Although substantial progress has been made on understanding the mechanism of HIV-1 entry into cells, much less is known about the process of virus transmission in vivo. What structural and functional properties of the viral Env protein differentiate the transmitted virus from other variants and facilitate transmission across mucosal surfaces? In this application, we propose to characterize genetically and biologically HIV-1 virus populations isolated from both the donor and recipient immediately following a transmission event in a unique cohort of discordant couples in Zambia. These studies will provide a unique opportunity to investigate the virologic determinants of heterosexual transmission specified by the variable regions of gp120 in biologically relevant viral envelope genes using samples from a large, well-characterized discordant couple cohort that represents the predominant subtype (C) of HIV-1 worldwide. Our hypothesis is that the extreme genetic bottleneck that we have observed, which appears to select for viruses with more compact, neutralization sensitive envelope glycoproteins selects for a virus, which has biological properties that confer unique advantages for transmission and establishment of infection. Partners in concordantly positive couples, particularly those where both are infected by different viruses, are at high risk for superinfection and subsequent virus recombination. We hypothesize that risk of superinfection will depend on virus diversity, will be enhanced by acute infection in one partner, will reflect an inability to immunologically defend against the incoming virus, and that studies of these events will inform on the breadth of protection conferred by immunity to natural infection. For these studies we will follow prospectively, in both Rwanda and Zambia, both partners of couples where we have documented infection of the seronegative partner by a genetically unrelated virus from that in their spouse and monitor for superinfection. Specifically we will: 1. Determine which biological properties of subtype C newly transmitted variants could facilitate establishment of infection in a new host and correlate these with structural features of Env that characterize these isolates, 2. Determine whether a genetic bottleneck occurs in the genital compartment of subtype C infected donor partners or if there is a biological restriction of the transmitted virus population in the genital compartment of the recipients, and 3. Determine the frequency, kinetics and the virologic and immunologic ramifications of HIV superinfection in both partners following acute/early infection. The results of the proposed studies, which are aimed at characterizing the biological properties of newly infecting HIV-1, the origin of the genetic bottleneck observed in acutely infected individuals, and the details and consequences of HIV-1 superinfection, will enhance our understanding of the heterosexual transmission process and will yield novel information that is critical to the design and testing of globally effective vaccine candidates.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Method to Extend Research in Time (MERIT) Award (R37)
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AIDS Molecular and Cellular Biology Study Section (AMCB)
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Sharma, Opendra K
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Emory University
Schools of Medicine
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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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