Abstract
BackgroundThe integrin α4β7 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 α4β7 in HIV infection and the contribution of viral and host factors.ResultsReplication of 60 HIV-1 subtype C viruses collected over time from 11 individuals in the CAPRISA cohort were partially inhibited by antibodies targeting α4β7. However, dependence on α4β7 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, α4β7 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 α4β7 reactivity, whereas mutating P/SDI/V to LDI/L motifs was associated with reduced α4β7 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-1α in the genital tract had T/F viruses with higher α4β7 dependence for replication, suggesting that viruses with P/SDI/V motifs may be preferentially transmitted in the presence of BV in this population.ConclusionsCollectively, these data suggest a role for α4β7 in HIV infection that is influenced by both viral and host factors including the sequence of the α4β7 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 α4β7 in this geographical region.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-015-0183-3) contains supplementary material, which is available to authorized users.
Highlights
The integrin α4β7 mediates the trafficking of immune cells to the gut associated lymphoid tissue (GALT) and is an attachment factor for the HIV gp120 envelope glycoprotein
Impact of host factors at transmission on α4β7 dependence for replication Since the role of α4β7 is likely to be most relevant at transmission, we focused on the 8 transmitted/ founder (T/F) viruses included in this study
The disproportionate distribution of P/SDI/V genotypes in the South African-based CAPRISA cohort may in part explain why this study has enabled us to more clearly define a role for α4β7 in HIV infection
Summary
The integrin α4β7 mediates the trafficking of immune cells to the gut associated lymphoid tissue (GALT) and is an attachment factor for the HIV gp120 envelope glycoprotein. The primary site of HIV replication following infection is the gut associated lymphoid tissue (GALT) [1, 2]. There appears to be significant variation in the levels of α4β7 reactivity among viruses from different individuals [3] This suggests that it is the contact residues in gp120 that influence α4β7 affinity. This is bolstered by data that showed differences in the sequence of the α4β7 tri-peptide motif were linked to the differential dissemination potential of distinct HIV-1 genetic forms in China [16]. Tassaneetrithep et al described a tri-peptide sequence just upstream of the α4β7 motif as a determinant of integrin binding [17], suggesting that additional viral properties play a role in reactivity with α4β7
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