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.

Summary The VH1-2 restricted VRC01-class of antibodies targeting the HIV envelope CD4 binding site are a major focus of HIV vaccine strategies. However, a detailed analysis of VRC01-class antibody development has been limited by the rare nature of these responses during natural infection and the lack of longitudinal sampling of such responses. To inform vaccine strategies, we mapped the development of a VRC01-class antibody lineage (PCIN63) in the subtype C infected IAVI Protocol C neutralizer PC063. PCIN63 monoclonal antibodies had the hallmark VRC01-class features and demonstrated neutralization breadth similar to the prototype VRC01 antibody, but were 2- to 3-fold less mutated. Maturation occurred rapidly within ∼24 months of emergence of the lineage and somatic hypermutations accumulated at key contact residues. This longitudinal study of broadly neutralizing VRC01-class antibody lineage reveals early binding to the N276-glycan during affinity maturation, which may have implications for vaccine design.

Although fishing communities (FCs) in Uganda are disproportionately affected by HIV-1 relative to the general population (GP), the transmission dynamics are not completely understood. We earlier found most HIV-1 transmissions to occur within FCs of Lake Victoria. Here, we test the hypothesis that HIV-1 transmission in FCs is isolated from networks in the GP. We used phylogeography to reconstruct the geospatial viral migration patterns in 8 FCs and 2 GP cohorts and a Bayesian phylogenetic inference in BEAST v1.8.4 to analyse the temporal dynamics of HIV-1 transmission. Subtype A1 (pol region) was most prevalent in the FCs (115, 45.1%) and GP (177, 50.4%). More recent HIV transmission pairs from FCs were found at a genetic distance (GD) <1.5% than in the GP (Fisher’s exact test, p = 0.001). The mean time depth for pairs was shorter in FCs (5 months) than in the GP (4 years). Phylogeographic analysis showed strong support for viral migration from the GP to FCs without evidence of substantial viral dissemination to the GP. This suggests that FCs are a sink for, not a source of, virus strains from the GP. Targeted interventions in FCs should be extended to include the neighbouring GP for effective epidemic control.

Investment in SARS-CoV-2 sequencing in Africa over the past year has led to a major increase in the number of sequences generated, now exceeding 100,000 genomes, used to track the pandemic on the continent. Our results show an increase in the number of African countries able to sequence domestically, and highlight that local sequencing enables faster turnaround time and more regular routine surveillance. Despite limitations of low testing proportions, findings from this genomic surveillance study underscore the heterogeneous nature of the pandemic and shed light on the distinct dispersal dynamics of Variants of Concern, particularly Alpha, Beta, Delta, and Omicron, on the continent. Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve, while the continent faces many emerging and re-emerging infectious disease threats. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century.