Enhanced fidelity of 3TC-selected mutant HIV-1 reverse transcriptase

Mark A. Wainberg, William C. Drosopoulos, Horacio Salomon, Mayla Hsu, Gadi Borkow, Michael A. Parniak, Zhengxian Gu, Qingbin Song, Jayanthi Manne, Sabina Islam, Gino Castriota, Vinayaka R. Prasad

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Abstract

Monotherapy with (-)2',3'-dideoxy-3'-thiacytidine (3TC) leads to the appearance of a drug-resistant variant of human immunodeficiency virus-type 1 (HIV-1) with the methionine-184 → valine (M184V) substitution in the reverse transcriptase (RT). Despite resulting drug resistance, treatment for more than 48 weeks is associated with a lower plasma viral burden than that at baseline. Studies to investigate this apparent contradiction revealed the following. (i) Titers of HIV-neutralizing antibodies remained stable in 3TC-treated individuals in contrast to rapid declines in those treated with azidothymidine (AZT). (ii) Unlike wild-type HIV, growth of M184V HIV in cell culture in the presence of d4T, AZT, Nevirapine, Delavirdine, or Saquinavir did not select for variants displaying drug resistance. (iii) There was an increase in fidelity of nucleotide insertion by the M184V mutant compared with wild-type enzyme.

Original languageEnglish (US)
Pages (from-to)1282-1285
Number of pages4
JournalScience
Volume271
Issue number5253
StatePublished - Mar 1 1996

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Valine
Methionine
HIV-1
Zidovudine
Drug Resistance
Delavirdine
HIV
Saquinavir
Nevirapine
HIV Antibodies
Lamivudine
RNA-Directed DNA Polymerase
Neutralizing Antibodies
Viral Load
Nucleotides
Cell Culture Techniques
Enzymes
Growth
Pharmaceutical Preparations
Human immunodeficiency virus 1 reverse transcriptase

ASJC Scopus subject areas

  • General

Cite this

Wainberg, M. A., Drosopoulos, W. C., Salomon, H., Hsu, M., Borkow, G., Parniak, M. A., ... Prasad, V. R. (1996). Enhanced fidelity of 3TC-selected mutant HIV-1 reverse transcriptase. Science, 271(5253), 1282-1285.

Enhanced fidelity of 3TC-selected mutant HIV-1 reverse transcriptase. / Wainberg, Mark A.; Drosopoulos, William C.; Salomon, Horacio; Hsu, Mayla; Borkow, Gadi; Parniak, Michael A.; Gu, Zhengxian; Song, Qingbin; Manne, Jayanthi; Islam, Sabina; Castriota, Gino; Prasad, Vinayaka R.

In: Science, Vol. 271, No. 5253, 01.03.1996, p. 1282-1285.

Research output: Contribution to journalArticle

Wainberg, MA, Drosopoulos, WC, Salomon, H, Hsu, M, Borkow, G, Parniak, MA, Gu, Z, Song, Q, Manne, J, Islam, S, Castriota, G & Prasad, VR 1996, 'Enhanced fidelity of 3TC-selected mutant HIV-1 reverse transcriptase', Science, vol. 271, no. 5253, pp. 1282-1285.
Wainberg MA, Drosopoulos WC, Salomon H, Hsu M, Borkow G, Parniak MA et al. Enhanced fidelity of 3TC-selected mutant HIV-1 reverse transcriptase. Science. 1996 Mar 1;271(5253):1282-1285.
Wainberg, Mark A. ; Drosopoulos, William C. ; Salomon, Horacio ; Hsu, Mayla ; Borkow, Gadi ; Parniak, Michael A. ; Gu, Zhengxian ; Song, Qingbin ; Manne, Jayanthi ; Islam, Sabina ; Castriota, Gino ; Prasad, Vinayaka R. / Enhanced fidelity of 3TC-selected mutant HIV-1 reverse transcriptase. In: Science. 1996 ; Vol. 271, No. 5253. pp. 1282-1285.
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N2 - Monotherapy with (-)2',3'-dideoxy-3'-thiacytidine (3TC) leads to the appearance of a drug-resistant variant of human immunodeficiency virus-type 1 (HIV-1) with the methionine-184 → valine (M184V) substitution in the reverse transcriptase (RT). Despite resulting drug resistance, treatment for more than 48 weeks is associated with a lower plasma viral burden than that at baseline. Studies to investigate this apparent contradiction revealed the following. (i) Titers of HIV-neutralizing antibodies remained stable in 3TC-treated individuals in contrast to rapid declines in those treated with azidothymidine (AZT). (ii) Unlike wild-type HIV, growth of M184V HIV in cell culture in the presence of d4T, AZT, Nevirapine, Delavirdine, or Saquinavir did not select for variants displaying drug resistance. (iii) There was an increase in fidelity of nucleotide insertion by the M184V mutant compared with wild-type enzyme.

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