-literature

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Virus subtype-specific features of natural simian immunodeficiency virus SIVsmm infection in sooty mangabeys.

Apetrei Cristian C Gautam Rajeev R Sumpter Beth B Carter Anders C AC Gaufin Thaidra T Staprans Silvija I SI Else James J Barnes Mary M Cao Robert R Garg Seema S Milush Jeffrey M JM Sodora Donald L DL Pandrea Ivona I Silvestri Guido G

Journal of virology 20070516 15

Simian immunodeficiency virus (SIV) SIV(smm) naturally infects sooty mangabeys (SMs) and is the source virus of pathogenic infections with human immunodeficiency virus type 2 (HIV-2) and SIV(mac) of humans and macaques, respectively. In previous studies we characterized SIV(smm) diversity in naturally SIV-infected SMs and identified nine different phylogenetic subtypes whose genetic distances are similar to those reported for the different HIV-1 group M subtypes. Here we report that, within the ...[more]

PMID: 17507488

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Project description:The extent of zoonotic infections in rural Sierra Leone, where both feral and pet sooty mangabeys harbor divergent members of the human immunodeficiency virus type 2 (HIV-2)-sooty mangabey simian immunodeficiency virus (SIVsm) family, was tested in blood samples collected from 9,309 human subjects in 1993. Using HIV-1- and HIV-2-specific enzyme immunoassays and confirmatory Western blot analysis to test for antibodies to SIVsm-related lentiviruses, we found only nine subjects (0.096%) who tested positive for HIV: seven tested positive for HIV-1 and two tested positive for HIV-2. Compared with other rural West African communities, Sierra Leone displayed the lowest seroprevalence (0.021%) of HIV-2 infection yet reported, much lower than the previously reported seroprevalence in SIVsm-infected feral and household pet sooty mangabeys. Heteroduplex analysis demonstrated that two of the newly found HIV-1 strains belonged to subtype A, the most common HIV-1 subtype in Africa, but this is the first report of subtype A in Sierra Leone. The two HIV-2-infected individuals harbored two distinct HIV-2 strains, designated 93SL1 and 93SL2. Phylogenetic analysis indicated that HIV-2 93SL1 is a member of HIV-2 subtype A, the first strain of this HIV-2 subtype found in Sierra Leone. In contrast, HIV-2 93SL2 belongs to none of the five previously characterized HIV-2 subtypes (A to E) but is a new subtype, herein designated F, having the most divergent transmembrane sequences yet reported for HIV-2. The fact that both of the two most divergent HIV-2 subtypes known, E and F, are rare and found as single occurrences in persons from Sierra Leone may be related to the fact that this small region of West Africa also contains free-living and household pet sooty mangabeys with highly divergent variants of SIVsm. This finding provides support for the hypotheses that new HIV-2 subtypes result from independent cross-species transmission of SIVsm to the human population and that these single-occurrence transmission events had not spread widely into the population by 1993.

Project description:In contrast to HIV infection in humans and SIV in macaques, SIV infection of natural hosts including sooty mangabeys (SM) is non-pathogenic despite robust virus replication. We identified a novel SM CCR5 allele containing a two base pair deletion (?2) encoding a truncated molecule that is not expressed on the cell surface and does not support SIV entry in vitro. The allele was present at a 26% frequency in a large SM colony, along with 3% for a CCR5?24 deletion allele that also abrogates surface expression. Overall, 8% of animals were homozygous for defective CCR5 alleles and 41% were heterozygous. The mutant allele was also present in wild SM in West Africa. CD8+ and CD4+ T cells displayed a gradient of CCR5 expression across genotype groups, which was highly significant for CD8+ cells. Remarkably, the prevalence of natural SIVsmm infection was not significantly different in animals lacking functional CCR5 compared to heterozygous and homozygous wild-type animals. Furthermore, animals lacking functional CCR5 had robust plasma viral loads, which were only modestly lower than wild-type animals. SIVsmm primary isolates infected both homozygous mutant and wild-type PBMC in a CCR5-independent manner in vitro, and Envs from both CCR5-null and wild-type infected animals used CXCR6, GPR15 and GPR1 in addition to CCR5 in transfected cells. These data clearly indicate that SIVsmm relies on CCR5-independent entry pathways in SM that are homozygous for defective CCR5 alleles and, while the extent of alternative coreceptor use in SM with CCR5 wild type alleles is uncertain, strongly suggest that SIVsmm tropism and host cell targeting in vivo is defined by the distribution and use of alternative entry pathways in addition to CCR5. SIVsmm entry through alternative pathways in vivo raises the possibility of novel CCR5-negative target cells that may be more expendable than CCR5+ cells and enable the virus to replicate efficiently without causing disease in the face of extremely restricted CCR5 expression seen in SM and several other natural host species.

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Project description:UnlabelledDepletion of CD4(+) central memory T (TCM) cells dictates the tempo of progression to AIDS in simian immunodeficiency virus (SIV)-infected rhesus macaques (RMs) both in the natural history of infection and in the context of vaccination. CD4(+) TCM cells of sooty mangabeys (SMs), a natural host for SIV in which infection is nonpathogenic, are less susceptible to SIV infection than CD4(+) TCM cells of RMs. Whether this relative protection from infection translates into increased stability of CD4(+) TCM cells in natural versus nonnatural hosts has not yet been determined. Here we compared, both cross-sectionally and longitudinally, the levels of CD4(+) TCM cells in a large cohort of SMs and RMs and the association between CD4(+) TCM levels and the main virologic and immunologic markers of disease progression. Consistent with their lower susceptibility to infection, CD4(+) TCM cells of SIV-infected SMs are lost with kinetics 20 times slower than those of SIV-infected RMs. Remarkably, the estimated length of time of SIV infection needed for CD4(+) TCM cells to fall to half of their initial levels is <16 months for RMs but >17 years for SMs. Furthermore, the fraction of proliferating CD4(+) TCM cells is significantly lower in SIV-infected SMs than in SIV-infected RMs, and the extent of CD4(+) TCM cell proliferation is associated positively with CD4(+) T cell levels in SIV-infected SMs but negatively with CD4(+) T cell levels in SIV-infected RMs. Collectively, these findings identify increased stability and maintenance of the prohomeostatic role of CD4(+) TCM cells as features distinguishing nonprogressive from progressive SIV infections and support the hypothesis of a direct mechanistic link between the loss of CD4(+) TCM cells and disease progression.ImportanceComparison of the immunologic effects of simian immunodeficiency virus (SIV) infection on rhesus macaques (RMs), a species characterized by progression to AIDS, and natural host sooty mangabeys (SMs), a species which remains AIDS free, has become a useful tool for identifying mechanisms of human immunodeficiency virus (HIV) disease progression. One such distinguishing feature is that CD4(+) central memory T (TCM) cells in SIV-infected SMs are less infected than the same cells in RMs. Here we investigated whether lower levels of infection in SMs translate into a better-preserved CD4(+) TCM compartment. We found that the CD4(+) TCM compartment is significantly more stable in SIV-infected SMs. Likely to compensate for this cell loss, we also found that CD4(+) TCM cells increase their level of proliferation upon SIV infection in RMs but not in SMs, which mechanistically supports their preferential infectivity. Our study provides new insights into the importance of long-term maintenance of CD4(+) TCM homeostasis during HIV/SIV infection.

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Dataset Information

Virus subtype-specific features of natural simian immunodeficiency virus SIVsmm infection in sooty mangabeys.

Publications

Virus subtype-specific features of natural simian immunodeficiency virus SIVsmm infection in sooty mangabeys.

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