INFECTION OF HUMAN MACROPHAGES WITH AN ENDOGENOUS TUMOR-NECROSIS-FACTOR-ALPHA (TNF-ALPHA)-INDEPENDENT HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 ISOLATE IS UNRESPONSIVE TO THE TNF-ALPHA SYNTHESIS INHIBITOR RP-55778

Monocyte-derived macrophages (MDM) were demonstrated to be susceptible to productive infection by the monocytotropic human immunodeficiency virus type 1 (HIV-1) strain HIV-1/Ba-L and by three primary HIV-1 isol ates, HIV-1/DAS, HIV-1/PAR and HIV-1/THI. Production of tumour necrosi s factor-alpha (TNF-alpha), interleukin-6 (IL-6) and IL-1 beta was mon itored between days 3 and 26 after MDM infection. TNF-alpha and IL-6 w ere detected in cell culture supernatants from days 16 to 21 following HIV-1/DAS, HIV-1/PAR and HIV-1/Ba-L infection, at the time of high vi ral replication. IL-1 beta was not found at the same time points. TNF- alpha mRNA expression occurred around the peak of both TNF-alpha level s and supernatant RT activities. In HIV-1/THI-infected macrophage cult ures no endogenously produced TNF-alpha was observed, despite high lev els of HIV-1 in MDM. This result demonstrates that a primary isolate m ay replicate independently of TNF-alpha in MDM. To investigate the rel ationship between TNF-alpha and viral replication we used a TNF-alpha synthesis inhibitor, RP 55778. Treatment throughout the course of cell culture resulted in a significant decrease in both TNF-alpha levels a nd viral production in HIV-1/DAS-, HIV-1/PAR- and HIV-1/Ba-L-infected MDM cultures. This phenomenon is reversed by adding recombinant human TNF-alpha to the RP 55778-treated cell cultures from day 14 postinfect ion. No effect of RP 55778 was observed in MDM cultures infected with the primary isolate HIV-1/THI, whose replication is independent of TNF -alpha production and therefore remained unchanged after RP 55778 trea tment. We conclude that the clinical value of such a drug is directly dependent on the ability of the HIV-1 strains involved to induce TNF-a lpha production at the time of viral replication.