TY - JOUR
T1 - Mutational studies of human immunodeficiency virus type 1 reverse transcriptase
T2 - The involvement of residues 183 and 184 in the fidelity of DNA synthesis
AU - Bakhanashvili, Mary
AU - Avidan, Orna
AU - Hizi, Amnon
N1 - Funding Information:
Boyer for providingth e mutantso f HIV-I RT. This researchw as supportedb y grantsf rom the Israeli CancerA ssociation( Grant 952013-B)a, ndfrom the IsraelC ancerR esearchF und(ICRF).
PY - 1996/8/12
Y1 - 1996/8/12
N2 - The 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.
AB - The 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.
KW - DNA synthesis
KW - Fidelity
KW - HIV
KW - Mutant
KW - Reverse transcriptase
UR - https://www.scopus.com/pages/publications/0030581311
U2 - 10.1016/0014-5793(96)00747-8
DO - 10.1016/0014-5793(96)00747-8
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AN - SCOPUS:0030581311
SN - 0014-5793
VL - 391
SP - 257
EP - 262
JO - FEBS Letters
JF - FEBS Letters
IS - 3
ER -
