COMPARATIVE-ANALYSIS OF ANTI-HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 ACTIVITIES OF DIDEOXYNUCLEOSIDE ANALOGS IN RESTING AND ACTIVATED PERIPHERAL-BLOOD MONONUCLEAR-CELLS

We determined the anti-human immunodeficiency virus type 1 (anti-HIV-1 ) activities of various dideoxynucleoside analogs by using phytohemagg lutinin-activated peripheral blood mononuclear cells (PHA-PBMs) and re sting PBMs (R-PBMs) as target cells. The comparative order of anti-HIV -1 activity in PHA-PBMs was azidothymidine (AZT) > dideoxycytidine (dd C) > dideoxythymidinene (d4T) > dideoxyinosine (ddI) and 9-(2-phosphon ylmethoxyethyl)adenine (PMEA) > 2'-beta-fluoro-dideoxyadenosine (F-ara -ddA), while that in R-PBMs was ddC > ddI, PMEA, and F-ara-ddA, >> AZT and d4T. A pronucleotide, bis-(S-acetylthioethanol)phosphotriester-dd AMP, which bypasses the anabolic monophosphorylation step for the intr acellular delivery of ddAMP, was highly active both in PHA-PBMs and R- PBMs. These data may have basic and clinical relevance in the design o f anti-HIV chemotherapy, particularly combination chemotherapy with di deoxynocleosides, and in the development of active pronucleotides.