Investigator's Application): The capacity of HIV-1 to establish a state of latent infection at the level of individual cells provides mechanism for viral persistence in the face of aggressive antiretroviral therapy. The goal of the proposed research is to understand that nature of latent cellular reservoirs for HIV-1, focusing on the viral reservoirs that persist in individuals on highly active antiretroviral therapy (HAART). The investigators central hypothesis is that resting memory CD4+ T cells with integrated HIV-1 DNA provide a long term reservoir for the virus that must be eliminated if eradication is to be achieved. In preliminary studies, they have directly demonstrated the presence of resting CD4+T cells with replication-competent provirus and have measured the frequency of these cells in the blood nd lymph nodes of infected individuals. Most importantly, the investigators have recently found that with appropriate stimulation methods, infectious virus can be routinely recovered from the resting CD4+T cells of individuals on HAART, including those who have had no detectable plasma virus for up to 30 months and for whom standard virus culture assays are negative. Preliminary estimates of the decay rate of this reservoir suggest that it may constitute the most significant long term viral reservoir in patients treated with HAART. Thus studies of the size, turnover rate, and immunologic and virologic characteristics of this reservoir are thus important for determining whether therapy should be given with the concrete goal of virus eradication. The major gaol of this proposal is to define the frequency nd rate of decay of latently infected CD4+T cells in infected individuals on HAART. The half-line of this compartment will be used to estimate the minimum time to virus eradication. In addition, the investigators will attempt to define important immunologic and virologic characteristics of the latent proviral reservoir in resting CD4+T cells. Viruses isolated from latently infected CD4+T cells will be characterized with respect to properties that are important for understanding their potential to cause disease following cessation of therapy. These include tropism, cytopthicity, and resistance to the relevant antiretroviral agents. Finally, the investigators will develop an experimental system for identifying stimuli that could be used to mobilize the latent reservoir for elimination.
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