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Persistence versus Reversion of 3TC Resistance in HIV-1 Determine the Rate of Emergence of NVP Resistance
Center for AIDS Research, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
Department of Pediatrics, Division of Pneumonology-Immunology, Charité University Medical Center, Berlin 13353, Germany
Division of Biostatistics, Stanford University School of Medicine, Stanford, CA 94305, USA
* Author to whom correspondence should be addressed.
Received: 11 July 2012; in revised form: 3 August 2012 / Accepted: 6 August 2012 / Published: 7 August 2012
Abstract: When HIV-1 is exposed to lamivudine (3TC) at inhibitory concentrations, resistant variants carrying the reverse transcriptase (RT) substitution M184V emerge rapidly. This substitution confers high-level 3TC resistance and increased RT fidelity. We established a novel in vitro system to study the effect of starting nevirapine (NVP) in 3TC-resistant/NNRTI-naïve clinical isolates, and the impact of maintaining versus dropping 3TC pressure in this setting. Because M184V mutant HIV-1 seems hypersusceptible to adefovir (ADV), we also tested the effect of ADV pressure on the same isolates. We draw four conclusions from our experiments simulating combination therapy in vitro. (1) The presence of low-dose (1 μM) 3TC prevented reversal to wild-type from an M184V mutant background. (2) Adding low-dose 3TC in the presence of NVP delayed the selection of NVP-associated mutations. (3) The presence of ADV, in addition to NVP, led to more rapid reversal to wild-type at position 184 than NVP alone. (4) ADV plus NVP selected for greater numbers of mutations than NVP alone. Inference about the “selection of mutation” is based on two statistical models, one at the viral level, more telling, and the other at the level of predominance of mutation within a population. Multidrug pressure experiments lend understanding to mechanisms of HIV resistance as they bear upon new treatment strategies.
Keywords: HIV-1; lamivudine; nevirapine; adefovir; resistance; selection; serial passage
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Rath, B.A.; Olshen, R.A.; Halpern, J.; Merigan, T.C. Persistence versus Reversion of 3TC Resistance in HIV-1 Determine the Rate of Emergence of NVP Resistance. Viruses 2012, 4, 1212-1234.
Rath BA, Olshen RA, Halpern J, Merigan TC. Persistence versus Reversion of 3TC Resistance in HIV-1 Determine the Rate of Emergence of NVP Resistance. Viruses. 2012; 4(8):1212-1234.
Rath, Barbara A.; Olshen, Richard A.; Halpern, Jerry; Merigan, Thomas C. 2012. "Persistence versus Reversion of 3TC Resistance in HIV-1 Determine the Rate of Emergence of NVP Resistance." Viruses 4, no. 8: 1212-1234.