POTENT INHIBITION OF HUMAN-IMMUNODEFICIENCY-VIRUS AND HERPES-SIMPLEX VIRUS TYPE-1 BY 9-(2-PHOSPHONYLMETHOXYETHYL)ADENINE IN PRIMARY MACROPHAGES IS DETERMINED BY DRUG-METABOLISM, NUCLEOTIDE POOLS, AND CYTOKINES

The efficacy of 9-(2-phosphonylmethoxyethyl)adenine (PMEA) against the replication of human immunodeficiency virus (HIV) and herpes simplex virus type 1 (HSV-1) and its cellular metabolism were investigated in human primary macrophages from seronegative donors. PMEA potently inhi bited the replication of both HIV and HSV-1 in macrophages, with simil ar EC(50) values (0.025 and 0.032 mu M, respectively), whereas the EC( 50) values of PMEA in lymphocytic C8166 cells and fibroblastoid Vero c ells were 150-200-fold higher (3.5 and 7.9 mu M, respectively). Granul ocyte/macrophage colony-stimulating factor and macrophage colony-stimu lating factor, two cytokine enhancers of the replication of HIV (and H SV-1), decreased the activity of PMEA against both viruses, yet EC(50) values were still lower than in lymphocytes and fibroblasts. Thus, th e selectivity index of PMEA in macrophages was > 2 orders of magnitude higher than that in lymphocytes and fibroblasts and still > 1 log hig her under conditions of enhancement of virus replication in macrophage s. The intracellular levels of 2'-deoxyadenosine-5'triphosphate, the n atural competitor of PMEA-diphosphate at the level of viral DNA polyme rase (either RNA or DNA dependent), were 5-12-fold lower in macrophage s than in other cells. Furthermore, intracellular concentrations of PM EA-diphosphate (the active metabolite of PMEA) were unusually much hig her in macrophages (with or without cytokines) than in lymphocytes and fibroblasts. Consequently, the ratio of PMEA-diphosphate to 2'-deoxya denosine-5'-triphosphate in monocytes/macrophages was similar to 2 ord ers of magnitude higher in macrophages than in the other cells and cor related closely with the pronounced antiviral potency of PMEA. The dua l potent activity of PMEA against HIV and HSV-1 stresses the importanc e of clinical trials to assess the role of this drug in the therapy of HIV-related disease.