Despite efficient suppression of plasma viremia in HIV-infected patients on cART, replication competent virus is still recoverable from a variety of anatomic sites and most notably quiescent memory CD4+ T lymphocytes. Although empirical evidence suggests latent HIV is present throughout the oral mucosae, the full spectrum of infected cells in the oral cavity is undefined, and the contribution of the unique anatomy of these tissues to the systemic viral reservoir is unknown. In addition to being a potential reservoir for HIV/SIV, the oral cavity is home to a wide range of normally benign pathogens that during co-infection induced immunosuppression are major sources of co-morbidities. Although the underlying mechanisms for emergence of opportunistic viruses are not entirely clear, oral complications of HIV disease are widespread even with successful ARV therapy. Natural killer (NK) cells provide rapid early responses to HIV/SIV infections and contribute substantially to disease modulation and vaccine protection. Traditionally, NK cells have been considered to be nonspecific components of innate immunity, but recent studies in mice have shown that NK cells can also demonstrate features of antigen-specific memory. We also now demonstrate for the first time evidence of NK cell memory in higher primates specifically against HIV and SIV antigens (Reeves et al., Nat Imm, 2015). In this innovative proposal we will utilize the SIV-co-infected macaque model to test the central hypothesis that NK cells distributed throughout the oral mucosae are a common critical component for modulation of reservoirs of SIV and opportunistic viral infections. Specifically we will: (1) Define and quantify SIV reservoirs in the oral mucosa during cART; (2) Evaluate mechanisms of innate and antigen-specific NK cell modulation of SIV replication and reservoir seeding in the oral mucosae; and (3) Explore the effects of NK cell depletion on SIV reservoirs and rhLCV and rhCMV co-infections. Application of these data could lead to future HIV/SIV vaccines, immunotherapeutics, or reservoir purging strategies that harness the potent antiviral potential of NK cells.

Public Health Relevance

Although the advent of combination antiretroviral therapy (cART) has changed the face of the HIV epidemic, the cost, difficulty with sustained adherence, and ongoing morbidities due to chronic immune activation demonstrate an urgent need for therapeutics to purge the viral reservoir. The best studied HIV reservoir is resting memory CD4+ T cells in gastrointestinal and secondary lymphoid tissues, but novel oral reservoirs remain largely unexplored. Furthermore, co-infections in the oral mucosae can activate and exhaust oral immune responses thereby dysregulating potential mechanisms of reservoir clearance. Herein we demonstrate that NK cells, including newly described memory NK cells, modulate replication of SIV and other oral herpesviruses, and could represent a novel target for immunotherapeutic elimination of oral HIV/SIV reservoirs.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Special Emphasis Panel (ZDE1)
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Weatherspoon, Darien Jerome
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Beth Israel Deaconess Medical Center
United States
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Huot, Nicolas; Bosinger, Steven E; Paiardini, Mirko et al. (2018) Lymph Node Cellular and Viral Dynamics in Natural Hosts and Impact for HIV Cure Strategies. Front Immunol 9:780
Ram, Daniel R; Kroll, Kyle; Reeves, R Keith (2018) Indirect activation of rhesus macaque (Macaca mulatta) NK cells in oral and mucosal draining lymph nodes. J Med Primatol 47:302-304
Manickam, Cordelia; Nwanze, Chiadika; Ram, Daniel R et al. (2018) Progressive lentivirus infection induces natural killer cell receptor-expressing B cells in the gastrointestinal tract. AIDS 32:1571-1578
Ram, Daniel R; Manickam, Cordelia; Hueber, Brady et al. (2018) Tracking KLRC2 (NKG2C)+ memory-like NK cells in SIV+ and rhCMV+ rhesus macaques. PLoS Pathog 14:e1007104
Shah, Spandan V; Manickam, Cordelia; Ram, Daniel R et al. (2018) CMV Primes Functional Alternative Signaling in Adaptive ?g NK Cells but Is Subverted by Lentivirus Infection in Rhesus Macaques. Cell Rep 25:2766-2774.e3
Paust, Silke; Blish, Catherine A; Reeves, R Keith (2017) Redefining Memory: Building the Case for Adaptive NK Cells. J Virol 91:
Huot, Nicolas; Jacquelin, Beatrice; Garcia-Tellez, Thalia et al. (2017) Natural killer cells migrate into and control simian immunodeficiency virus replication in lymph node follicles in African green monkeys. Nat Med 23:1277-1286