ABSTRACT
The human immunodeficiency virus (HIV) is a retrovirus that is responsible for acquired immunodeficiency syndrome (AIDS) (1). Human immunodeficiency vi rus requires the activity of three enzymes during its life cycle (2). Pharmaceutical agents targeting two of these enzymes, reverse transcriptase and protease, are in clinical use. These pharmaceutical agents are not ideal, however, due to the rise of resistant viral strains after treatment is initiated (3,4). The third enzyme, in tegrase (IN), is the least explored enzyme target for HIV treatment (5), with one agent undergoing clinical trials, although evidence indicates that IN is not its primary target in vivo (6). Integrase is responsible for two essential (7,8) catalytic activities that result in incorporation of viral DNA into host DNA. These activities are shown schematically in Figure 1. The first is 3' processing, in which the 3' ends of viral DNA are recessed by removal of two bases. The second is strand transfer, in which the viral DNA is joined to the 5' phosphate of a staggered cut in the host DNA. This activity places the IN enzyme into the polynucleotidyl-
transferase family, which also includes RNase H, the Mu transpose, and Ruv C (9,10). The polynucleotidyltransferases characteristically contain an organometallic active site, with a divalent metal cation playing a critical role in the catalysis of the DNA or RNA strand transfer reactions.
