Title: Establishment, maintenance and elimination of the HIV reservoir
Abstract: The HIV reservoir is a population of 1-10 million anatomically dispersed memory CD4+ T cells which are latently infected with HIV-1. The size of the reservoir is remarkably stable through years and even decades of effective antiretroviral therapy (ART). While the elimination of reservoir cells is required for cure of HIV, this task has proven to be daunting. Typically, only one copy of HIV is integrated within human chromosomal DNA in each infected cell and efforts to pharmacologically reactivate the virus have had limited success. HIV protein expression and signaling to the immune system is also nearly absent during viral latency posing challenges for immunotherapeutic approaches. I will describe my group’s mathematical models which are based on the premise that a deep understanding of the mechanisms underlying reservoir formation and sustainment are required to develop optimal curative approaches. Our models suggest that the laws governing proliferation of memory CD4+ T cells are responsible for generation of nearly all infected cells in the reservoir after ART initiation and that massive cellular proliferation is vital for reservoir formation during the first several weeks of untreated primary infection. Our results suggest that lymphocyte proliferation is a promising therapeutic target for HIV cure, which we recently tested in a clinical trial of mycophenolate mofetil (MMF) in chronically infected persons. I will discuss the results of this study and also present further modeling which demonstrate that cellular proliferation could present unforeseen barriers to other promising HIV cure interventions including stem cell transplantation approaches and immunotherapies.