Reduced susceptibility of human immunodeficiency virus type 1 (HIV-1) from patients with primary HIV infection to nonnucleoside reverse transcriptase inhibitors is associated with variation at novel amino acid sites

A. J. Leigh Brown, H. M. Precious, J. M. Whitcomb, J. K. Wong, M. Quigg, W. Huang, E. S. Daar, R. T. D'Aquila, Philip Keiser, E. Connick, N. S. Hellmann, C. J. Petropoulos, D. D. Richman, S. J. Little

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Abstract

Recently, significant numbers of individuals with primary human immunodeficiency virus (HIV) infection have been found to barbor viral strains with reduced susceptibility to antiretroviral drugs. In one study, HIV from 16% of such antiretroviral-naive individuals was shown to have a susceptibility to nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) between 2.5- and 10-fold lower than that of a wild-type control. Mutations in the RT domain that had previously been associated with antiretroviral resistance were not shared by these strains. We have analyzed by logistic regression 46 variable amino acid sites in RT for their effect on susceptibility and have identified two novel sites influencing susceptibility to NNRTIs: amino acids 135 and 283 in RT. Eight different combinations of amino acids at these sites were observed among these patients. These combinations showed a 14-fold range in mean susceptibility to both nevirapine and delavirdine. In vitro mutagenesis of the control strain combined with a phenotypic assay confirmed the significance of amino acid variation at these sites for susceptibility to NNRTIs.

Original languageEnglish (US)
Pages (from-to)10269-10273
Number of pages5
JournalJournal of Virology
Volume74
Issue number22
DOIs
StatePublished - 2000
Externally publishedYes

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Reverse Transcriptase Inhibitors
RNA-directed DNA polymerase
HIV infections
Virus Diseases
Human immunodeficiency virus 1
HIV-1
RNA-Directed DNA Polymerase
HIV
Amino Acids
amino acids
Delavirdine
Nevirapine
Mutagenesis
Logistic Models
Human immunodeficiency virus
mutagenesis
Mutation
Pharmaceutical Preparations
mutation
assays

ASJC Scopus subject areas

  • Immunology

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Reduced susceptibility of human immunodeficiency virus type 1 (HIV-1) from patients with primary HIV infection to nonnucleoside reverse transcriptase inhibitors is associated with variation at novel amino acid sites. / Leigh Brown, A. J.; Precious, H. M.; Whitcomb, J. M.; Wong, J. K.; Quigg, M.; Huang, W.; Daar, E. S.; D'Aquila, R. T.; Keiser, Philip; Connick, E.; Hellmann, N. S.; Petropoulos, C. J.; Richman, D. D.; Little, S. J.

In: Journal of Virology, Vol. 74, No. 22, 2000, p. 10269-10273.

Research output: Contribution to journalArticle

Leigh Brown, AJ, Precious, HM, Whitcomb, JM, Wong, JK, Quigg, M, Huang, W, Daar, ES, D'Aquila, RT, Keiser, P, Connick, E, Hellmann, NS, Petropoulos, CJ, Richman, DD & Little, SJ 2000, 'Reduced susceptibility of human immunodeficiency virus type 1 (HIV-1) from patients with primary HIV infection to nonnucleoside reverse transcriptase inhibitors is associated with variation at novel amino acid sites', Journal of Virology, vol. 74, no. 22, pp. 10269-10273. https://doi.org/10.1128/JVI.74.22.10269-10273.2000
Leigh Brown, A. J. ; Precious, H. M. ; Whitcomb, J. M. ; Wong, J. K. ; Quigg, M. ; Huang, W. ; Daar, E. S. ; D'Aquila, R. T. ; Keiser, Philip ; Connick, E. ; Hellmann, N. S. ; Petropoulos, C. J. ; Richman, D. D. ; Little, S. J. / Reduced susceptibility of human immunodeficiency virus type 1 (HIV-1) from patients with primary HIV infection to nonnucleoside reverse transcriptase inhibitors is associated with variation at novel amino acid sites. In: Journal of Virology. 2000 ; Vol. 74, No. 22. pp. 10269-10273.
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