HIV-1 persists in patients despite years of suppressive treatment with antiretroviral therapy resulting in disease relapse when treatment is interrupted. One major barrier to treatment eradication is a reservoir of latently infected CD4+ T-cells. Whether these give rise to low-level ongoing replication or episodically activate and produce virus is controversial but this viral persistence likely contributes to ongoing immuno-pathologic effects that include incomplete T cell restoration and the global immune activation that are implicated in HIV associated cardiovascular, renal and hepatic disease even among those on highly active antiretroviral therapy (HAART). Most advances in our understanding of the latent reservoir have come from the study of cell line models of latency and of lymphocytes from peripheral blood. Our work and that of others suggests that the latent viral reservoir may be heterogeneous in composition in vivo and the molecular mechanisms underlying viral latency are likely complex. Recent attention has focused on the gut associated lymphoid tissue (GALT) as an important site of HIV persistence. Long appreciated for its permissive role in active HIV replication, new data suggest that large numbers of infected cells are retained in GALT even after 10 years of successful suppression of viremia. Our preliminary data in patients on suppressive ART confirm a reservoir of infected cells in GALT that may exceed early total body estimates by approximately 10 fold. Moreover, our preliminary data using short-term treatment intensification with Raltegravir suggest that some sites like terminal ileum could be supporting low level HIV replication. In the current proposal we will attempt to confirm these preliminary findings by performing treatment intensification with Raltegravir in patients already on suppressive antiretroviral therapy and comparing pre and post intensification levels of viral RNA, total and integrated viral DNA and 2LTR circles. Additionally, in subjects on stable ART we will track sequence changes in HIV RNA in tissue from terminal ileum, rectum and PBMC over a two year period as additional evidence of viral replication. Finally, GALT and PBMC from patients on ART will be studied before and after addition of the Histone Deacetylase I (HDAC) inhibitor, valproic acid to determine whether there is differential induction of HIV transcription in GALT. When these studies are complete, we will have determined whether some GALT tissues support cryptic HIV replication during conventional therapy and have a better understanding of the limitations of HDAC inhibition as a strategy to purge latent HIV.
Despite years of treatment with anti-HIV drugs, HIV persists in the body. The gut harbors a large number of HIV infected cells even many years after starting treatment. The studies proposed here will tell us whether HIV is still able to reproduce in the gut despite anti-HIV drugs and may point to new strategies for better treatment.
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