Most studies of clinical drug resistance to nucleoside and nonnucleoside reverse transcriptase (RT) inhibitors (NRTIs and NNRTIs, respectively) analyze the first 300 amino acids of RT and do not include the C-terminal connection subdomain (CN) or the RNase H domain (RH). We observed that several mutations in the CN and RH reduce RNase H activity, thereby affecting the balance between RNA degradation and nucleotide excision, and enhancing NRTI resistance. Our recent studies have demonstrated that mutations in the CN and the RH can also increase resistance to NNRTIs, and suggest a parallel mechanism by which resistance to both classes of RT inhibitors can be increased. It has been observed that CN mutations are present in drug-naive patients, and we are exploring the mechanisms by which CN mutations may be selected prior to initiation of antiviral therapy. While investigating the functional relevance of A3G localization to P bodies, we found that P body-associated protein Mov10 potently inhibits HIV-1 replication by reducing virus production and inhibiting reverse transcription. We are elucidating the mechanisms by which Mov10 inhibits HIV-1 particle production and reverse transcription. While examining the effects of A3G and A3F on viral DNA integration, we observed that uracil DNA glycosylase activity in the target cells, not the virus producer cells, results in nicking of the minus-strand DNA. We are exploring the significance of this unexpected phenotype to viral replication. [Corresponds to Pathak Project 3 in the October 2011 site visit report of the HIV Drug Resistance Program]

National Institute of Health (NIH)
National Cancer Institute (NCI)
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National Cancer Institute Division of Basic Sciences
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Nikolaitchik, Olga A; Dilley, Kari A; Fu, William et al. (2013) Dimeric RNA recognition regulates HIV-1 genome packaging. PLoS Pathog 9:e1003249
Murgai, Meera; Thomas, James; Cherepanova, Olga et al. (2013) Xenotropic MLV envelope proteins induce tumor cells to secrete factors that promote the formation of immature blood vessels. Retrovirology 10:34
Delviks-Frankenberry, Krista; Paprotka, Tobias; Cingoz, Oya et al. (2013) Generation of multiple replication-competent retroviruses through recombination between PreXMRV-1 and PreXMRV-2. J Virol 87:11525-37
Hatch, Steven C; Sardo, Luca; Chen, Jianbo et al. (2013) Gag-dependent enrichment of HIV-1 RNA near the uropod membrane of polarized T cells. J Virol 87:11912-5