title: Antagonism between the HIV-1 reverse-transcriptase mutation K65R and thymidine-analogue mutations at the genomic level.
abstract: Prior virologic and biochemical studies have shown phenotypic antagonism between K65R and multiple thymidine-analogue mutations (TAMs) in site-directed mutants tested in vitro. We hypothesized, on the basis of this observed antagonism, that K65R and T215Y/F with multiple TAMs would not be selected on the same human immunodeficiency virus type 1 genome in vivo. We searched a large database of patient genotypes (n=59,262) for the frequency of K65R in combination with >or=3 TAMs as determined by standard population sequencing. K65R and multiple TAMs were rarely detected (<0.1%) in the same plasma sample. Samples with both K65R and >or=3 TAMs (n=21) were further analyzed by use of single-genome sequencing. K65R was never found on the same genome with T215F/Y and >or=2 other TAMs, except in the presence of the Q151M multiple nucleoside reverse-transcriptase inhibitor (NRTI)--resistance complex. These results indicate that antagonism between the K65R and T215Y/F pathways of NRTI resistance occurs at the genomic level. Therapy with NRTI combinations that select both pathways simultaneously may delay the emergence of NRTI resistance and prolong treatment response.
authors.affiliation: Department of Medicine, Division of Infectious Diseases, University of Pittsburgh School of Medicine, PA 15261, USA.
authors.forename: Urvi M
authors.initials: UM
authors.lastname: Parikh
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Barnas
authors.forename: Hawazin
authors.initials: H
authors.lastname: Faruki
authors.forename: John W
authors.initials: JW
authors.lastname: Mellors
mesh_terms: D019943:Amino Acid Substitution; D002986:Clinical Trials as Topic; D016679:Genome, Viral; D005838:Genotype; D054303:HIV Reverse Transcriptase / Q000235:genetics*; D015497:HIV-1 / Q000201:enzymology / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D013936:Thymidine
chemical_list: D054303:HIV Reverse Transcriptase; D013936:Thymidine