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. (2016) Hormonal Contraceptive Use Among HIV-Positive Women and HIV Transmission Risk to Male Partners, Zambia, 1994-2012. J Infect Dis 214:1063-71|
|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|
|Carlson, Jonathan M; Du, Victor Y; Pfeifer, Nico et al. (2016) Impact of pre-adapted HIV transmission. Nat Med 22:606-13|
|MÃ³naco, 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|
|Yue, Ling; Pfafferott, Katja J; Baalwa, Joshua et al. (2015) Transmitted virus fitness and host T cell responses collectively define divergent infection outcomes in two HIV-1 recipients. PLoS Pathog 11:e1004565|
|Claiborne, Daniel T; Prince, Jessica L; Scully, Eileen et al. (2015) Replicative fitness of transmitted HIV-1 drives acute immune activation, proviral load in memory CD4+ T cells, and disease progression. Proc Natl Acad Sci U S A 112:E1480-9|
|Dilernia, Dario A; Chien, Jung-Ting; Monaco, Daniela C et al. (2015) Multiplexed highly-accurate DNA sequencing of closely-related HIV-1 variants using continuous long reads from single molecule, real-time sequencing. Nucleic Acids Res 43:e129|
|Karita, Etienne; Price, Matt A; Lakhi, Shabir et al. (2015) High Transmitter CD4+ T-Cell Count Shortly after the Time of Transmission in a Study of African Serodiscordant Couples. PLoS One 10:e0134438|
|Kamali, Anatoli; Price, Matt A; Lakhi, Shabir et al. (2015) Creating an African HIV clinical research and prevention trials network: HIV prevalence, incidence and transmission. PLoS One 10:e0116100|
|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-Î± Resistance. PLoS Pathog 11:e1005154|
Showing the most recent 10 out of 38 publications