Enhanced fidelity of drug-selected M184V mutated reverse transcriptase as the basis for the effectiveness of 3TC in HIV clinical trials.
Originally Published on May 12, 1999
Wainberg MA; Salomon H; Hsu M; Li Z; Borkow G; Parniak MA; Gu Z.
3rd Conf Retro and Opportun Infect. 1996 Jan 28-Feb 1;:54.
ABSTRACT:
HIV-infected individuals, who received 3TC monotherapy over one year, had lower plasma viral burden than at base-line, in spite of high-level resistance to this compound and the appearance of the M184V substitution in the HIV reverse transcriptase (RT) gene, responsible for resistance to 3TC. This apparent contradiction is explained by an increase in the fidelity of the HIV RT, conferred by the M184V mutation, on the basis of the following;
Titers of viral neutralizing antibodies, as measured against sequential autologous HIV isolates, remained stable in this population in contrast to rapid declines in patients treated with other drugs. This suggests that increased fidelity of M184V RT may limit variability in the HIV env gene and result in protracted effectiveness of anti-viral immune responsiveness;
Studies with purified recombinant RT showed an approximate 6-fold increase in fidelity of DNA-dependent-DNA polymerization by the M184V mutant compared to wild-type enzyme;
Recombinant HIV, that contained the M184V substitution in RT, could not replicate in the presence of d4T, AZT, Nevirapine, Delavirdine or Saquinavir, using established protocols for the generation of drug resistance in vitro;
Immunological escape variants could not easily be detected following growth of M184V-containing viruses in the presence of patient neutralizing antibodies, in contradistinction to results obtained with wild-type viruses;
long-term replication of 184V-containing viruses in T-cell lines led to at least a ten-fold increase in TCID50:p24 ratios in culture fluids, due to a presumed decrease in numbers of lethal mutations.
