STRATEGIES IN THE TREATMENT OF AIDS AND RELATED DISEASES - THE LESSONS OF CANCER-CHEMOTHERAPY

The replication cycle of human immunodeficiency virus type 1 (HIV-1) c onsists of four distinct stages, each of which can be targeted for spe cific antiviral chemotherapy. The stages are (1) the attachment of vir us to the CD4 receptor at the cell surface; (2) the uncoating of viral nucleic acid and its conversion via viral reverse transcriptase activ ity to DNA; (3) cellular multiplication, accompanied by the replicatio n of integrated proviral DNA and production of viral RNA and proteins; and (4) the assembly and liberation of progeny virus from the cell an d the potential reinitiation of the replication cycle in previously un infected cells. Since each of these steps represents a potential targe t for anti-HIV chemotherapy, it is apparent that the rationale for the use of antiviral drugs is not dissimilar from the manner in which ant ineoplastic agents are targeted to specific stages in the replication cycle of tumor cells. As in the case of anticancer chemotherapy, it is hoped that combinations of drugs, which act against different steps i n the viral replication cycle, might have synergistic potential. AZT o r zidovudine is the most widely used drug to date to impede the replic ation of HIV-1; it is significant that this compound was designed init ially with anticancer chemotherapy in mind. Although AZT therapy has b een reasonably successful, this drug has had important toxic side effe cts. As in the case of many cancer chemotherapeutic agents, drug resis tance to AZT is likely to be an important problem, and there have been several reports of the isolation of drug-resistant variants of HIV-1.