Involvement of Novel Human Immunodeficiency Virus Type 1 Reverse Transcriptase Mutations in the Regulation of Resistance to Nucleoside Inhibitors

Abstract

We characterized 16 additional mutations in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) whose role in drug resistance is still unknown by analyzing 1,906 plasma-derived HIV-1 subtype B pol sequences from 551 drug-naïve patients and 1,355 nucleoside RT inhibitor (NRTI)-treated patients. Twelve mutations positively associated with NRTI treatment strongly correlated both in pairs and in clusters with known NRTI resistance mutations on divergent evolutionary pathways. In particular, T39A, K43E/Q, K122E, E203K, and H208Y clustered with the nucleoside analogue mutation 1 cluster (NAM1; M41L؉L210W؉T215Y). Their copresence in this cluster was associated with an increase in thymidine analogue resistance. Moreover, treatment failure in the presence of K43E, K122E, or H208Y was significantly associated with higher viremia and lower CD4 cell count. Differently, D218E clustered with the NAM2 pathway (D67N؉K70R؉K219Q؉T215F), and its presence in this cluster determined an increase in zidovudine resistance. In contrast, three mutations (V35I, I50V, and R83K) negatively associated with NRTI treatment showed negative correlations with NRTI resistance mutations and were associated with increased susceptibility to specific NRTIs. In particular, I50V negatively correlated with the lamivudine-selected mutation M184V and was associated with a decrease in M184V/lamivudine resistance, whereas R83K negatively correlated with both NAM1 and NAM2 clusters and was associated with a decrease in thymidine analogue resistance. Finally, the association pattern of the F214L polymorphism revealed its propensity for the NAM2 pathway and its strong negative association with the NAM1 pathway. Our study provides evidence of novel RT mutational patterns that regulate positively and/or negatively NRTI resistance and strongly suggests that other mutations beyond those currently known to confer resistance should be considered for improved prediction of clinical response to antiretroviral drugs.

Effect of the Human Immunodeficiency Virus Type 1 Reverse Transcriptase Polymorphism Leu-214 on Replication Capacity and Drug Susceptibility

“…The present study evaluates the in vitro effect of Leu-214 on the single TAM1 Trp-210 and Tyr-215, since they showed a stronger negative association with Leu-214 in ART-experienced patients (3,29). In a similar way, the effect of Leu-214 on the single TAM2 Phe-215 was also assessed.…”

“…10 to 20% of antiretroviral treatment (ART)-naive and ART-experienced patients carrying any of the major HIV-1 subtypes A, B, or C (3, 4; http://www.hiv.lanl .gov/). A negative association between Leu-214 and the TAM1 pattern and a positive association with the TAM2 pattern have been observed (29). Moreover, it has recently been demonstrated the association of the Leu-214 with a favorable virological response to thymidine analogue-containing ART (3).…”

Resistance pathways of human immunodeficiency virus type 1 against the combination of zidovudine and lamivudine

“…The presence of mutations 43Q and 208Y has been linked to TAM1, whilst mutations 20R and 218E have been associated with TAM2 (Svicher et al, 2006;Gonzales et al, 2003;Rhee et al, 2005;Saracino et al, 2006;). The exact role of other minor mutations in the regulation of resistance is less clear.…”

Hiv-1 Drug Resistance in Treatment-Naive, Chronically Infected Patients in Jamaica

“…However, the V75I mutation, in combination with the Q151M complex, causes high level resistance to all NRTIs [16] while the K101Q has been identified to have a clinically significant impact on NNRTI activity [17].…”