Boyer P, Hughes SH.

Abstr Meet Groups Stud Struct AIDS Relat Syst Their Appl Target Drug Des. 1995 Jun 5-7; 9: (unnumbered abstract).

ABL/BRP/NCI/FCRDC/ABL/BRP, Frederick, MD, USA.

We have studied the effects of the mutations Met184Ile, Met184Val, Met184Leu, and Met184Ala on HIV-1 RT processivity. All of these variants show high levels of RNA-dependent DNA polymerase activity and show considerable resistance to ddITP. However, the mutants varied in their ability to polymerize processively. The mutants that were selected for resistance to oxathiolane-cytosine nucleoside analogs in vitro, Met184Ile and Met184Val, had only slight reductions in processivity compared to the wild-type enzyme; however, the mutants Met184Leu and Met184Ala, which have not been isolated by selection, were considerably reduced in their processivity. We have also studied the effects of nonnucleoside inhibitor resistance mutations on processivity. Two mutants, Leu100Ile and Lys103Asn, were less processive than wild-type RT, while the mutant Glu138Lys was significantly more processive than wild-type RT. Adding wild-type RT to a mixture of template-primer and 8-C1 TIBO considerably reduces RT processivity. Binding the template-primer to wild-type RT before the addition of the inhibitor results in only a modest decrease in processivity. A similar pattern is seen for the variant Pro236Leu, which is not resistant to TIBO derivatives. The variants Leu100Ile, Lys103Asn, Tyr181Ile, and Tyr188Leu, which have high levels of resistance to TIBO derivatives, show little or no difference in processivity regardless of when 8-C1 TIBO is added to the reaction. Val106Ala and Glu138Lys, which have lower levels of resistance to 8Cl TIBO, show a decrease in processivity if the enzymes are added to a mixture of template-primer and 8-Cl TIBO. Taken together, the data show that in several cases, mutations that confer resistance to nucleoside or nonnucleoside inhibitors result in an RT that is less efficient than the wild-type enzyme. One of the goals of drug design should be to develop inhibitors for which the escape mutants are the most impaired.

Publication Types:

• Meeting Abstracts

Keywords:

• HIV-1
• In Vitro
• Mutation
• RNA-Directed DNA Polymerase
• Selection (Genetics)
• genetics

Other ID:

• 96095627

UI: 102215234

From Meeting Abstracts