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1. DHAP Mechanisms of susceptibility to HIV infection
J. McNicholl, E. Kersh
A clearer understanding of the immunologic mechanisms controlling mucosal transmission of HIV is essential to better inform development of biomedical interventions to prevent infection. Using a macaque model of mucosal simian virus exposure, we are conducting studies on how HIV crosses the mucosal barrier and establishes infection. Immunologic mechanisms that impact susceptibility to infection by suppressing local HIV replication and mucosal transmission will be examined and ultimately identified. The results from these studies have implications for microbicide and vaccine development as well as for the understanding natural resistance to HIV infection.
Promadej-Lanier N, Hanson DL, Srinivasan P, Luo W, Adams DR, Guenthner PC, Butera S, Otten RA, Kersh EN. 2010. Resistance to Simian HIV infection is associated with high plasma interleukin-8, RANTES and Eotaxin in a macaque model of repeated virus challenges. J Acquir Immune Defic Syndr 53: 574-81
Kersh EN, Adams DR, Youngpairoj AS, Luo W, Zheng Q, Cong ME, Aung W, Mitchell J, Otten R, Hendry RM, Heneine W, McNicholl J, Garcia-Lerma JG. 2011. T Cell Chemo-Vaccination Effects after Repeated Mucosal SHIV Exposures and Oral Pre-Exposure Prophylaxis. PLoS One 6: e19295
Vishwanathan SA, Guenthner PC, Lin CY, Dobard C, Sharma S, Adams DR, Otten RA, Heneine W, Hendry RM, McNicholl JM, Kersh EN. 2011. High Susceptibility to Repeated, Low-Dose, Vaginal SHIV Exposure Late in the Luteal Phase of the Menstrual Cycle of Pigtail Macaques. J Acquir Immune Defic Syndr.
Henning T, Fakile Y, Phillips C, Sweeney E, Mitchell J, Otten R, D. P, Sturdevant G, Caldwell HD, Secor WE, Papp J, Hendry R, McNicholl J, Kersh E. 2011. Development of a Pigtail Macaque Model of Sexually-Transmitted Infection/ HIV Coinfection Utilizing Chlamydia trachomatis, Trichomonas vaginalis, and SHIVSF162P3. Journal of Medical Primatology in press
Kersh, EN; Wei Luo; Qi Zheng; Debra R. Adams; Debra Hanson; Ae S. Youngpairoj; Mian-er Cong; Katherine Butler; R. Michael Hendry; Janet M. McNicholl; Walid Heneine; J. Gerardo Garcia-Lerma; Reduced inflammation and CD4 loss in acute SHIV infection during oral PrEP; Journal of Infectious Diseases 2012; doi: 10.1093/infdis/jis422
2. DHAP Human Studies of factors associated with resistance to HIV-1 infection
J. McNicholl, E. Kersh
Lack of infection despite HIV-1 exposure may occur in several settings. One, where there is apparent natural resistance to HIV (in highly exposed, persistently seronegative persons) and another, in persons who are HIV exposed but remain uninfected when being treated with anti-HIV drugs such as tenofovir (pre-exposoure prophylaxis or PrEP). We are conducting studies on immune factors associated with these exposures, including T cell, cytokine and mucosal factors. Other aspects of the studies include analysis of risk behavior, sexually transmitted infections, partner’s virus (where available). Studies of these factors may elucidate natural host factors that reduce infection risk, or that may be induced under the umbrella of PrEP, and provide new avenues to identify or improve biomedical preventions for HIV infection.
Our previous work in highly exposed HIV resistant women in Thailand has uncovered a mixture of cellular and host genetic factors that may contribute to infection. Our recent studies in non-human primates indicates (S)HIIV exposure during PrEP induces SHIV-specific T cells. Research continues on several CDC studies of individuals with high HIV exposure who appear to be naturally HIV resistant. The research focuses on identifying additional genetic, mucosal or innate factors that may be associated with reduced risk of HIV infection in individuals with HIV exposure whether receiving PrEP or not. Samples are available from highly HIV-1 exposed men and women, including individuals who have received PrEP in clinical trials. Studies focus on identifying whether these individuals have potentially protective immune or innate responses that may be associated with reducing HIV infection risk or controlling viral load if there is subsequent HIV infection.
McNicholl JM, Promadej N. 2004. Insights into the role of host genetic and T-cell factors in resistance to HIV transmission from studies of highly HIV-exposed Thais. Immunol Res 29: 161-74.
Promadej N, Costello C, Wernett MM, Kulkarni PS, Robison VA, Nelson KE, Hodge TW, Suriyanon V, Duerr A, McNicholl JM. 2003. Broad human immunodeficiency virus (HIV)-specific T cell responses to conserved HIV proteins in HIV-seronegative women highly exposed to a single HIV-infected partner. J Infect Dis 187: 1053-63.
Sriwanthana B, Hodge T, Mastro TD, Dezzutti CS, Bond K, Stephens HA, Kostrikis LG, Limpakarnjanarat K, Young NL, Qari SH, Lal RB, Chandanayingyong D, McNicholl JM. 2001. HIV-specific cytotoxic T lymphocytes, HLA-A11, and chemokine-related factors may act synergistically to determine HIV resistance in CCR5 delta32-negative female sex workers in Chiang Rai, northern Thailand. AIDS Res Hum Retroviruses 17: 719-34.
Kersh EN, Adams DR, Youngpairoj AS, Luo W, Zheng Q, Cong M, Aung W, Mitchell J, Otten R, Hendry RM, Heneine W, McNicholl J, Garcia-Lerma JG; Mucosal SHIV exposures and oral PrEP can induce specific T cell responses, and can have a chemo-vaccination effect, submitted.