The long-term goal of this proposal is to define the contribution of two major components of the innate immune system (accessory and Natural Killer cells) in controlling HIV replication and thereby modifying disease progression. The short-term goal of this project is to address the consequences of immune reconstitution following antiretroviral therapy on innate immunity with particular emphasis on correlates of DC and NK cell function with viral suppression. Based on our preliminary data on NK and DC dysfunction during HIV replication in vivo and: (1) the observed effects of antiretroviral therapy on DC and NK cell subsets, (2) the inverse correlation between viral load and DC subsets in untreated HIV positive subjects and (3) our observations of augmented NK lytic activity by activated DC, we propose to perform longitudinal analysis and mechanistic experiments on DC/HIV interactions to test the hypothesis that HAART- mediated viral suppression restores mature NK and DC subsets necessary to activate innate mechanisms of antiviral control through lysis of infected cells, To test our hypothesis, we will characterize the in-vivo and in vitro interactions between MV infection and innate immunity cell function by (1) longitudinal analysis of the consequences of HAART- mediated suppression (i.e., recovery of function as a correlate of viral suppression) or known clinical outcomes (Multiple AIDS Cohort Study National Repository) and (2) in vitro analysis of the effects of HIV on APC subsets that bear on NK activity. Specifically, we propose to determine the significance of our preliminary observations by addressing the association between innate cell function and HIV infection by: (1) Defining the phenotypic and functional changes in APCs (monocytes and DC) and NK cells in seroconverters with fast or delayed disease progression and in chronically infected patients starting HAART at different CD4 count stages through longitudinal analysis of: changes in DC (MDCIPDC) and mature CD161KD56 NK cell subsets; changes in accessory cell-surface expression of functional molecules (CD40, CD54, MHC Class I, CD1 IC, CD16, CD80, CD86) and activation molecule CD95; changes in APC viability and APC-dependent endocytosis, cytokine secretion (IL- 12 and IFN-a ), and allogeneic responses; and changes in activated CD161KD56 NK cytokines, lytic molecules (granzyme, perforin) and cytotoxic activity. (2) Defining the mechanisms and consequences of APC impairment and loss in HIV-1 infection by analysis of in vivo-derived MDC and PDC subsets exposed to HIV-1 and analyzed for viability, function, infection as part of an overall aim to define how HIV interactions with DC affect NK function. This study represents a hypothesis-driven collaborative effort by The Wistar Institute, the Infectious Disease Division of the University of Pennsylvania Hospital, Philadelphia FIGHT, Schering-Plough and the Multiple AIDS Cohort Study

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-AARR-1 (12))
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Wassef, Nabila M
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Wistar Institute
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Tomescu, Costin; Tebas, Pablo; Montaner, Luis J (2017) IFN-? augments natural killer-mediated antibody-dependent cellular cytotoxicity of HIV-1-infected autologous CD4+ T cells regardless of major histocompatibility complex class 1 downregulation. AIDS 31:613-622
Tomescu, Costin; Tebas, Pablo; Montaner, Luis J (2017) IFN-? augments NK-mediated antibody-dependent cellular cytotoxicity (ADCC) of HIV-1 infected autologous CD4+ T cells regardless of MHC-I downregulation. AIDS :
Tomescu, Costin; Mavilio, Domenico; Montaner, Luis J (2015) Lysis of HIV-1-infected autologous CD4+ primary T cells by interferon-alpha-activated NK cells requires NKp46 and NKG2D. AIDS 29:1767-73
Chehimi, Jihed; Papasavvas, Emmanouil; Tomescu, Costin et al. (2010) Inability of plasmacytoid dendritic cells to directly lyse HIV-infected autologous CD4+ T cells despite induction of tumor necrosis factor-related apoptosis-inducing ligand. J Virol 84:2762-73
Foulkes, A S; Azzoni, L; Li, X et al. (2010) Prediction based classification for longitudinal biomarkers. Ann Appl Stat 4:1476-1497
Tomescu, Costin; Chehimi, Jihed; Maino, Vernon C et al. (2009) Retention of viability, cytotoxicity, and response to IL-2, IL-15, or IFN-alpha by human NK cells after CD107a degranulation. J Leukoc Biol 85:871-6
Papasavvas, Emmanouil; Moore, Elizabeth C; Sun, Junwei et al. (2008) HIV type 1 viremia on ART is positively associated with polyclonal T cell proliferation in subjects with T cell IFN-gamma secretion levels comparable to those of uninfected subjects. AIDS Res Hum Retroviruses 24:1203-8
Chehimi, Jihed; Azzoni, Livio; Farabaugh, Matthew et al. (2007) Baseline viral load and immune activation determine the extent of reconstitution of innate immune effectors in HIV-1-infected subjects undergoing antiretroviral treatment. J Immunol 179:2642-50
Tomescu, Costin; Chehimi, Jihed; Maino, Vernon C et al. (2007) NK cell lysis of HIV-1-infected autologous CD4 primary T cells: requirement for IFN-mediated NK activation by plasmacytoid dendritic cells. J Immunol 179:2097-104
Azzoni, Livio; Chehimi, Jihed; Zhou, Lan et al. (2007) Early and delayed benefits of HIV-1 suppression: timeline of recovery of innate immunity effector cells. AIDS 21:293-305

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