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Integrin ?4?7 expression on peripheral blood CD4+ T cells predicts HIV acquisition and disease progression outcomes.

ABSTRACT: The gastrointestinal (GI) mucosa is central to HIV pathogenesis, and the integrin ?4?7 promotes the homing of immune cells to this site, including those that serve as viral targets. Data from simian immunodeficiency virus (SIV) animal models suggest that ?4?7 blockade provides prophylactic and therapeutic benefits. We show that pre-HIV infection frequencies of ?4?7+ peripheral blood CD4+ T cells, independent of other T cell phenotypes and genital inflammation, were associated with increased rates of HIV acquisition in South African women. A similar acquisition effect was observed in a Kenyan cohort and in nonhuman primates (NHPs) after intravaginal SIV challenge. This association was stronger when infection was caused by HIV strains containing V2 envelope motifs with a preference for ?4?7 binding. In addition, pre-HIV ?4?7+ CD4+ T cells predicted a higher set-point viral load and a greater than twofold increased rate of CD4+ T cell decline. These results were confirmed in SIV-infected NHPs. Increased frequencies of pre-HIV ?4?7+ CD4+ T cells were also associated with higher postinfection expression of lipopolysaccharide binding protein, a microbial translocation marker, suggestive of more extensive gut damage. CD4+ T cells expressing ?4?7 were rapidly depleted very early in HIV infection, particularly from the GI mucosa, and were not restored by early antiretroviral therapy. This study provides a link between ?4?7 expression and HIV clinical outcomes in humans, in line with observations made in NHPs. Given the availability of a clinically approved anti-?4?7 monoclonal antibody for treatment of inflammatory bowel disease, these data support further evaluation of targeting ?4?7 integrin as a clinical intervention during HIV infection.

SUBMITTER: Sivro A

PROVIDER: S-EPMC6820005 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Project description:Chemokine receptors (CKRs), the primordial receptors for primate lentiviruses, are sufficient to mediate virus-cell fusion. Several different fusogenic CKRs and related receptors provide a broad potential host cell range, presumably advantageous for viral spread within a given infected individual, and across species. By contrast, the additional constraint of obligatory CD4 binding, just prior to CKR engagement, radically restricts potential host cells within an individual (or lymph node microenvironment), and might also limit xenotransmission, as CD4 sequences vary among primates. In spite of these potential drawbacks, CD4 dependent entry for SIV and HIV is the rule rather than the exception, and is generally thought to have evolved by selection for 1) stabilization of virus-cell surface interactions, and 2) conformational shielding of readily neutralized CKR binding epitopes. CD4 binding residues of SIV and HIV envelope are recessed, (relatively hidden from immune detection) and may exhibit a strong degree of automimicry, thus benefitting from self tolerance.Documented evolution, within individual macaques, of neutralization-resistant CD4-dependent SIV, derived from CD4-independent inocula, supports these ideas, but does not explain CD4's exclusive role as the penultimate receptor-even more striking, given the wide diversity of CKRs and other surface molecules that can serve as actual fusion receptors for SIV. We, therefore, explored the additional, non-exclusive, hypothesis that surface CD4 on leukocytes is a marker of a more favorable host cell environment, as compared to CD8, NK, or B cell surface markers.We demonstrate progressive in vitro evolution of two SIV strains to CD4-dependence (and CXCR4 tropism) in normal human PBMCs (hPBMCs). The two CD4-independent strains of SIV tested developed nearly complete CD4 dependence over several months of serial passage in hPBMCs, correlating with a limited number of non-synonymous env region mutations, some previously reported to be determinants of CD4-dependency. The initial ability of SIV stocks to grow to significant (albeit, relatively low) levels in CD4(-), CD14(-) cells was also lost with long term passage. Rapid emergence and subsequent prominence of G ? A and A ? G mutations within env regions associated with CD4 dependence was seen.Progressive acquisition of strict CD4 tropism, independent of immunoselection, supports the idea that surface CD4 identifies optimal host cells having intracellular environments most favorable to viral replication. The prominence of mutations involving G to A, or A to G, suggests that APOBEC 3 mediated infidelity may facilitate rapid switching of cell surface receptor usage within SIV swarms encountering fluctuating availability of optimal CD4+CKR+ targets. These observations of non-immune selection are compatible with, and may accelerate, simultaneous selection for previously described CD4-dependent neutralization resistance in vivo.

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Integrin ?4?7 expression on peripheral blood CD4+ T cells predicts HIV acquisition and disease progression outcomes.

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