Impact of human immunodeficiency virus type 1 reverse transcriptase inhibitor drug resistance mutation interactions on phenotypic susceptibility

Vinod Trivedi, Jana Von Lindern, Miguel Montes-Walters, Daniel R. Rojo, Elisabeth J. Shell, Neil Parkin, William A. O'Brien, Monique Ferguson

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

The role specific reverse transcriptase (RT) drug resistance mutations play in influencing phenotypic susceptibility to RT inhibitors in virus strains with complex resistance interaction patterns was assessed using recombinant viruses that consisted of RT-PCR-amplified pol fragments derived from plasma HIV-1 RNA from two treatment-experienced patients. Specific modifications of key RT amino acids were performed by site-directed mutagenesis. A panel of viruses with defined genotypic resistance mutations was assessed for phenotypic drug resistance. Introduction of M184V into several different clones expressing various RT resistance mutations uniformly decreased susceptibility to abacavir, lamivudine, and didanosine, and increased susceptibility to zidovudine, stavudine, and tenofovir; replication capacity was decreased. The L74V mutation had similar but slightly different effects, contributing to decreased susceptibility to abacavir, lamivudine, and didanosine and increased susceptibility to zidovudine and tenofovir, but in contrast to M184V, L74V contributed to decreased susceptibility to stavudine. In virus strains with the nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations K101E and G190S, the L74V mutation increased replication capacity, consistent with published observations, but replication capacity was decreased in strains without NNRTI resistance mutations. K101E and G190S together tend to decrease susceptibility to all nucleoside RT inhibitors, but the K103N mutation had little effect on nucleoside RT inhibitor susceptibility. Mutational interactions can have a substantial impact on drug resistance phenotype and replication capacity, and this has been exploited in clinical practice with the development of fixed-dose combination pills. However, we are the first to report these mutational interactions using molecularly cloned recombinant strains derived from viruses that occur naturally in HIV-infected individuals.

Original languageEnglish (US)
Pages (from-to)1291-1300
Number of pages10
JournalAIDS Research and Human Retroviruses
Volume24
Issue number10
DOIs
StatePublished - Aug 1 2008

Fingerprint

Reverse Transcriptase Inhibitors
Drug Resistance
HIV-1
Mutation
Tenofovir
Viruses
RNA-Directed DNA Polymerase
Stavudine
Didanosine
Zidovudine
Nucleosides
Human immunodeficiency virus 1 reverse transcriptase
Site-Directed Mutagenesis
Reverse Transcriptase Polymerase Chain Reaction
Clone Cells
HIV
RNA
Phenotype
Amino Acids

ASJC Scopus subject areas

  • Immunology
  • Virology
  • Infectious Diseases

Cite this

Impact of human immunodeficiency virus type 1 reverse transcriptase inhibitor drug resistance mutation interactions on phenotypic susceptibility. / Trivedi, Vinod; Von Lindern, Jana; Montes-Walters, Miguel; Rojo, Daniel R.; Shell, Elisabeth J.; Parkin, Neil; O'Brien, William A.; Ferguson, Monique.

In: AIDS Research and Human Retroviruses, Vol. 24, No. 10, 01.08.2008, p. 1291-1300.

Research output: Contribution to journalArticle

Trivedi, Vinod ; Von Lindern, Jana ; Montes-Walters, Miguel ; Rojo, Daniel R. ; Shell, Elisabeth J. ; Parkin, Neil ; O'Brien, William A. ; Ferguson, Monique. / Impact of human immunodeficiency virus type 1 reverse transcriptase inhibitor drug resistance mutation interactions on phenotypic susceptibility. In: AIDS Research and Human Retroviruses. 2008 ; Vol. 24, No. 10. pp. 1291-1300.
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