MOLECULAR-BASIS AND CLINICAL-SIGNIFICANCE OF HIV-1 RESISTANCE TO NUCLEOSIDE COMPOUNDS

The prolonged use of anti-viral nucleosides (ZDV, ddI, ddC) in HIV-inf ected patients has given rise to the isolation of viral variants that display resistance against these compounds. Tissue culture selection e xperiments, involving increasing concentrations of anti-viral compound s, have likewise been shown to select for drug-resistant strains of HI V. Cloning, sequencing and site-directed mutagenesis have shown that a series of point mutations in the viral reverse transcriptase (RT) are responsible for this phenomenon. A different series of mutations in R T are responsible for resistance against non-nucleoside inhibitors of this enzyme. These mutations are due to the error-prone nature of RT d uring viral replication. Mutated forms of recombinant RT, that derive from drug-resistant viruses, have reduced affinity for relevant tripho sphorylated nucleosides.