A Combination of Amino Acid Mutations Leads to Resistance to Multiple Nucleoside Analogs in Reverse Transcriptases from HIV-1 Subtypes B and C.

Resistance to anti-Human Immunodeficiency Virus (HIV) drugs has been a problem from the beginning of antiviral drug treatments. The recent expansion of combination antiretroviral therapy worldwide has led to an increase in resistance to antiretrovirals; understanding the mechanisms of resistance is increasingly important. In this study, we analyzed reverse transcriptase (RT) variants based on sequences derived from an individual who had a low-level rebound viremia while undergoing therapy with abacavir, azidothymidine (AZT or Zidovudine), and (-)-L-2',3'-dideoxy-3'-thiacytidine (Lamivudine or 3TC). The RT had mutations at positions 64, 67, 70, 184, 219, and a threonine insertion after amino acid 69 in RT. The virus remained partially susceptible to the nucleoside reverse transcriptase inhibitor (NRTI) regimen. We show how these mutations affect the ability of NRTIs to inhibit DNA synthesis by RT. The presence of the inserted threonine reduced the susceptibility of the RT mutant to inhibition by Tenofovir.