The K65R mutation in human immunodeficiency virus type 1 reverse transcriptase exhibits bidirectional phenotypic antagonism with thymidine analog mutations.

TitleThe K65R mutation in human immunodeficiency virus type 1 reverse transcriptase exhibits bidirectional phenotypic antagonism with thymidine analog mutations.
Publication TypeJournal Article
Year of Publication2006
AuthorsParikh UM, Bacheler L, Koontz D, Mellors JW
JournalJ Virol
Volume80
Issue10
Pagination4971-7
Date Published2006 May
ISSN0022-538X
KeywordsAdenine, Amino Acid Substitution, Anti-HIV Agents, Arginine, Didanosine, Dideoxynucleosides, Drug Resistance, Multiple, Viral, Genotype, HIV Reverse Transcriptase, HIV-1, Humans, Lysine, Organophosphonates, Phenotype, Point Mutation, Reverse Transcriptase Inhibitors, Tenofovir, Thymidine, Zalcitabine, Zidovudine
Abstract

The K65R mutation in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) is selected in vitro by many D-nucleoside analog RT inhibitors (NRTI) but has been rarely detected in treated patients. In recent clinical trials, the K65R mutation has emerged frequently in patients experiencing virologic failure on antiretroviral combinations that do not include 3'-azidothymidine (AZT). The reason for this change is uncertain. To gain insight, we examined trends in the frequency of K65R in a large genotype database, the association of K65R with thymidine analog mutations (TAMs) and other NRTI mutations, and the viral susceptibility profile of HIV-1 with K65R alone and in combination with TAMs. Among >60,000 clinical samples submitted for genotype analysis that contained one or more NRTI resistance mutations, the frequency of K65R increased from 0.4% in 1998 to 3.6% in 2003. Among samples with K65R, a strong negative association was evident with the TAMs M41L, D67N, L210W, T215Y/F, and K219Q/E (P<0.005) but not with other NRTI mutations, including the Q151M complex. This suggested that K65R and TAMs are antagonistic. To test this possibility, we generated recombinant HIV-1 encoding K65R in two different TAM backgrounds: M41L/L210W/T215Y and D67N/K70R/T215F/K219Q. K65R reduced AZT resistance from >50-fold to <2.5-fold in both backgrounds. In addition, TAMs antagonized the phenotypic effect of K65R, reducing resistance to tenofovir, abacavir, 2',3'-dideoxycytidine, dideoxyinosine, and stavudine. In conclusion, K65R and TAMs exhibit bidirectional phenotypic antagonism. This antagonism likely explains the negative association of these mutations in genotype databases, the rare emergence of K65R with antiretroviral therapies that contain AZT, and its more frequent emergence with combinations that exclude AZT.

DOI10.1128/JVI.80.10.4971-4977.2006
Alternate JournalJ. Virol.
PubMed ID16641288
PubMed Central IDPMC1472090
Grant ListU01AI38858 / AI / NIAID NIH HHS / United States