The Impact of Multidideoxynucleoside Resistance-conferring Mutations in Human Immunodeficiency Virus Type 1 Reverse Transcriptase on Polymerase Fidelity and Error Specificity

Overview

Journal J Virol

Publisher American Society for Microbiology

Date 1998 Apr 3

PMID 9525609

Citations 22

Authors

L F Rezende

K Curr

T Ueno

H Mitsuya

V R Prasad

Affiliations

Soon will be listed here.

Abstract

Variants of human immunodeficiency virus type 1 (HIV-1) that are highly resistant to a number of nucleoside analog drugs have been shown to develop in some patients receiving 2',3'-dideoxy-3'-azidothymidine therapy in combination with 2',3'-dideoxycytidine or 2',3'-dideoxyinosine. The appearance, in the reverse transcriptase (RT), of the Q151M mutation in such variants precedes the sequential appearance of three or four additional mutations, resulting in a highly resistant virus. Three of the affected residues are proposed to lie in the vicinity of the template-primer in the three-dimensional structure of the HIV-1 RT-double-stranded DNA complex. The amino acid residue Q151 is thought to be very near the templating base. The nucleoside analog resistance mutations in the beta9-beta10 (M184V) and the beta5a (E89G) strands of HIV-1 RT were previously shown to increase the fidelity of deoxynucleoside triphosphate insertion. Therefore, we have examined wild-type HIV-1BH10 RT and two nucleoside analog-resistant variants, the Q151M and A62V/V75I/F77L/F116Y/Q151M (VILYM) RTs, for their overall forward mutation rates in an M13 gapped-duplex assay that utilizes lacZ alpha as a reporter. The overall error rates for the wild-type, the Q151M, and the VILYM RTs were 4.5 x 10(-5), 4.0 x 10(-5), and 2.3 x 10(-5) per nucleotide, respectively. Although the mutant RTs displayed minimal decreases in the overall error rates compared to wild-type RT, the error specificities of both mutant RTs were altered. The Q151M RT mutant generated new hot spots, which were not observed for wild-type HIV-1 RT previously. The VILYM RT showed a marked reduction in error rate at two of the predominant mutational hot spots that have been observed for wild-type HIV-1 RT.

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References

Preston B, Poiesz B, Loeb L . Fidelity of HIV-1 reverse transcriptase. Science. 1988; 242(4882):1168-71. DOI: 10.1126/science.2460924. View

Wainberg M, Drosopoulos W, Salomon H, Hsu M, Borkow G, Parniak M . Enhanced fidelity of 3TC-selected mutant HIV-1 reverse transcriptase. Science. 1996; 271(5253):1282-5. DOI: 10.1126/science.271.5253.1282. View

Mendelman L, Boosalis M, Petruska J, Goodman M . Nearest neighbor influences on DNA polymerase insertion fidelity. J Biol Chem. 1989; 264(24):14415-23. View

Bebenek K, Abbotts J, Roberts J, Wilson S, Kunkel T . Specificity and mechanism of error-prone replication by human immunodeficiency virus-1 reverse transcriptase. J Biol Chem. 1989; 264(28):16948-56. View

Poch O, Sauvaget I, Delarue M, Tordo N . Identification of four conserved motifs among the RNA-dependent polymerase encoding elements. EMBO J. 1989; 8(12):3867-74. PMC: 402075. DOI: 10.1002/j.1460-2075.1989.tb08565.x. View

Ricchetti M, Buc H . Reverse transcriptases and genomic variability: the accuracy of DNA replication is enzyme specific and sequence dependent. EMBO J. 1990; 9(5):1583-93. PMC: 551854. DOI: 10.1002/j.1460-2075.1990.tb08278.x. View

Richman D . HIV drug resistance. AIDS Res Hum Retroviruses. 1992; 8(6):1065-71. DOI: 10.1089/aid.1992.8.1065. View

Shirasaka T, Yarchoan R, OBRIEN M, Husson R, Anderson B, Kojima E . Changes in drug sensitivity of human immunodeficiency virus type 1 during therapy with azidothymidine, dideoxycytidine, and dideoxyinosine: an in vitro comparative study. Proc Natl Acad Sci U S A. 1993; 90(2):562-6. PMC: 45703. DOI: 10.1073/pnas.90.2.562. View

Abbotts J, Bebenek K, Kunkel T, Wilson S . Mechanism of HIV-1 reverse transcriptase. Termination of processive synthesis on a natural DNA template is influenced by the sequence of the template-primer stem. J Biol Chem. 1993; 268(14):10312-23. View

10.

