Intensive efforts in recent years have been devoted to the discovery of a widely applicable anti-HIV/AIDS vaccine or functional cure. Though these efforts continue, the hope of reaching either goal in the near future seems dim. By contrast, combination antiretroviral therapy has over the past 20 years in large part kept HIV-1 in check from running rampant worldwide. Despite this medical milestone, significant numbers of new infections each year initiate from drug resistant viral strains, and many of the utilized drugs have unwanted side effects. New combinatorial formulations are therefore required to stay ahead of the virus for the foreseeable future. A vast repertoire of largely untapped drug targets stem from the multitude of specific interactions the virus must make with the host cell in order to support its replication. After HIV-1 enters a new cell, the viral RNA genome is converted into a linear DNA molecule by reverse transcription. The resulting preintegration complex, which is composed of the viral DNA as well as viral and host proteins, traffics along microtubules to the cell nucleus, where it is transported into the nucleus in an energy-dependent manner. Once inside, the preintegration complex traffics to active genes, which are the sites of preferential HIV-1 integration. Using a variety of molecular biology, virology, biochemistry, cell biology, and bioinformatic approaches, this basic science grant will discover and characterize virus-host interactions that are critical for the steps of preintegration complex nuclear import and subsequent intranuclear trafficking to the sites of viral DNA integration. Such information will critically inform downstream programs that aim to target these essential steps of the HIV-1 replication cycle for drug discovery.
Continued success of combination antiretroviral therapy will require the discovery and development of novel drug targets moving forward. The work described in this grant application will characterize HIV-host interactions critical for HIV-1 nuclear import and preintegration trafficking, and will accordingly inform future efforts to develop small molecules that aim to inhibit these critical steps of the viral replication cycle.
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