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

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.

The HIV-1 transmission bottleneck

“…Binding of the gp120 to the α4β7 integrin is not an essential requirement as is the binding to CD4 receptor or the CCR5 co-receptor but it is thought to be important only in the early stages of HIV-1 infection [171]. In fact, is has recently been shown in an acute infection cohort that the interaction with α4β7 varied between isolates and within individuals over time [177]. Nevertheless, HIV-1 target cells with high concentration of α4β7 has been shown to be more susceptible to HIV-1 infection, a factor that may also be attributable to the high levels of CCR5 found in these cells as well [178].…”

“…A recent study has shown that challenging macaques intravenously with anti α4β7 antibodies protects them from a repeated dose challenge with SIV mac251 infection due to their GALT being protected from infection [179–181]. In sum, α4β7 is used as an attachment factor that lowers the entropic barrier for binding of HIV-1 to CD4 and CCR5 which overall gives a selective advantage to the virus during the early stages of infection [177]. Some in vitro studies have failed to confirm the contribution of this integrin in HIV-1 infection [98, 163, 182, 183].…”

Select gp120 V2 domain specific antibodies derived from HIV and SIV infection and vaccination inhibit gp120 binding to α4β7

“…However, our findings raise the possibility that there exists a link between the gut-tropic aspect of HIV infection and this physical interaction. It is possible that α 4 β 7 functions simply as an attachment factor [ 18 ]. However, gp120 binding to α 4 β 7 , like mucosal addressin cellular adhesion molecule (MAdCAM) transduces signals to primary CD4 + T cells, suggesting that such signals may be relevant to infection in vivo [ 9 , 17 , 19 ].…”

Heterosexual Transmission of Subtype C HIV-1 Selects Consensus-Like Variants without Increased Replicative Capacity or Interferon-α Resistance

“…A number of prior studies have identified distinctive properties of TF variants [ 4 , 7 – 19 ], particularly in analyses of the TF viral envelope (Env) glycoprotein. Reported characteristics of TF virus Envs include a selection for CCR5-tropism [ 2 , 20 ], a predominance of shorter and less glycosylated Env proteins [ 1 , 11 , 15 , 18 , 19 ], a preference for binding α4β7 [ 10 , 21 ] and a selection for more ancestral variants [ 8 , 22 ]. Although these studies observed selection of viral traits, others found that acute and chronic variants had similar characteristics.…”