South African HIV-1 subtype C transmitted variants with a specific V2 motif show higher dependence on α4β7 for replication

Background: The integrin alpha 4 beta 7 mediates the trafficking of immune cells to the gut associated lymphoid tissue (GALT) and is an attachment factor for the HIV gp120 envelope glycoprotein. We developed a viral replication inhibition assay to more clearly evaluate the role of alpha 4 beta 7 in HIV infection and the contribution of viral and host factors. Results: Replication of 60 HIV-1 subtype C viruses collected over time from 11 individuals in the CAPRISA cohort were partially inhibited by antibodies targeting alpha 4 beta 7. However, dependence on alpha 4 beta 7 for replication varied substantially among viral isolates from different individuals as well as over time in some individuals. Among 8 transmitted/founder (T/F) viruses, alpha 4 beta 7 reactivity was highest for viruses having P/SDI/V tri-peptide binding motifs. Mutation of T/F viruses that had LDI/L motifs to P/SDI/V resulted in greater alpha 4 beta 7 reactivity, whereas mutating P/SDI/V to LDI/L motifs was associated with reduced alpha 4 beta 7 binding. P/SDI/V motifs were more common among South African HIV subtype C viruses (35%) compared to subtype C viruses from other regions of Africa (<8%) and to other subtypes, due in part to a founder effect. In addition, individuals with bacterial vaginosis (BV) and who had higher concentrations of IL-7, IL-8 and IL-1 alpha in the genital tract had T/F viruses with higher alpha 4 beta 7 dependence for replication, suggesting that viruses with P/SDI/V motifs may be preferentially transmitted in the presence of BV in this population. Conclusions: Collectively, these data suggest a role for alpha 4 beta 7 in HIV infection that is influenced by both viral and host factors including the sequence of the alpha 4 beta 7 binding motif, the cytokine milieu and BV in the genital tract. The higher frequency of P/SDI/V sequences among South African HIV-1 subtype C viruses may have particular significance for the role of alpha 4 beta 7 in this geographical region.