The impact of multidideoxynucleoside resistance-conferring mutations in human immunodeficiency virus type 1 reverse transcriptase on polymerase fidelity and error specificity

Lisa F. Rezende, Kenneth Curr, Takamasa Ueno, Hiroaki Mitsuya, Vinayaka R. Prasad

Research output: Contribution to journalArticle

46 Citations (Scopus)

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 transcriprase (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 β9-β10 (M184V) and the β5a (E89G) strands of HIV-1 RT were previously shown to increase the fidelity of deoxynucleoside triphosphate insertion. Therefore, we have examined wild- type HIV-1(BH10) RT and two nucleoside analog-resistant variants, the Q151M and A62V/V751/F77L/F116Y/Q151M (VILYM) RTs, for their overall forward mutation rates in an M13 gapped-duplex assay that utilizes lacZα 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.

Original languageEnglish (US)
Pages (from-to)2890-2895
Number of pages6
JournalJournal of Virology
Volume72
Issue number4
StatePublished - Apr 1998

Fingerprint

RNA-directed DNA polymerase
Human immunodeficiency virus 1
HIV-1
mutation
Mutation
nucleosides
Nucleosides
mutants
Zalcitabine
Didanosine
Zidovudine
Mutation Rate
Human immunodeficiency virus 1 reverse transcriptase
Nucleotides
nucleotides
Viruses
Amino Acids
drugs
viruses
therapeutics

ASJC Scopus subject areas

  • Immunology

Cite this

The impact of multidideoxynucleoside resistance-conferring mutations in human immunodeficiency virus type 1 reverse transcriptase on polymerase fidelity and error specificity. / Rezende, Lisa F.; Curr, Kenneth; Ueno, Takamasa; Mitsuya, Hiroaki; Prasad, Vinayaka R.

In: Journal of Virology, Vol. 72, No. 4, 04.1998, p. 2890-2895.

Research output: Contribution to journalArticle

@article{e5fd7c442aeb439c928187a43ae54323,
title = "The impact of multidideoxynucleoside resistance-conferring mutations in human immunodeficiency virus type 1 reverse transcriptase on polymerase fidelity and error specificity",
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 transcriprase (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 β9-β10 (M184V) and the β5a (E89G) strands of HIV-1 RT were previously shown to increase the fidelity of deoxynucleoside triphosphate insertion. Therefore, we have examined wild- type HIV-1(BH10) RT and two nucleoside analog-resistant variants, the Q151M and A62V/V751/F77L/F116Y/Q151M (VILYM) RTs, for their overall forward mutation rates in an M13 gapped-duplex assay that utilizes lacZα 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.",
author = "Rezende, {Lisa F.} and Kenneth Curr and Takamasa Ueno and Hiroaki Mitsuya and Prasad, {Vinayaka R.}",
year = "1998",
month = "4",
language = "English (US)",
volume = "72",
pages = "2890--2895",
journal = "Journal of Virology",
issn = "0022-538X",
publisher = "American Society for Microbiology",
number = "4",

}

TY - JOUR

T1 - The impact of multidideoxynucleoside resistance-conferring mutations in human immunodeficiency virus type 1 reverse transcriptase on polymerase fidelity and error specificity

AU - Rezende, Lisa F.

AU - Curr, Kenneth

AU - Ueno, Takamasa

AU - Mitsuya, Hiroaki

AU - Prasad, Vinayaka R.

PY - 1998/4

Y1 - 1998/4

N2 - 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 transcriprase (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 β9-β10 (M184V) and the β5a (E89G) strands of HIV-1 RT were previously shown to increase the fidelity of deoxynucleoside triphosphate insertion. Therefore, we have examined wild- type HIV-1(BH10) RT and two nucleoside analog-resistant variants, the Q151M and A62V/V751/F77L/F116Y/Q151M (VILYM) RTs, for their overall forward mutation rates in an M13 gapped-duplex assay that utilizes lacZα 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.

AB - 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 transcriprase (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 β9-β10 (M184V) and the β5a (E89G) strands of HIV-1 RT were previously shown to increase the fidelity of deoxynucleoside triphosphate insertion. Therefore, we have examined wild- type HIV-1(BH10) RT and two nucleoside analog-resistant variants, the Q151M and A62V/V751/F77L/F116Y/Q151M (VILYM) RTs, for their overall forward mutation rates in an M13 gapped-duplex assay that utilizes lacZα 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.

UR - http://www.scopus.com/inward/record.url?scp=0031897968&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0031897968&partnerID=8YFLogxK

M3 - Article

C2 - 9525609

AN - SCOPUS:0031897968

VL - 72

SP - 2890

EP - 2895

JO - Journal of Virology

JF - Journal of Virology

SN - 0022-538X

IS - 4

ER -