Worldwide most HIV-1 infections are due to sexual transmission, however the precise source of HIV that contributes to mucosal transmission is poorly defined, in particular, whether the transmitted virus originate as cell-free or cell-associated viruses from the blood or the genital secretions of the infected individuals. Identifyin such information may help to design better and more targeted prevention efforts to block the establishment of infection. Multiple studies have shown that during sexual transmission HIV-1 viral diversity is significantly reduced and the newly transmitted HIV-1 variants that promotes establishment of infection could possibly be influenced by host and viral factors. Viral factors have been shown to increase transmission fitness of viruses and possibly favor early establishment of infection with the transmitting viruses having compact/shorter envelope hyper-variable loops and less potential N-linked glycosylation sites (PNGS), relative to quasispecies present in the donor at the time of transmission. Host factors may also be important and recent studies showed that integrin alpha4beta7 (?47), a gut-homing receptor present on the activated CD4+ T cells in mucosal tissues has a specific affinity and binds to the HIV-1 envelope gp120, that could play a critical role in the infection of CD4+ T cells. Thus, the host and viral factors could provide a selective advantage for the newly sexually transmitted virus in launching a productive infection, but this hypothesis has yet to be tested in transmission pairs. In this proposed study we hypothesize that female-to- male sexually transmitted HIV-1 variants are cell-associated from genital secretions and the early transmitted viruses have unique properties that are distinct, and these characteristics may be influenced by viral and host factors. We propose to identify the primary source of HIV-1 variants that get selected for sexual transmission by examining the early transmitted viruses and comparing whether they are more similar to cell- associated or cell-free variants of chronically infected source partner in blood o genital compartments in transmission pairs from prospective discordant couple cohort. Additionally, we will examine the genetic properties of early transmitted viruses, like the envelope length, number of PNGS and presence of binding region of ?47 integrin homing receptor and compare them to viral sequences from source partner as well as sequences from non-transmitters. Furthermore, we will examine if the early transmitted variants that have 'exposed' ?47 binding site on V2 loop are highly efficient in binding the ?47 receptor on CD4+ T cells compared to the viruses from chronically infected subjects by performing 'in-vitro' binding experiments.
This research will identify the primary source of heterosexually transmitted HIV-1 from chronically infected source partner and determine the characteristics of early transmitted viruses in the newly infected partner that favor establishment of infection in transmission pairs from a prospective discordant couple cohort. The findings of this study will be able to determine the primary source of sexually transmitted HIV-1 and characteristics of early transmitted viruses that may help design better targeted preventions efforts like vaccines and inhibitors to block establishment of sexually transmitted HIV-1 infections.