MOLECULAR MECHANISMS OF HIV POST-INTEGRATION LATENCY

University Of California At Davis, Davis CA

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Despite the near complete suppression of detectable virus in many HIV infected patients undergoing highly active antiretroviral therapy, viremia reemerges rapidly after interruption of treatment. Postintegration latency refers to latently infected resting memory CD4+ T cells containing transcriptionally silent integrated HIV-1 genomes. Postintegration latency contributes to the persistence of the virus under HAART and represents a known barrier to eradication of HIV infection. To investigate novel approaches for AIDS therapy, our nonhuman primate model uses RT-SHIV, a chimera of simian immunodeficiency virus containing the HIV-1 reverse transcriptase (RT). Methods were developed for extraction, pre-amplification and real-time PCR analyses of viral DNA (vDNA) and viral RNA (vRNA) in tissues from RT-SHIV-infected macaques. These methods were used to identify viral reservoirs in RT-SHIV-infected macaques treated with a potent HAART regimen consisting of efavirenz, emtricitabine and tenofovir. Viral RNA and DNA were detected during HAART in tissues from numerous anatomical locations. The highest levels of vDNA and vRNA in HAART-treated macaques were in lymphoid tissues, particularly spleen, lymph nodes, and gastrointestinal tract tissues. This study is the first comprehensive analysis of tissue and organ distribution of a primate AIDS virus during HAART. These data demonstrate widespread persistence of residual virus in tissues during HAART.