Persistence versus Reversion of 3TC Resistance in HIV-1 Determine the Rate of Emergence of NVP Resistance

Barbara A Rath,Thomas C Merigan,Jerry Halpern,Richard A Olshen

doi:10.3390/v4081212

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.

Highlights

For improved visualization of HIV evolution and dynamics during serial passage experiments, we summarized in vitro responses to different drug combinations in an innovative fashion using a Serial
Passage Integrated Display (“Cube Model”) with 2-by-4 tables based on reversal/no reversal and the number of newly selected mutations per clinical isolate (“cube”)
In our study we investigate the overall effect of maintaining versus withdrawing 3TC pressure in clinical isolates at the first-time use of nonnucleoside analogue reverse transcriptase inhibitors (NNRTIs)

Summary

Introduction

Several antiretroviral agents have been licensed to treat infections with the human immunodeficiency virus Type 1 (HIV-1). Antiviral drugs that inhibit RT activity in wild-type HIV-1 select rapidly for drug-resistant variants. Current guidelines recommend the use of several antiretroviral agents concomitantly rather than sequentially [1,2,3]. Two classes of drugs are active against the reverse transcriptase enzyme of HIV-1. The nucleotide analogue RT inhibitors (NRTI) compete with the natural substrate and act as chain terminators in the RT catalytic site. The nonnucleoside analogue reverse transcriptase inhibitors (NNRTIs) are noncompetitive inhibitors that bind exclusively to a hydrophobic pocket in HIV type 1

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Conclusion