HIV-1 DNA and the HIV-1 Viral Reservoir

HIV-1 infected resting memory CD4+ T cells are major contributors to the HIV-1 viral reservoir, which is established during early infection, maintaining HIV-1 infection for an individuals life. The effect the timing of therapy initiation has on the size and decay of the HIV-1 viral reservoir, the contribution of CD4+ T cell subsets to the viral reservoir and HIV-1 DNA decay dynamics were investigated to further our understanding of the formation, maintenance and location of the HIV-1 viral reservoir.Total, 2-LTR and integrated HIV-1 DNA were quantified within memory CD4+ T cell populations and/or total CD4+ T cells from patients with chronic untreated HIV-1; treatment naïve patients with primary or chronic HIV-1 infection initiating therapy containing raltegravir; and within treatment naïve patients receiving no therapy, versus a short or long course of therapy. The examination of memory CD4+ T cell subsets indicated that gut-homing, T regulatory cells, and activated or resting memory CD4+ T cells all contributed to the viral reservoir but were not preferentially infected. Therapy initiation led to a general biphasic decay of total and/or integrated HIV-1 DNA levels, however treatment initiation during primary infection curbed the size of the viral reservoir. Therapy containing raltegravir inhibited HIV-1 DNA integration and increased the level of 2-LTR circles during both primary and chronic HIV-1 infection, which were comparable regardless of disease stage prior to and following 52 weeks of therapy in total CD4+ T cells. Also, preceding the initiation of treatment, the majority of 2-LTR HIV-1 DNA was contained within resting memory CD4+ T cells, which was also reflected by the higher ratio of 2-LTR:integrated HIV-1 DNA in these cells. While therapy initiation during primary HIV-1 infection curbed the size of the viral reservoir, some of the data presented here supports the possibility of ongoing replication or de novo reactivation of latent virus despite suppressive therapy. Further investigation is needed to determine the long-term effects of early treatment initiation on the viral reservoir. The results from this thesis suggest therapeutic intervention will likely involve the targeting of several memory CD4+ T cell reservoirs for the eradication of HIV-1