Role of codon-69 variants in reduced susceptibility to nucleoside analogues

Simon Collins and Polly Clayden, HIV i-Base

Winters and Merigan analysed the occurrence and prevalence of codon-69 mutations performed from the Stanford RT and Protease Sequence Database [1].

The T69D mutation has been associated with reduced susceptibility to zalcitabine, however several other mutations at codon 69 have been observed in antiretroviral-treated people.

Codon-69 variants were found in 127/602 people treated with nucleoside analogues, but not in 330 drug-naive people and were significantly more prevalent in heavily treated patients. Treatment history revealed that a majority of people with codon-69 mutations had been treated with zalcitabine. However many patients who had never previously taken zalcitabine developed codon-69 mutations during antiretroviral therapy, including zidovudine monotherapy.

In vitro assays showed a viral construct containing T69N had reduced susceptibility to zidovudine, didanosine and zalcitabine, a T69S to zalcitabine and a T69A to zidovudine. These data suggest that the T69D mutation is not the only codon-69 variant associated with resistance nor is zalcitabine the only drug affected by codon-69 variants.


  1. Winters MA et al. Variants other than aspartic acid at codon 69 of the HIV-1 reverse transcriptase gene affect susceptibility to nucleoside analogues. Antiviral Therapy 2001; 6 (Supplement1):56. Abstract 75

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