Inhibitors of HIV-1 Reverse Transcriptase and Fidelity of In Vitro DNA Replication

Abstract

Mechanisms of the effects of the dTTP analogues 3′-azido-3′-deoxythymidine 5′-triphosphate (AZTTP) and 3′-amino-3′-deoxythymidine 5′-triphosphate (NH₂TTP) upon the HIV-1 reverse transcriptase (RT) are discussed. These compounds block the RT in vitro and do so by different kinetic mechanisms. Infidelity of replication is a hallmark of the HIV-1 RT, and replication errors by the enzyme on RNA and DNA templates are discussed. The enzyme's infidelity has ramifications for inhibition: On the one hand, the propensity to produce mutations enhances the ability of the virus to escape inhibitors whereas on the other hand, the infidelity of the reverse transcriptase may allow the development of imaginative inhibitor strategies.

Key Words: :

• HIV-1
• reverse transcriptase
• enzyme inhibition
• DNA replication fidelity
• frameshift mutation
• processivity