Development of Antiretroviral Therapy for the Acquired Immunodeficiency Syndrome and Related Disorders

Abstract

We review the rationale for, and progress in, the development of antiviral therapy for the acquired immunodeficiency syndrome (AIDS). A consideration of the replicative cycle of the human immunodeficiency virus (HIV) can lead to the identification of several steps that represent potential targets for antiretroviral therapy, and several substances that can inhibit the replication of HIV in vitro have already been identified. The 2′,3′-dideoxynucleosides are a class of nucleoside analogues in which the 3′-hydroxy group is modified so that it cannot form phosphodiester linkages for nucleic acid chains. Some are potent in vitro inhibitors of HIV replication, possibly acting as chain terminators of viral DNA during reverse transcription. One of these dideoxynucleoside analogues, 3′-azido2′,3′-dideoxythymidine (AZT), has now been administered for up to 18 months to patients with AIDS. The drug has been shown to improve immunologic function, to reverse, at least partially, HIV-induced neurologic dysfunction in some patients, and to improve certain other clinical abnormalities associated with AIDS. The principal toxic effect associated with AZT is dose-dependent suppression of bone marrow, resulting particularly in anemia and leukopenia; however, most patients in whom this toxic effect occurs can subsequently tolerate a lower dose of the drug. The demonstration that AZT can be beneficial in patients with AIDS has removed some of the uncertainty about the rationale for an antiretroviral intervention in HIV infection.