EFFECT OF 3'-AZIDO-3'-DEOXYTHYMIDINE ON HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 REPLICATION IN HUMAN FETAL BRAIN MACROPHAGES

We investigated whether cells derived from the fetal central nervous s ystem can support productive infection by a human immunodeficiency vir us type 1 (HIV-1) isolate termed UHC-1, produced by a cellular clone d erived from HIV-I strain HIV-III, chronically infected U-937 promonocy tic cells, and what the effect of nucleoside analogs might be on viral replication in this system. Fractionation of human fetal brain tissue into two different populations, enriched for either astrocytes or mac rophages, showed that only the latter were able to support productive UHC-1 replication and generation of detectable progeny virus. Pretreat ment of fetal brain macrophages with either of two nucleoside analogs, 3'-azido-3'-deoxythymidine (AZT) or the (-) enantiomer of 2'-deoxy-3' -thiacytidine, efficiently blocked production of progeny virus. Genera tion of unintegrated proviral DNA and HIV-1 transcripts were inhibited by pretreatment of fetal brain macrophages with 1 muM AZT. Administra tion of AZT at 24 h postinfection led to a slight reduction in viral t ranscript levels and viral progeny production by day 15 postinfection; however, brain macrophages under these conditions did not contain det ectable amounts of unintegrated viral DNA. These results suggest that AZT may interfere with the accumulation of unintegrated HIV-1 DNA in b rain macrophages. This is the first demonstration that nucleoside anal ogs are able to block HIV-1 replication in primary cultures of brain c ells.