Mutational studies of human immunodeficiency virus type 1 reverse transcriptase : the involvement of residues 183 and 184 in the fidelity of DNA synthesis
1996; Wiley; Volume: 391; Issue: 3 Linguagem: Inglês
10.1016/0014-5793(96)00747-8
ISSN1873-3468
AutoresMary Bakhanashvili, Orna Avidan, Amnon Hizi,
Tópico(s)HIV/AIDS Research and Interventions
ResumoThe high error rates characteristic of human immunodeficiency virus type‐1 reverse transcriptase (HIV‐1 RT) are a presumptive source of the viral hypermutability that impedes prevention and therapy of acquired immunodeficiency syndrome (AIDS). We have analyzed two mutants of HIV‐1 RT by conducting a comparative study of the accuracy of DNA synthesis. Each mutant bears a single amino acid substitution adjacent to the two aspartic acid residues at positions 185 and 186 in the highly conserved DNA polymerase active site. The first mutant, Met 184 →Leu (M184L), displays a marked reduction in both misinsertion and mispair extension, suggesting a fidelity of DNA synthesis significantly higher than that of the wild‐type HIV‐1 RT. The second mutant, Tyr 183→Phe (Y183F), shows a decrease in mispair extension with no significant change in misincorporation. Thus, the overall pattern of error‐proneness of DNA synthesis is: wild‐type HIV‐1 RT > Y183F > M184L. Taken together, it is possible that residues 183 and 184 contribute to the low fidelity of DNA synthesis characteristic of the reverse transcriptases of HIV‐1, HIV‐2 and possibly, of other lentiviruses. Our observations may bear on the nature of potential mutations responsible for resistance to the nucleoside analogs used in chemotherapy of AIDS.
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