Rare individuals appear naturally resistant to overt HIV-1 infection despite repeated sexual exposures. These persons, termed exposed seronegatives (ES) represent a unique population to evaluate mechanisms by which HIV-1 replication is either controlled or aborted. In late 1995 we initiated a cohort study of healthy HIV-1 seronegative persons, each reporting repeated unprotected sexual contact with their HIV-1-infected partner. Approximately one-third (13/36) have detectable HIV-1-specific CTL and 10 percent have low levels of HIV-1-specific lymphoproliferation (Goh). We discovered HIV-1 transcripts in very low copy numbers in the resting CD4+ T cell population of two ES with cytotoxic responses. These findings suggest that the HIV-specific T cell responses may exert an acquired immune defense against overt infection. In this proposal we intend to address this issue more rigorously in our existing cohort of 48 ES and 24 of their infected partners.
In Aim 1, we will determine longitudinally the quantity, phenotype and function of HIV-1-specific CD8+ T cells in ES using improved technology to detect antigen-specific CD8+ T cells IFN-gamma ELISpot and flow cytometric-based analyses). We hypothesize that the CD8+ T cell responses in ES will correlate with detectable HIV-1 in semen of the HIV+ sexual partner, the frequency of recent exposures to HIV-1, and/or the detection of latent virus in resting CD4+ T cells in ES.
In Aim 2, we will examine the HIV-1 epitope specificities, cytolytic and anti-viral activities of the antigen reactive CD8+ T cells in ES. We predict the specificities will cross react with the autologous latent virus (if found) and virus in semen from the infected partner, and be directed to conserved HIV-1 sequences.
In Aim 3, we will determine the specificity and phenotype of CD4+ T helper (Th) responses to HIV-1 antigens and assess DTH responses to an HIV-1 Gag protein. We predict that Th responses will be directed to conserved helper epitopes, exhibit the Th1 phenotype, and be associated with Gag-specific DTH responses. Our studies will provide new understanding of the factors that drive T cell immunity with HIV-1 exposure and shape the immune repertoire, and how these responses may be relevant to curtailing HIV-1 replication. These insights can be applied to vaccine design, to assess induction of immune responses by HIV vaccine candidates and to guide the definition of endpoints related to vaccine efficacy.
|Sunshine, Justine; Kim, Moon; Carlson, Jonathan M et al. (2014) Increased sequence coverage through combined targeting of variant and conserved epitopes correlates with control of HIV replication. J Virol 88:1354-65|
|Pattacini, Laura; Murnane, Pamela M; Kahle, Erin M et al. (2013) Differential regulatory T cell activity in HIV type 1-exposed seronegative individuals. AIDS Res Hum Retroviruses 29:1321-9|
|Zheng, Natalie N; McElrath, M Juliana; Sow, Papa Salif et al. (2011) Association between peripheral ?? T-cell profile and disease progression in individuals infected with HIV-1 or HIV-2 in West Africa. J Acquir Immune Defic Syndr 57:92-100|
|Pine, Samuel O; McElrath, M Juliana; Bochud, Pierre-Yves (2009) Polymorphisms in toll-like receptor 4 and toll-like receptor 9 influence viral load in a seroincident cohort of HIV-1-infected individuals. AIDS 23:2387-95|
|Doehle, Brian P; Hladik, Florian; McNevin, John P et al. (2009) Human immunodeficiency virus type 1 mediates global disruption of innate antiviral signaling and immune defenses within infected cells. J Virol 83:10395-405|
|Liu, Yi; Woodward, Amanda; Zhu, Haiying et al. (2009) Preinfection human immunodeficiency virus (HIV)-specific cytotoxic T lymphocytes failed to prevent HIV type 1 infection from strains genetically unrelated to viruses in long-term exposed partners. J Virol 83:10821-9|
|Speelmon, Emily C; Livingston-Rosanoff, Devon; Desbien, Anthony L et al. (2008) Impaired viral entry cannot explain reduced CD4+ T cell susceptibility to HIV type 1 in certain highly exposed individuals. AIDS Res Hum Retroviruses 24:1415-27|
|Zheng, Natalie N; McElrath, M Juliana; Sow, Papa-Salif et al. (2007) Role of human immunodeficiency virus (HIV)-specific T-cell immunity in control of dual HIV-1 and HIV-2 infection. J Virol 81:9061-71|
|Moodie, Zoe; Huang, Yunda; Gu, Lin et al. (2006) Statistical positivity criteria for the analysis of ELISpot assay data in HIV-1 vaccine trials. J Immunol Methods 315:121-32|
|Zheng, N N; Kiviat, N B; Sow, P S et al. (2004) Comparison of human immunodeficiency virus (HIV)-specific T-cell responses in HIV-1- and HIV-2-infected individuals in Senegal. J Virol 78:13934-42|
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