With over 30 million HIV-1 infected individuals worldwide, and a rate of 4 new infections for every infected person who can receive anti-retroviral therapy (ART), there is still a critical need for developing and deploying preventive measures, including microbicides and prophylactic vaccines. However, the recent failure of a CTL- inducing adenovirus-based vaccine in human trials highlights our lack of understanding of what constitutes a protective immunity against this rapidly evolving virus, and how humans can effectively suppress ongoing virus replication. Understanding the interplay between the host immune response and the virus in natural infection is essential to designing novel strategies for circumventing viral immune escape and promoting endurable immunity. The major goal of this multi-investigator application is to define in detail the role that the innate and adaptive cellular immune systems play in modulating the process of HIV-1 transmission and viral control. This will be based on a comprehensive analyses of informative, initially HIV-1 discordant couples enrolled in Lusaka and Ndola, Zambia. By evaluating transmitted and non-transmitting couples with quarterly follow-up visits, our investigation will pursue two main goals. First, we will determine whether cellular immune responses influence heterosexual HIV-1 transmission through three related mechanisms: a) accumulation in the chronically infected index partners of CTL-induced viral mutations with fitness costs, b) the CTL response to conserved or un- mutated viral epitopes in exposed and uninfected partners among HLA-I discordant couples (compared to those that share HLA-I alleles), c) involvement of natural killer (NK) cell function in transmitting and non- transmitting couples . Second, we will assess the role that cellular immune responses can play in modifying control of early HIV-1 infection in seroconverters with known (epidemiologically-linked) virus donors. This work will focus on pathways and kinetics of CTL escape and reversion of both conventional and cryptic epitopes (epitopes encoded by alternate reading frames) across the viral proteome. The importance of NK and T-helper cell to the control of early HIV-1 containment will be tested as well. Collectively, these comprehensive and multidisciplinary studies will provide critical basic information about HIV- 1 immunopathogenesis at the time of and shortly after transmission. A clear understanding of innate and adaptive cellular immune responses to HIV-1 infection will benefit the ultimate goal of developing preventive tools that can reduce the further spread of HIV-1 infection.

Public Health Relevance

Understanding how HIV-1 interacts with the host immune system in order to escape its inhibitory effects during acute and early infection is critical if we are to devise preventive approaches to reduce the epidemic. The goals of this proposal address this problem directly by characterizing the impact of both the innate and adaptive cellular responses on transmission and acute/early infection. A clear understanding of this virus-host interplay will benefit the ultimate goal of developing preventive tools that can reduce the further spread of HIV- 1 infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI064060-10
Application #
8641300
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Sharma, Opendra K
Project Start
2005-02-15
Project End
2015-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Emory University
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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Monaco, Daniela C; Ende, Zachary; Hunter, Eric (2017) Virus-Host Gene Interactions Define HIV-1 Disease Progression. Curr Top Microbiol Immunol 407:31-63
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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; 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
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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
Du, Victor Y; Bansal, Anju; Carlson, Jonathan et al. (2016) HIV-1-Specific CD8 T Cells Exhibit Limited Cross-Reactivity during Acute Infection. J Immunol 196:3276-86
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
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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