SANCTUARY GROWTH OF HUMAN-IMMUNODEFICIENCY-VIRUS IN THE PRESENCE OF 3'-AZIDO-3'-DEOXYTHYMIDINE

Human immunodeficiency virus (HIV) resistance to the nonnucleoside rev erse transcriptase inhibitors emerges very rapidly under selection in culture and in patients. In contrast, zidovudine (3'-azido-3'-deoxythy midine [AZT])-resistant HIV generally emerges in patients only after m ore-prolonged therapy. Although HIV can be cultured from many patients shortly after the initiation of AZT treatment, characterization of th e virus that is cultured generally indicates that it is sensitive to A ZT. To initiate an evaluation of the mechanisms contributing to early HIV breakthrough in the presence of AZT and other nucleoside analogs, we have utilized replication-defective HIV encoding reporter genes. Th ese recombinant HIV allow a quantitative analysis of a single cycle of infection. Results with these defective HIV indicate that early infec tion in the presence of AZT often results from the infection of a cell which is refractory to the antiretroviral effects of AZT. Characteriz ation of a cell line derived from one such cell has demonstrated decre ased accumulation of AZT triphosphate, increased phosphorylation of th ymidine to thymidine triphosphate, and increased levels of thymidine k inase activity. In addition, AZT inhibition of replication-competent H IV infection is also significantly impaired in this cell line. Attempt s to detect and characterize the mechanisms responsible for early vira l infection after initiation of AZT therapy may result in the developm ent of new strategies for prolonged suppression of viral infection pri or to the emergence of drug-resistant virus.