ANALYSIS OF HIV-2 RT MUTANTS PROVIDES EVIDENCE THAT RESISTANCE OF HIV-1 RT AND HIV-2 RT TO NUCLEOSIDE ANALOGS INVOLVES A REPOSITIONING OF THE TEMPLATE-PRIMER

Mutations that confer resistance to nucleoside analogs do not cluster around the deoxynucleotide triphosphate (dNTP) binding site. Instead, these mutations appear to lie along the groove in the enzyme where the template-primer binds. Based on such structural data and on complemen tary biochemical analyses, it has been suggested that resistance to nu cleoside analogs involves repositioning of the template-primer. We hav e prepared mutations in HIV-2 RT that are the homologs of mutations th at confer resistance to nucleoside analogs in HIV-1 RT. Analysis of th e behavior of HIV-2 RT mutants (Leu74Val, Glu89Gly, Ser215Tyr, Leu74-V al/Ser215Tyr and Glu89Gly/Ser215Tyr) in vitro confirms the results obt ained with HIV-1 RT: resistance is a function of the length of the tem plate overhang. These analyses also suggest that the homolog in HIV-2 RT of one of the mutations that confers resistance to AZT in HIV-1 RT (Thr215Tyr) confers resistance by repositioning of the template-primer .