Heterosexual transmission of HIV-1 remains the dominant mechanism by which the epidemic is sustained worldwide and increasingly is the route by which the virus is spreading within the US. It is now well established that in a majority of transmissions, infection is initiated by a single genetic variant, the transmitted founder (TF) virus, from the transmitting partner quasispecies. This severe severe genetic bottleneck, in which one or a limited number of variants from the diverse population present in the transmitting (donor) partner establish productive infection in the previously uninfected partner is the result of both stochastic and selective processes. Although we and others have shown that selection for less evolved (more ancestral) variants present in the donor?s viral quasispecies are favored during selection, the biological traits that define this enhanced transmissibility remained to be fully elucidated. In this renewal application, we are proposing 3 Specific Aims that combine cohort-level viral genetics analyses, in vitro phenotypic characterization, as well as an in vivo model for HIV-1 transmission, to define the viral properties that are advantageous during transmission. These approaches together have the potential to provide more definitive information on whether there are biological phenotypes of HIV-1 that are linked to transmission and could be targeted for intervention. Specifically we will: 1. Define specific virologic traits that correlate with the selection of more consensus-like viruses through a broad analysis of subtype A and C transmission pairs, coupled with novel assay methodologies. 2. Characterize the nature, impact and extent of selection bias across genomic regions and subtypes using a novel PacBio sequencing approach to define the donor quasispecies and the TF virus. 3. Determine, using humanized BLT mice, whether preferential transmission of TF viruses over donor- matched NT viruses occurs in this model and reveals viral and host determinants of transmission. A knowledge gap remains in our understanding of the genetic bottleneck associated with HIV-1 transmission. The experiments proposed will narrow this gap by conducting a thorough interrogation of the biological characteristics of the transmitted founder virus that are linked to its preferential transmission, using an expanded panel of transmission pairs from two African cohorts and novel technologies that have not been applied in this setting. Such traits, if defined, could provide new avenues for specifically targeting prevention approaches to the viruses most likely to initiate new infections.

Public Health Relevance

Heterosexual transmission of HIV-1 remains the dominant mechanism by which the epidemic is sustained worldwide and increasingly is the route by which the virus is spreading within the US. We propose experiments that will allow a definition of the biological characteristics of the transmitted founder virus that are linked to its preferential transmission. Such traits, if defined, could provide avenues for specifically targeting prevention approaches to the viruses most likely to initiate new infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI051231-19
Application #
9894710
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Refsland, Eric William
Project Start
2002-03-15
Project End
2023-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
19
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Emory University
Department
Pathology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Connolly, Sarah; Wall, Kristin M; Tang, Jianming et al. (2018) Fc-gamma receptor IIA and IIIA variants in two African cohorts: Lack of consistent impact on heterosexual HIV acquisition, viral control, and disease progression. Virology 525:132-142
Wall, Kristin M; Inambao, Mubiana; Kilembe, William et al. (2018) HIV testing and counselling couples together for affordable HIV prevention in Africa. Int J Epidemiol :
Haddad, Lisa B; Wall, Kristin M; Kilembe, William et al. (2018) Bacterial vaginosis modifies the association between hormonal contraception and HIV acquisition. AIDS 32:595-604
Joseph Davey, Dvora Leah; Wall, Kristin M; Kilembe, William et al. (2018) Difficult decisions: Evaluating individual and couple-level fertility intentions and HIV acquisition among HIV serodiscordant couples in Zambia. PLoS One 13:e0189869
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
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
Monaco, Daniela C; Ende, Zachary; Hunter, Eric (2017) Virus-Host Gene Interactions Define HIV-1 Disease Progression. Curr Top Microbiol Immunol 407:31-63
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
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
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

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