Antagonism between the HIV-1 reverse-transcriptase mutation K65R and thymidine-analogue mutations at the genomic level.
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.
Parikh
Urvi M
UM
Department of Medicine, Division of Infectious Diseases, University of Pittsburgh School of Medicine, PA 15261, USA.
Barnas
Douglas C
DC
Faruki
Hawazin
H
Mellors
John W
JW
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
D054303:HIV Reverse Transcriptase; D013936:Thymidine