Role of Connection and RNase H Domains of HIV-1 RT in Antiviral Drug Resistance

Pathak, Vinay K.

Abstract

The role of CN and RH mutations in conferring antiviral drug resistance in non-B subtypes is poorly defined. We will characterize CN and RH mutations in subtype C and CRF01_AE and determine their impact on resistance to NRTIs and NNRTIs. We will genotype patients who are failing a regimen containing NNRTI therapy to determine whether the presence of CN and RH mutations can predict a higher rate of failure to AZT-containing salvage therapy. We will characterize the effects of CN mutations associated with drug resistance on viral fitness. We will determine the impact of CN mutations associated with drug resistance on viral fitness using competition assays in the presence and absence of antiviral drugs. We will dissect the mechanisms that contribute to genetic variation in CN and RH. [Corresponds to Pathak Project 2 in the April 2007 site visit report of the HIV Drug Resistance Program]

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Cancer Institute (NCI)
• Type: Investigator-Initiated Intramural Research Projects (ZIA)
• Project #: 1ZIABC010532-08
• Application #: 8157336
• Support Year: 8
• Fiscal Year: 2010
• Total Cost: $136,021

Institution

• Name: National Cancer Institute Division of Basic Sciences

Publications

Lengruber, Renan B; Delviks-Frankenberry, Krista A; Nikolenko, Galina N et al. (2011) Phenotypic characterization of drug resistance-associated mutations in HIV-1 RT connection and RNase H domains and their correlation with thymidine analogue mutations. J Antimicrob Chemother 66:702-8

Delviks-Frankenberry, Krista A; Nikolenko, Galina N; Pathak, Vinay K (2010) The ""Connection"" Between HIV Drug Resistance and RNase H. Viruses 2:1476-1503

Nikolenko, Galina N; Delviks-Frankenberry, Krista A; Pathak, Vinay K (2010) A novel molecular mechanism of dual resistance to nucleoside and nonnucleoside reverse transcriptase inhibitors. J Virol 84:5238-49

Delviks-Frankenberry, Krista A; Nikolenko, Galina N; Maldarelli, Frank et al. (2009) Subtype-specific differences in the human immunodeficiency virus type 1 reverse transcriptase connection subdomain of CRF01_AE are associated with higher levels of resistance to 3'-azido-3'-deoxythymidine. J Virol 83:8502-13

Delviks-Frankenberry, Krista A; Nikolenko, Galina N; Boyer, Paul L et al. (2008) HIV-1 reverse transcriptase connection subdomain mutations reduce template RNA degradation and enhance AZT excision. Proc Natl Acad Sci U S A 105:10943-8

Santos, Andre F A; Lengruber, Renan B; Soares, Esmeralda A et al. (2008) Conservation patterns of HIV-1 RT connection and RNase H domains: identification of new mutations in NRTI-treated patients. PLoS ONE 3:e1781