Suppression of HIV replication requires life-long antiretroviral therapy, and while previous hopes included the possibility that the therapy would eventually lead to a decay and gradual deletion of the reservoir, evidence now suggests that current therapeutic approaches will not eliminate the reservoir. Conversely, over the past decade 4 unique instances including the Berlin patient, the Mississippi baby, the Parisian post-treatment controllers, and the Portland monkeys all point to the possibility of that more aggressive therapeutic interventions coupled to HAART may lead to a cure. Moreover, intense investigation is now underway to develop new classes of therapeutics able to resurrect and drive the virus out of latency, however, once reactivated, few strategies exist to eliminate these cells from the body. Several groups have speculated that vaccine induced or naturally occurring cytotoxic T cell responses may recognize and eliminate reactivated cells, however these cells may be impaired, lack the capacity to traffic to sites harboring latently infected cells, or all together miss latently infected cells due to epitope variation or low level epitope availability. Conversely, in the context of tumor cell therapeutics, significant efforts has been invested over the past 2 decades in developing cytolytic monoclonal antibody therapeutics, like rituximab, that can rapidly eliminate target cells, both in the blood and tissues through the recruitment of innate immune cellular activity. These types of cytolytic antibodies are naturally induced during natural infection, accumulate in the context of HAART, are enriched in long-term non-progressors, and are easily induced via vaccination. However, whether these types of antibodies can kill reactivated latently infected cells is unknown. Here we propose to begin to define whether a monoclonal therapeutic strategy, coupled to resurrection of the viral reservoir, may aide in the eradication of the viral reservoir. Moreover, we will define the specific monoclonal antibodies that recognize latently infected cells most effectively following reactivation, determine whether these antibodies can recruit distinct innate effector cells to eliminate reactivated cells, and finlly to optimize monoclonal therapeutics to most aggressively kill the viral reservoir. Coupled to current eradication approaches, such a monoclonal therapeutic eradication strategy may offer a second line or alternate approach eliminate the viral reservoir either through passive immunization, gene transfer of the antibody, or vaccine-induced antibody induction.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZAI1-JRR-A (S4))
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Conley, Tony J
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Massachusetts General Hospital
United States
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Alter, Galit; Barouch, Dan (2018) Immune Correlate-Guided HIV Vaccine Design. Cell Host Microbe 24:25-33
Sips, M; Krykbaeva, M; Diefenbach, T J et al. (2016) Fc receptor-mediated phagocytosis in tissues as a potent mechanism for preventive and therapeutic HIV vaccine strategies. Mucosal Immunol 9:1584-1595