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Therapy for HIV Infection

Second to the identification of HIV as the causative agent for AIDS, the most impressive scientific advances have occurred in the development of effective antiretroviral drugs for treating individuals infected with HIV. The spectrum of drug discovery for HIV centers on an appreciation of vulnerable targets in the replication cycle of the virus (Fig. 2). The first effective drug against HIV was the reverse transcriptase inhibitor azidovudine (zidovudine), or AZT.[43] It was identified by a screening process using large numbers of compounds that had been already produced for other purposes. AZT was originally developed as an anticancer drug but did not prove effective in that capacity. It was licensed instead as the first antiretroviral drug in 1987.

The replication cycle of HIV and targets for antiretroviral therapy.

Subsequently, more sophisticated science in the form of targeted drug design has been the rule as drugs have been developed to target specific vulnerable points in the virus replication cycle, providing a cogent example of the importance of the basic research endeavors in viral biology and the translational approaches in drug development.[44] The prototype of this approach was the expression, purification and crystallization of the HIV protease enzyme to facilitate the tailored design of protease inhibitors—a class of antiretroviral drug that was first approved by the US Food and Drug Administration (FDA) in 1995 (ref. 45).

The newest class of drug, fusion inhibitors, represents another example of successful targeted drug development led by basic science discovery.[44] These compounds block the fusion of the viral envelope to the cell membrane, and became available with the FDA approval of enfuvirtide (Fuzeon) in 2003 (ref. 46). New and improved drugs in all three classes (reverse transcriptase inhibitors, protease inhibitors, and fusion and entry inhibitors) are being actively pursued along with drugs against alternative targets such as the viral integrase.[44] Currently, there are 20 FDA-approved drugs or combinations of drugs for HIV ( Table 1 ). The availability of these therapeutics and their use in combinations of three or more drugs have transformed the treatment of individuals infected with HIV such that morbidity and mortality owing to HIV disease have sharply declined in developed nations where such drugs are readily available.[25]