Characterisation of foscarnet-resistant strains of human immunodeficiency virus type 1

Virology
G TachedjianJ Mills

Abstract

Foscarnet is a broad-spectrum viral DNA polymerase inhibitor active in vitro and in vivo against human immunodeficiency virus type 1 (HIV-1). Strains of HIV-1 resistant to foscarnet were selected by in vitro passage in increasing concentrations of drug. Reduced susceptibility to foscarnet was evident at the levels of both HIV-1 replication and reverse transcriptase. Biologically cloned, foscarnet-resistant strains with distinct genotypes were hypersensitive to zidovudine, azidodeoxyuridine, nevirapine, and R82913 but had unchanged susceptibility to zalcitibine and didanosine. The reverse transcriptase of foscarnet-resistant strains had unique substitutions Glu89-Lys, Leu92-Ile, or Ser156-Ala, the third being associated with six polymorphic changes. Introduction of these mutations into wild-type HIV-1 by site-directed mutagenesis confirmed their role in foscarnet resistance. In the three-dimensional structure of the reverse transcriptase enzyme these amino acids are located close to the template strand of the template primer and far away from the putative pyrophosphate binding site, suggesting that the mechanism by which HIV-1 becomes resistant to foscarnet is indirect. Foscarnet resistance is thus likely to be mediated through ...Continue Reading

Citations

Aug 26, 1998·AIDS Research and Human Retroviruses·G TachedjianJ Mills
Sep 2, 2008·Journal of Clinical Virology : the Official Publication of the Pan American Society for Clinical Virology·Charlotte CharpentierChristophe Piketty
Apr 26, 2005·International Journal of Antimicrobial Agents·Cândida F PereiraHans S L M Nottet
Aug 16, 2001·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Dominique Arion, Michael A. Parniak
Jun 5, 2010·Viruses·Antonio J Acosta-Hoyos, Walter A Scott
Oct 31, 2014·The Journal of Biological Chemistry·Jean A BernatchezMatthias Götte

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