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.