Heterosexual transmission of HIV-1 remains the dominant mechanism by which the epidemic is sustained woridwide. In a majority of transmissions, infection is established by a single genetic variant (the transmitted founder, TF) from the quasispecies of the transmitting partner (TP), with evidence for reduced Env glycosylation relative to their chronic counterparts. This concept of selection of virus with traits that favor transmission has been supported by our recent studies of viruses in the genital tract (GT), but it remains to be determined what functional properties differentiate TF viruses from their transmitting partner counterparts We hypothesize that differences in TF virus proteins allow preferential infection of key cell types within the genital mucosa and through interactions with antigen presenting cells signal the influx of activated CD4 T cells that can home to gut tissues. In this context, we will generate and characterize full-length single HIV-1 TF virus genomes and genomes amplified from TP bloodand GT in 20 Rwandan and Zambian transmission pairs;determine their abilities to productively infect vaginal and cervical tissue explants, determine whether different cells are infected by donor and recipient viruses, investigate their ability to interact with alpha-4, beta-7 molecules on mucosal T-cells and to induce the release of cytokines in antigen presenting cells capable of signaling trafficking of relevant activated T-cell populations. Newly infected partners in couples infected by different strains of HIV-1, are at high risk for superinfection and subsequent virus recombination. Based on preliminary data, we hypothesize that susceptibility to superinfection is related to low levels of neutralizing antibodies immediately prior to superinfection and that studies of superinfection will inform on the nature of protection required for an effective vaccine. We will therefore determine the frequency, kinetics and the virologic/immunologic ramifications of HIV superinfection in this cohort, as well as determine whether specific immunologic defects, such as low levels of protective antibody contribute to susceptibility to superinfection. The results of these studies will yield novel information that is critical to the design and testing of globally effective vaccine candidates.
The experimental approaches described in this proposal will enhance our understanding ofthe eariiest aspects of heterosexual transmission of HIV-1 and will yield novel information regarding natural immunity that is critical to the design and testing of globally effective HlV-1 vaccines.
|Wall, Kristin M; Kilembe, William; Vwalika, Bellington et al. (2017) Risk of heterosexual HIV transmission attributable to sexually transmitted infections and non-specific genital inflammation in Zambian discordant couples, 1994-2012. Int J Epidemiol 46:1593-1606|
|Joseph Davey, Dvora L; Wall, Kristin M; Kilembe, William et al. (2017) HIV Incidence and Predictors of HIV Acquisition From an Outside Partner in Serodiscordant Couples in Lusaka, Zambia. J Acquir Immune Defic Syndr 76:123-131|
|Joseph Davey, Dvora; Kilembe, William; Wall, Kristin M et al. (2017) Risky Sex and HIV Acquisition Among HIV Serodiscordant Couples in Zambia, 2002-2012: What Does Alcohol Have To Do With It? AIDS Behav 21:1892-1903|
|Mónaco, Daniela C; Dilernia, Dario A; Fiore-Gartland, Andrew et al. (2016) Balance between transmitted HLA preadapted and nonassociated polymorphisms is a major determinant of HIV-1 disease progression. J Exp Med 213:2049-63|
|Wall, Kristin M; Kilembe, William; Haddad, Lisa et al. (2016) Hormonal Contraception, Pregnancy, Breastfeeding, and Risk of HIV Disease Progression Among Zambian Women. J Acquir Immune Defic Syndr 71:345-52|
|Sutherland, Katherine A; Collier, Dami A; Claiborne, Daniel T et al. (2016) Wide variation in susceptibility of transmitted/founder HIV-1 subtype C Isolates to protease inhibitors and association with in vitro replication efficiency. Sci Rep 6:38153|
|Smith, S Abigail; Burton, Samantha L; Kilembe, William et al. (2016) Diversification in the HIV-1 Envelope Hyper-variable Domains V2, V4, and V5 and Higher Probability of Transmitted/Founder Envelope Glycosylation Favor the Development of Heterologous Neutralization Breadth. PLoS Pathog 12:e1005989|
|Wall, Kristin M; Kilembe, William; Vwalika, Bellington et al. (2016) Hormonal Contraceptive Use Among HIV-Positive Women and HIV Transmission Risk to Male Partners, Zambia, 1994-2012. J Infect Dis 214:1063-71|
|Carlson, Jonathan M; Du, Victor Y; Pfeifer, Nico et al. (2016) Impact of pre-adapted HIV transmission. Nat Med 22:606-13|
|Deymier, Martin J; Ende, Zachary; Fenton-May, Angharad E et al. (2015) Heterosexual Transmission of Subtype C HIV-1 Selects Consensus-Like Variants without Increased Replicative Capacity or Interferon-? Resistance. PLoS Pathog 11:e1005154|
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