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Research ArticleArticle

Susceptibility of Feline Immunodeficiency Virus/Human Immunodeficiency Virus Type 1 Reverse Transcriptase Chimeras to Non-Nucleoside RT Inhibitors

Joeri Auwerx, Robert Esnouf, Erik De Clercq and Jan Balzarini
Molecular Pharmacology January 2004, 65 (1) 244-251; DOI: https://doi.org/10.1124/mol.65.1.244
Joeri Auwerx
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Robert Esnouf
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Erik De Clercq
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Jan Balzarini
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Abstract

To map the determinants of the lack of susceptibility of feline immunodeficiency virus (FIV) reverse transcriptase (RT) to anti human immunodeficiency virus type 1 (HIV-1) non-nucleoside RT inhibitors (NNRTIs), a variety of chimeric HIV-1/FIV RTs were constructed. The majority of chimeric RTs had an affinity (Km) for their natural substrates comparable with that of the wild-type HIV-1 and FIV RTs, but their catalytic efficacy was decreased. Whereas HIV-1 RT could be made entirely insensitive to NNRTIs by exchanging the amino acid sequence 97 through 205 of FIV RT, none of the reverse FIV/HIV-1 RT chimeras gained susceptibility to NNRTIs. The amino acids that are thought to be involved in NNRTI susceptibility and that are different from those in HIV-1 RT have also been introduced in FIV RT. These mutant RTs gained virtually no susceptibility to efavirenz or capravirine. Vice versa, when these HIV-1-specific amino acids were replaced by their FIV RT counterparts in HIV-1 RT, susceptibility to the NNRTIs was lost. Thus, replacing segments or substituting relevant amino acids in FIV RT by their HIV-1 RT counterparts did not suffice to make FIV RT sensitive toward NNRTIs and was often accompanied by a decrease or even total loss of polymerase activity. It is postulated that, in contrast to the results found for HIV-1/HIV-2 RT chimeras and supported by the crystal structure of HIV-2 RT, there exist significant differences in the structure and/or flexibility of FIV RTs that may prevent NNRTIs from interacting with the FIV RT.

  • Received July 14, 2003.
  • Accepted October 1, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 65 (1)
Molecular Pharmacology
Vol. 65, Issue 1
1 Jan 2004
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Research ArticleArticle

Susceptibility of Feline Immunodeficiency Virus/Human Immunodeficiency Virus Type 1 Reverse Transcriptase Chimeras to Non-Nucleoside RT Inhibitors

Joeri Auwerx, Robert Esnouf, Erik De Clercq and Jan Balzarini
Molecular Pharmacology January 1, 2004, 65 (1) 244-251; DOI: https://doi.org/10.1124/mol.65.1.244

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Research ArticleArticle

Susceptibility of Feline Immunodeficiency Virus/Human Immunodeficiency Virus Type 1 Reverse Transcriptase Chimeras to Non-Nucleoside RT Inhibitors

Joeri Auwerx, Robert Esnouf, Erik De Clercq and Jan Balzarini
Molecular Pharmacology January 1, 2004, 65 (1) 244-251; DOI: https://doi.org/10.1124/mol.65.1.244
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