SARS-CoV-2 Omicron (B.1.1.529) BA.4 and BA.5 sub-lineages, first detected in South Africa, have changes relative to Omicron BA.1 including substitutions in the spike receptor binding domain. Here we isolated live BA.4 and BA.5 viruses and measured BA.4/BA.5 neutralization elicited by BA.1 infection either in the absence or presence of previous vaccination as well as from vaccination without BA.1 infection. In BA.1-infected unvaccinated individuals, neutralization relative to BA.1 declines 7.6-fold for BA.4 and 7.5-fold for BA.5. In vaccinated individuals with subsequent BA.1 infection, neutralization relative to BA.1 decreases 3.2-fold for BA.4 and 2.6-fold for BA.5. The fold-drop versus ancestral virus neutralization in this group is 4.0-fold for BA.1, 12.9-fold for BA.4, and 10.3-fold for BA.5. In contrast, BA.4/BA.5 escape is similar to BA.1 in the absence of BA.1 elicited immunity: fold-drop relative to ancestral virus neutralization is 19.8-fold for BA.1, 19.6-fold for BA.4, and 20.9-fold for BA.5. These results show considerable escape of BA.4/BA.5 from BA.1 elicited immunity which is moderated with vaccination and may indicate that BA.4/BA.5 may have the strongest selective advantage in evading neutralization relative to BA.1 in unvaccinated, BA.1 infected individuals.

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.

Several clinical trials have demonstrated that antiretroviral (ARV) drugs, taken as pre-exposure prophylaxis (PrEP), can prevent HIV infection1, with the magnitude of protection ranging from -49 to 86%2–11. While these divergent outcomes are thought to be due primarily to product adherence12, biological factors likely contribute13. Despite selective recruitment of higher risk participants for prevention trials, HIV risk is heterogeneous, even within higher risk groups14–16. To determine whether this heterogeneity could influence PrEP outcomes, we undertook a post-hoc prospective analysis of the CAPRISA 004 tenofovir 1% gel trial (n=774), one of the first trials to demonstrate protection against HIV infection. Concentrations of nine pro-inflammatory cytokines were measured in cervicovaginal lavages at >2,000 visits, and a graduated cytokine score was used to define genital inflammation. In women without genital inflammation, tenofovir was 57% protective against HIV (95% CI: 7 to 80%), compared to 3% (95% CI: −104 to 54%) if genital inflammation was present. Among high gel adherers, tenofovir protection was 75% (95% CI: 25 to 92%) in women without inflammation compared to −10% (95% CI: −184 to 57%) in women with inflammation. Host immune predictors of HIV risk may modify the effectiveness of HIV prevention tools; reducing genital inflammation in women may augment HIV prevention efforts.