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Comparative Study
, 4 (8), 1212-34

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

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Comparative Study

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

Barbara A Rath et al. Viruses.

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; adefovir; lamivudine; nevirapine; resistance; selection; serial passage..

Figures

Figure 1
Figure 1
Sequencing Data—Review of Mutations and Reversals in Different Drug Combinations:A complete review of RT sequence changes under the following drug conditions: NVP_only, NVP+3TC, NVP+ADV, NVP+3TC+ADV, 3TC+ADV, No_drug. Individual isolates are displayed in different colors: #1 (green), #2 (dark blue), # 3 (light blue), #4 (pink), and #5 (orange). Sequence changes are listed with the passage number (PASS) and [NVP] where they were first observed. Any mutation away from wild-type is listed under ‘MUT’, reversal to wild-type under ‘REV’. Shaded areas within ‘REV’ indicate M184V-reversal.
Figure 2
Figure 2
Progression of Mutations With and Without M184V-reversal. All mutations and M184V-reversals for every passage and isolate are summarized. Isolates #1-5 (represented by colored cubes) started with a priori no mutations ‘MUT’ and no M184V-reversal (0MUT/0REV). At P1-P12, each cube could either remain in its position or move vertically to 1, 2, or 3 mutations and/or horizontally from 0 to 1 M184V-reversal. ‘Movements’ of cubes under defined drug pressures can be followed along P1-P12 or compared across equivalent passages.
Figure 3
Figure 3
Appearance of new mutations before and after 184 Reversal: All mutations generated (diamonds) per drug setting, before (M184V, left column) and after M184V-reversal (After 184 Reversal, right column) are summarized. We display the appearance of each selected mutation in relation to the respective passage number and NVP concentration on the y-axis. FOLD [NVP] represents the concentration at which a mutation first became prevalent. FOLD [NVP] =2p (with P = passage number). As reported in Figure 1, all observed mutations persisted up to P12. During drug escalation, the event of M184V-reversal is required for a mutation to appear in the right column. Diamonds in either column can therefore only be compared between different drug settings. Horizontal bars in the logarithmic FOLD [NVP] scale indicate the average [NVP] for mutations to appear.

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