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Enhanced fidelity of 3TC-selected mutant HIV-1 reverse transcriptase
M A Wainberg1, W C Drosopoulos, H Salomon
1McGill AIDS Centre, Jewish General Hospital, Montreal, Canada.
Science (New York, N.Y.)
|March 1, 1996
Summary
Monotherapy with 3TC, an HIV-1 drug, causes resistance mutations (M184V). However, this HIV variant shows increased fidelity and doesn't develop further resistance, leading to lower viral loads in patients.
Area of Science:
- Virology
- Antiviral Drug Resistance
- Molecular Biology
Background:
- Monotherapy with 3TC ((-)2',3'-dideoxy-3'-thiacytidine) for HIV-1 infection selects for the M184V mutation in reverse transcriptase.
- This M184V mutation confers resistance to 3TC.
- Paradoxically, long-term 3TC treatment is associated with reduced plasma viral burden despite resistance development.
Purpose of the Study:
- To investigate the reasons behind the reduced viral burden in HIV-1 patients treated with 3TC despite the emergence of drug-resistant M184V variants.
- To understand the in vitro characteristics of the M184V mutant HIV-1.
Main Methods:
- Comparative analysis of HIV-1 antibody titers in patients treated with 3TC versus AZT.
- In vitro growth studies of M184V mutant HIV-1 in the presence of various antiretroviral drugs (d4T, AZT, Nevirapine, Delavirdine, Saquinavir).
- Assessment of the fidelity of nucleotide insertion by wild-type and M184V mutant reverse transcriptase.
Main Results:
- HIV-1 patients on 3TC maintained stable titers of neutralizing antibodies, unlike those on AZT.
- The M184V mutant HIV-1 did not develop further drug resistance when cultured with other antiretrovirals.
- The M184V mutant reverse transcriptase exhibited increased fidelity in nucleotide insertion compared to the wild-type enzyme.
Conclusions:
- The M184V mutation, while conferring resistance to 3TC, may lead to a less virulent or more easily controlled virus.
- Increased fidelity of the M184V mutant may contribute to the observed reduction in viral burden.
- These findings highlight the complex interplay between drug resistance, viral fitness, and treatment outcomes in HIV-1 infection.