Research ArticleHIV

Integrin α4β7 expression on peripheral blood CD4+ T cells predicts HIV acquisition and disease progression outcomes

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Science Translational Medicine  24 Jan 2018:
Vol. 10, Issue 425, eaam6354
DOI: 10.1126/scitranslmed.aam6354

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Indicative integrins in HIV

The gut is thought to be a major viral reservoir in HIV infection, and studies in nonhuman primates suggest that targeting the α4β7 integrin on T cells may be a viable therapy. Sivro et al. now extend these findings to humans by examining HIV acquisition in multiple African cohorts. Higher frequencies of α4β7+ circulating CD4+ T cells before infection were associated with increased HIV acquisition, viral load at set point, and more rapid CD4+ T cell decline. These exciting data confirm that integrin targeting could help reduce the spread of HIV.

Abstract

The gastrointestinal (GI) mucosa is central to HIV pathogenesis, and the integrin α4β7 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 α4β7 blockade provides prophylactic and therapeutic benefits. We show that pre-HIV infection frequencies of α4β7+ 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 α4β7 binding. In addition, pre-HIV α4β7+ 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 α4β7+ 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 α4β7 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 α4β7 expression and HIV clinical outcomes in humans, in line with observations made in NHPs. Given the availability of a clinically approved anti-α4β7 monoclonal antibody for treatment of inflammatory bowel disease, these data support further evaluation of targeting α4β7 integrin as a clinical intervention during HIV infection.

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