Abstract
Emergence of human immunodeficiency virus type 1 (HIV-1) drug resistance arises from mutation fixation in the viral genome during antiretroviral therapy. Primary mutations directly confer antiviral drug resistance, while secondary mutations arise that do not confer drug resistance. The A62V amino acid substitution in HIV-1 reverse transcriptase (RT) was observed to be associated with multi-drug resistance, but is not known to be a resistance-conferring mutation. In particular, A62V was observed in various multi-dideoxynucleoside resistant (MDR) mutation complexes, including the Q151M complex (i.e., A62V, V75I, F77L, F116Y, and Q151M), and the T69SSS insertion complex, which has a serine–serine insertion between amino acid positions 69 and 70 (i.e., M41L, A62V, T69SSS, K70R, and T215Y). However, what selective advantage is conferred to the virus remains unresolved. In this study, we hypothesized that A62V could influence replication fidelity and viral fitness with viruses harboring the Q151M and T69SSS MDR mutation complexes. A single-cycle replication assay and a dual-competition fitness assay were used to assess viral mutant frequency and viral fitness, respectively. A62V was found to increase the observed lower mutant frequency identified with each of the viruses harboring the MDR mutation complexes in the single-cycle assay. Furthermore, A62V was observed to improve viral fitness of replication-competent MDR viruses. Taken together, these observations indicate an adaptive role of A62V in virus replication fidelity and viral fitness, which would likely enhance virus persistence during drug-selective pressure.
Highlights
Since the discovery of the human immunodeficiency virus type 1 (HIV-1), the etiological agent of acquired immunodeficiency syndrome (AIDS), in the early 1980s, approximately 30 million individuals have died of AIDS, and approximately 36 million are currently infected worldwide
HAART typically consists of nucleoside reverse transcriptase inhibitors (NRTIs) [2], non-nucleoside reverse transcriptase inhibitors (NNRTIs) [3], and protease inhibitors (PIs) or integrase inhibitors which target key steps of the viral life cycle
We tested the hypothesis that A62V provides a selective advantage to the virus in the amino context acid of multi-drug resistance by influencing replication fidelity and with fitness.multi-drug
Summary
Since the discovery of the human immunodeficiency virus type 1 (HIV-1), the etiological agent of acquired immunodeficiency syndrome (AIDS), in the early 1980s, approximately 30 million individuals have died of AIDS, and approximately 36 million are currently infected worldwide. Current treatment for HIV-1 infection consists of a combination drug therapy (highly-active antiretroviral therapy, HAART) [1]. HAART typically consists of nucleoside reverse transcriptase inhibitors (NRTIs) [2], non-nucleoside reverse transcriptase inhibitors (NNRTIs) [3], and protease inhibitors (PIs) or integrase inhibitors which target key steps of the viral life cycle. The high mutation rate of HIV-1 (i.e., 3.4 × 10−5 mutations per target bp per replication cycle) [7] arguably contributes to the evolution of drug resistance. This high mutation rate can, in principle, lead to the generation
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