INHIBITION OF REPLICATION OF HIV IN PRIMARY MONOCYTE MACROPHAGES BY DIFFERENT ANTIVIRAL DRUGS AND COMPARATIVE EFFICACY IN LYMPHOCYTES/

Several anti-HIV drugs acting on different steps of virus replication were tested in our experimental model of primary monocyte/macrophages; the results were compared with the activity found in lymphocytes, Nuc leoside analogues (AZT, ddI, ddC, d4T, PMEA, 3TC etc.) show greater,ac tivity in macrophages (M/M) than in lymphocytes. In particular, the EC 50 of AZT, ddC, and ddI in M/M is 2- to 100-fold lower than that found in lymphocytes, This greater efficacy of nucleoside analogues in M/M depends on the enhancement of their chain-terminating activity by the low levels of endogenous deoxynucleoside-triphosphates (dNTP) usually found in resting cells such as MN, Nonnucleoside reverse transcriptase inhibitors (NNRTI) do not act as chain terminators (thus their antivi ral effect is not related to the intracellular concentrations of dNTP) ; as a consequence the activity of TSAO, HEPT, TIBO, and other NNRTI t ested in M/M is similar to that found in lymphocytes. Regarding inhibi tors of binding and fusion of HN; we found that their anti-HIV activit y is markedly decreased (or even nullified) when M/M are treated with cytokine activators of M/M function and enhancers of HIV replication, More relevant from a clinical standpoint, protease inhibitors are able to inhibit HIV replication in chronically infected macrophages (i.e., cells carrying the proviral genome already integrated in the host gen ome), All other inhibitors of late stage of virus life cycle tested (a ntisense-rev, anti-tat, interferon-alpha and -gamma, phosphorothioate analogues, GLQ-223, etc.) were totally inactive in chronically infecte d macrophages, The different effects of various classes of HIV inhibit ors in lymphocytes and macrophages suggests that AIDS therapy should c onsider all aspects of the pathogenesis of HIV infection and must be r estricted to drugs, or combinations of drugs, active against both lymp hocytes and M/M in all body compartments where the virus hides and rep licates.