11 Inhibitors of HIV Reverse Transcriptase as Antiviral Agents and Drug Resistance

The fundamental role played by reverse transcriptase (RT) in the replication of retroviruses has made this enzyme a key target in the chemotherapy of human immunodeficiency virus (HIV) infection. The initial part of this chapter briefly reviews the most promising antiviral agents known to inhibit the function of HIV RT. These agents fall broadly into two classes: nucleoside analogs that are active in the triphosphorylated form and nonnucleosides that interact directly with RT. The nucleoside analog most prominent to date in the therapy of HIV disease and AIDS is zidovudine (3′-azido-3′-deoxythymidine, AZT) (Mitsuya et al. 1985; Furman et al. 1986), although a number of other nucleoside analogs are now being used clinically. Less advanced is the development of nonnucleosides for the potential treatment of HIV infection. However, a number of promising RT inhibitors of this nature have been described recently and are currently undergoing clinical investigation. Much of this chapter is devoted to the issue of drug resistance mediated by mutation of HIV RT. Not surprisingly, the bulk of our current knowledge relates to AZT resistance due to the extensive analysis of HIV isolates from treated individuals and from in vitro studies of RT and the virus. We initially describe RT mutagenesis studies where enzyme specificity toward various inhibitors was altered by making a number of amino acid substitutions. These experiments provided an early indication that resistance to RT inhibitors could potentially occur. We next review our knowledge of AZT resistance, derived mainly from the examination of HIV clinical isolates,...