Bebenek K, Abbotts J, Wilson S, Kunkel T . Error-prone polymerization by HIV-1 reverse transcriptase. Contribution of template-primer misalignment, miscoding, and termination probability to mutational hot spots. J Biol Chem. 1993; 268(14):10324-34. View

11.

Martin J, Wilson J, Haynes R, Furman P . Mechanism of resistance of human immunodeficiency virus type 1 to 2',3'-dideoxyinosine. Proc Natl Acad Sci U S A. 1993; 90(13):6135-9. PMC: 46882. DOI: 10.1073/pnas.90.13.6135. View

12.

Temin H . Retrovirus variation and reverse transcription: abnormal strand transfers result in retrovirus genetic variation. Proc Natl Acad Sci U S A. 1993; 90(15):6900-3. PMC: 47042. DOI: 10.1073/pnas.90.15.6900. View

13.

Beard W, Wilson S . Kinetic analysis of template.primer interactions with recombinant forms of HIV-1 reverse transcriptase. Biochemistry. 1993; 32(37):9745-53. DOI: 10.1021/bi00088a029. View

14.

ECKERT K, Kunkel T . Fidelity of DNA synthesis catalyzed by human DNA polymerase alpha and HIV-1 reverse transcriptase: effect of reaction pH. Nucleic Acids Res. 1993; 21(22):5212-20. PMC: 310639. DOI: 10.1093/nar/21.22.5212. View

15.

Shafer R, Kozal M, Winters M, Iversen A, Katzenstein D, Ragni M . Combination therapy with zidovudine and didanosine selects for drug-resistant human immunodeficiency virus type 1 strains with unique patterns of pol gene mutations. J Infect Dis. 1994; 169(4):722-9. DOI: 10.1093/infdis/169.4.722. View

16.

Shirasaka T, Kavlick M, Ueno T, Gao W, Kojima E, Alcaide M . Emergence of human immunodeficiency virus type 1 variants with resistance to multiple dideoxynucleosides in patients receiving therapy with dideoxynucleosides. Proc Natl Acad Sci U S A. 1995; 92(6):2398-402. PMC: 42491. DOI: 10.1073/pnas.92.6.2398. View

17.

Jaju M, Beard W, Wilson S . Human immunodeficiency virus type 1 reverse transcriptase. 3'-Azidodeoxythymidine 5'-triphosphate inhibition indicates two-step binding for template-primer. J Biol Chem. 1995; 270(17):9740-7. DOI: 10.1074/jbc.270.17.9740. View

18.

Sarafianos S, Pandey V, Kaushik N, Modak M . Glutamine 151 participates in the substrate dNTP binding function of HIV-1 reverse transcriptase. Biochemistry. 1995; 34(21):7207-16. DOI: 10.1021/bi00021a036. View

19.

Mansky L, Temin H . Lower in vivo mutation rate of human immunodeficiency virus type 1 than that predicted from the fidelity of purified reverse transcriptase. J Virol. 1995; 69(8):5087-94. PMC: 189326. DOI: 10.1128/JVI.69.8.5087-5094.1995. View

20.

Bebenek K, Beard W, Casas-Finet J, Kim H, Darden T, Wilson S . Reduced frameshift fidelity and processivity of HIV-1 reverse transcriptase mutants containing alanine substitutions in helix H of the thumb subdomain. J Biol Chem. 1995; 270(33):19516-23. DOI: 10.1074/jbc.270.33.19516. View