Analysis of HIV-2 RT mutants provides evidence that resistance of HIV-1 RT and HIV-2 RT to nucleoside analogs involves a repositioning of the template-primer

Journal of Molecular Biology
M PerachA Hizi

Abstract

Mutations that confer resistance to nucleoside analogs do not cluster around the deoxynucleotide triphosphate (dNTP) binding site. Instead, these mutations appear to lie along the groove in the enzyme where the template-primer binds. Based on such structural data and on complementary biochemical analyses, it has been suggested that resistance to nucleoside analogs involves repositioning of the template-primer. We have prepared mutations in HIV-2 RT that are the homologs of mutations that confer resistance to nucleoside analogs in HIV-1 RT. Analysis of the behavior of HIV-2 RT mutants (Leu74Val, Glu89Gly, Ser215Tyr, Leu74Val/Ser215Tyr and Glu89Gly/Ser215Tyr) in vitro confirms the results obtained with HIV-1 RT: resistance is a function of the length of the template overhang. These analyses also suggest that the homolog in HIV-2 RT of one of the mutations that confers resistance to AZT in HIV-1 RT (Thr215Tyr) confers resistance by repositioning of the template-primer.

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Citations

Jul 1, 2004·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Christopher MullinsPhyllis J Kanki
Aug 5, 1998·Proceedings of the National Academy of Sciences of the United States of America·J RenD K Stammers
Jul 3, 2004·The Journal of Biological Chemistry·Louise Z WangKenneth A Johnson
Aug 31, 1999·The Journal of General Virology·J P VartanianA Meyerhans
Aug 16, 2001·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Dominique Arion, Michael A. Parniak

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