South African HIV-1 subtype C transmitted variants with a specific V2 motif show higher dependence on alpha 4 beta 7 for replication

作者：Richardson Simone I; Gray Elin S; Mkhize Nonhlanhla N; Sheward Daniel J; Lambson Bronwen E; Wibmer Constantinos Kurt; Masson Lindi; Werner Lise; Garrett Nigel; Passmore Jo Ann S; Karim Quarraisha Abdool; Karim Salim S Abdool; Williamson Carolyn; Moore Penny L; Morris Lynn^*

来源：Retrovirology, 2015, 12(1): UNSP 54.

DOI：10.1186/s12977-015-0183-3

• HIV entry
• alpha 4 beta 7
• Tripeptide-binding motif
• Bacterial vaginosis
• Cytokines

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.

• 出版日期2015-6-24