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The frequency of ????(high) memory CD4? T cells correlates with susceptibility to rectal simian immunodeficiency virus infection.

ABSTRACT: BACKGROUND:Integrin ????(high) (????(high)) mediates the homing of CD4? T cells to gut-associated lymphoid tissues, which constitute a highly favorable environment for HIV expansion and dissemination. HIV and simian immunodeficiency virus (SIV) envelope proteins bind to and signal through ????(high) and during acute infection SIV preferentially infects ????(high) CD4? T cells. We postulated that the availability of these cells at the time of challenge could influence mucosal SIV transmission and acute viral load (VL). METHODS:We challenged 17 rhesus macaques with 3000 TCID50 of SIVmac239 rectally and followed the subsets of ????(high) T cells and dendritic cells (DCs) by flow cytometry in blood and tissues, before and after challenge. RESULTS:We found that the frequency of memory CD4? T cells that expressed high levels of ????(high) (????(high) memory CD4? T cells) in blood before challenge correlated strongly with susceptibility to infection and acute VL. Notably, not only at the time of challenge but also their frequency 3 weeks before challenge correlated with infection. This association extended to the rectal tissue as we observed a strong direct correlation between the frequency of ????(high) memory CD4? T cells in blood and rectum before and after challenge. The frequency of ?4?7 myeloid DCs and ????(high) CD80? DCs also correlated with infection and acute VL, whereas blood CCR5? and CD69? CD4? T cells could not be associated with infection. CONCLUSIONS:Our results suggest that animals with higher frequency of ????(high) CD4? T cells in circulation and in rectal tissue could be more susceptible to SIV rectal transmission.

SUBMITTER: Martinelli E

PROVIDER: S-EPMC3815485 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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The frequency of α₄β₇(high) memory CD4⁺ T cells correlates with susceptibility to rectal simian immunodeficiency virus infection.

Martinelli Elena E Veglia Filippo F Goode Diana D Guerra-Perez Natalia N Aravantinou Meropi M Arthos James J Piatak Michael M Lifson Jeffrey D JD Blanchard James J Gettie Agegnehu A Robbiani Melissa M

Journal of acquired immune deficiency syndromes (1999) 20131201 4

<h4>Background</h4>Integrin α₄β₇(high) (α₄β₇(high)) mediates the homing of CD4⁺ T cells to gut-associated lymphoid tissues, which constitute a highly favorable environment for HIV expansion and dissemination. HIV and simian immunodeficiency virus (SIV) envelope proteins bind to and signal through α₄β₇(high) and during acute infection SIV preferentially infects α₄β₇(high) CD4⁺ T cells. We postulated that the availability of these cells at the time of challenge could influence mucosal SIV transmis ...[more]

PMID: 23797688

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Project description:UnlabelledCD4 tropism is conserved among all primate lentiviruses and likely contributes to viral pathogenesis by targeting cells that are critical for adaptive antiviral immune responses. Although CD4-independent variants of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) have been described that can utilize the coreceptor CCR5 or CXCR4 in the absence of CD4, these viruses typically retain their CD4 binding sites and still can interact with CD4. We describe the derivation of a novel CD4-independent variant of pathogenic SIVmac239, termed iMac239, that was used to derive an infectious R5-tropic SIV lacking a CD4 binding site. Of the seven mutations that differentiate iMac239 from wild-type SIVmac239, a single change (D178G) in the V1/V2 region was sufficient to confer CD4 independence in cell-cell fusion assays, although other mutations were required for replication competence. Like other CD4-independent viruses, iMac239 was highly neutralization sensitive, although mutations were identified that could confer CD4-independent infection without increasing its neutralization sensitivity. Strikingly, iMac239 retained the ability to replicate in cell lines and primary cells even when its CD4 binding site had been ablated by deletion of a highly conserved aspartic acid at position 385, which, for HIV-1, plays a critical role in CD4 binding. iMac239, with and without the D385 deletion, exhibited an expanded host range in primary rhesus peripheral blood mononuclear cells that included CCR5(+) CD8(+) T cells. As the first non-CD4-tropic SIV, iMac239-ΔD385 will afford the opportunity to directly assess the in vivo role of CD4 targeting on pathogenesis and host immune responses.ImportanceCD4 tropism is an invariant feature of primate lentiviruses and likely plays a key role in pathogenesis by focusing viral infection onto cells that mediate adaptive immune responses and in protecting virions attached to cells from neutralizing antibodies. Although CD4-independent viruses are well described for HIV and SIV, these viruses characteristically retain their CD4 binding site and can engage CD4 if available. We derived a novel CD4-independent, CCR5-tropic variant of the pathogenic molecular clone SIVmac239, termed iMac239. The genetic determinants of iMac239's CD4 independence provide new insights into mechanisms that underlie this phenotype. This virus remained replication competent even after its CD4 binding site had been ablated by mutagenesis. As the first truly non-CD4-tropic SIV, lacking the capacity to interact with CD4, iMac239 will provide the unique opportunity to evaluate SIV pathogenesis and host immune responses in the absence of the immunomodulatory effects of CD4(+) T cell targeting and infection.

Dataset Information

The frequency of ????(high) memory CD4? T cells correlates with susceptibility to rectal simian immunodeficiency virus infection.

Publications

The frequency of α₄β₇(high) memory CD4⁺ T cells correlates with susceptibility to rectal simian immunodeficiency virus infection.

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