Emergence of human immunodeficiency virus type 1 variants with resistance to multiple dideoxynucleosides in patients receiving therapy with dideoxynucleosides

Takuma Shirasaka, Mark F. Kavlick, Takamasa Ueno, Wen Yi Gao, Eiji Kojima, Maria L. Alcaide, Sudhichai Chokekijchai, Birgit M. Roy, Edward Arnold, Robert Yarchoan, Hiroaki Mitsuya

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Abstract

A set of mutations [Ala-62 → Val(A62V), V751, F77L, F116Y, and Q151M] in the polymerase domain of reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) confers on the virus a reduced sensitivity to multiple antiretroviral dideoxynucleosides and has been seen in HIV-1 variants isolated from patients receiving combination chemotherapy with 3'-azido-3'- deoxythymidine (AZT) plus 2',3'-dideoxycytidine (ddC) or 2',3'-dideoxyinosine (ddI). The IC50 values of AZT, ddC, ddI, 2',3'-dideoxyguanosine, and 2',3'- didehydro-3'-deoxythymidine against an infectious clone constructed to include the five mutations were significantly higher than those of a wild- type infectious clone. The K(i) value for AZT 5'-triphosphate determined for the virus-associated RT from a posttherapy strain was 35-fold higher than that of RT from a pretherapy strain. Detailed analysis of HIV-1 strains isolated at various times during therapy showed that the Q151M mutation developed first in vivo, at the time when the viremia level suddenly increased, followed by the F116Y and F77L mutations. All five mutations ultimately developed, and the viremia level rose even further. Analyses based on the three-dimensional structure of HIV-1 RT suggest that the positions where at least several of the five mutations occur are located in close proximity to the proposed dNTP-binding site of RT and the first nucleotide position of the single-stranded template.

Original languageEnglish (US)
Pages (from-to)2398-2402
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume92
Issue number6
DOIs
StatePublished - Mar 14 1995

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Keywords

  • dNTP-binding site
  • multidrug resistance
  • reverse transcriptase

ASJC Scopus subject areas

  • Genetics
  • General

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