Integrin α ₄ β 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 αβ 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 αβ blockade provides prophylactic and therapeutic benefits. We show that pre-HIV infection frequencies of αβ 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 αβ binding. In addition, pre-HIV αβ 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 αβ 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 αβ 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 αβ expression and HIV clinical outcomes in humans, in line with observations made in NHPs. Given the availability of a clinically approved anti-αβ monoclonal antibody for treatment of inflammatory bowel disease, these data support further evaluation of targeting αβ integrin as a clinical intervention during HIV infection.

Live attenuated varicella-zoster virus vaccine does not induce HIV target cell activation

“…It is important to highlight that we were powered to detect increases or decreases equal to or greater than the ones shown in Supplemental Table 1, and it is possible that by using a larger sample size, one may detect smaller changes that were imperceptible here. Enhanced expression of α 4 β 7 integrin, a mucosal homing marker, has also been shown to contribute to susceptibility to HIV infection and to worsen HIV clinical prognosis (54). Further supporting a role for the integrin, α 4 β 7 blockade with a monoclonal antibody was recently shown to reduce HIV susceptibility and suppress viral load in NHPs (55,56).…”

Anti-α4β7 therapy targets lymphoid aggregates in the gastrointestinal tract of HIV-1 infected individuals

“…A growing body of evidence has demonstrated that α4β7 + CD4 + T cells represent an early target for HIV-1 (18,19,21). Accordingly, NHP studies utilizing an anti-α4β7 mAb, that is a close analogue of VDZ, either prior to infection, or in the context of SIV infected animals receiving cART, have yielded promising and provocative results (24,25).…”

“…Multiple lines of evidence demonstrate that α4β7-expressing cells represent early targets for the virus (16)(17)(18)(19)(20). This was highlighted in a recent report demonstrating that pre-infection frequencies of α4β7 on circulating CD4 + T cells may predict the risk of HIV-1 acquisition and disease progression independent of other T cell phenotypes and genital inflammation in a large cohort of at-risk South African women (21). Supporting this finding, STDs that have been linked with increased risk of HIV-1 acquisition, increase the frequency of α4β7 + CD4 + memory T cells in both the mucosa and blood (22,23).…”

Current Status of Latency Reversing Agents Facing the Heterogeneity of HIV-1 Cellular and Tissue Reservoirs

“…The integrin α4β7 has been shown on a T cell subset that is highly susceptible to HIV-1 infection (Cicala et al, 2009;Sivro et al, 2018). Moreover, the integrin α4β1 was shown to be expressed by more than 70% of infected cells both in untreated and ART-suppressed individuals (Pardons et al, 2019).…”