Antagonism between the HIV-1 Reverse-Transcriptase Mutation K65R and Thymidine-Analogue Mutations at the Genomic Level

Parikh, Urvi M.; Barnas, Douglas C.; Faruki, Hawazin; Mellors, John W.
September 2006
Journal of Infectious Diseases;9/1/2006, Vol. 194 Issue 5, p651
Academic Journal
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 ⩾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 ⩾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 ⩾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.


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