9 Human Immunodeficiency Virus Reverse Transcriptase

Abstract

To stem the alarming progression of AIDS, the human immunodeficiency viruses, HIV-1 and HIV-2, although similar in many respects to other well-characterized retroviruses, have rapidly become the most intensely studied retroviruses of the last decade (Barre-Sinoussi et al. 1983; Gallo et al. 1984; Muessing et al. 1985; Ratner et al. 1985; Sanchez-Pescador et al. 1985; Wain-Hobson et al. 1985). Until an effective vaccine is available, accurate diagnosis and chemotherapy remain the most effective means of controlling the spread of HIV infection. A primary candidate for therapeutic intervention is the multifunctional reverse transcriptase (RT, deoxynucleoside-triphosphate:DNA deoxynucleotidyl-transferase, RNA-directed E.C. 2.7.7.49). In addition to its RNA-dependent DNA polymerase, DNA-dependent DNA polymerase, and ribonuclease H (RNase H) activities, preliminary data have also uncovered a second RNase activity, designated RNase D, that results in hydrolysis of double-stranded RNA (Ben-Arzti et al. 1992; S.P. Goff, pers. comm.). The affinity of HIV RT for its cognate replication primer, tRNA^Lys-3 (Barat et al. 1989Barat et al. 1991), represents an additional feature that might be exploited in the development of inhibitors. Finally, dimeric forms of both the HIV-1 and HIV-2 enzymes have been proposed as the enzymatically proficient and biologically relevant species (Restle et al. 1990, Müller et al. 1991b), raising the possibility of developing agents designed to impair subunit association. As the novel features of these highly versatile enzymes are unveiled, they will hopefully result in development of a new generation of drugs with improved efficacy and enhanced selectivity.

Following early purification and characterization of virion-associated HIV-1 RT (Rey et...