TARGETING THE HIV-1 LATENT RESERVOIR FOR ERADICATION USING SMALL MOLECULES

HIV-1;HIV/AIDS;Virology;HIV-1 Latency;HIV-1 Latent Reservoir;not listed

Laird, Gregory M.Corden, Jeffry L. ;

Johns Hopkins University

关键词: HIV-1;    HIV/AIDS;    Virology;    HIV-1 Latency;    HIV-1 Latent Reservoir;    not listed;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/39539/LAIRD-DISSERTATION-2015.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

Despite effective antiretroviral therapy, human immunodeficiency virus type 1 (HIV-1) persists in all infected individuals as a quiescent provirus within resting CD4+ T lymphocytes. These transcriptionally silent proviruses, which exist as integrated DNA within the genome of the infected cell, are not targeted by antiretroviral therapy nor by the host immune response. While the majority of these latent HIV-1 proviruses are defective, a fraction of these proviruses retains the ability to replicate. Upon the interruption or cessation of antiretroviral therapy, stochastic reactivation of these replication-competent latent proviruses leads to rebound in viremia within weeks. The population of latently infected, resting CD4+ T lymphocytes is very stable, with a half-life estimated at 44 months. Therefore, this stably persistent latent reservoir of replication competent HIV-1 is the major barrier to curing HIV-1 infection. HIV-1 latency reversal has been proposed as a curative strategy. Under this approach, latency reversing agents would reignite HIV-1 gene expression, driving the elimination of latently infected CD4+ lymphocytes via viral cytopathic effects or clearance by the immune system. To advance this approach, I have developed a number of new assays for measuring the latency reversing potential of candidate latency reversing agents in lymphocytes taken directly from HIV-1 infected individuals. Using these assays, I have identified effective combinations of HIV-1 latency reversing agents, which are predicted to potently reverse latency in vivo. Furthermore, the quantitative approach described herein will facilitate future identification and characterization of candidate latency reversing agents with the goal of eliminating the HIV-1 latent reservoir.