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Infection of human macrophages with an endogenous tumour necrosis factor- (TNF-)-independent human immunodeficiency virus type 1 isolate is unresponsive to the TNF- synthesis inhibitor RP 55778

¹ Laboratoire de Neuropathologie Expérimentale et Neurovirologie, CRSSA, DSV/DPTE, Institut Paris-Sud sur les Cytokines, Commissariat à l'Energie Atomique, BP 6, 92265 Fontenay aux Roses cedex
and² Rhône-Poulenc Rorer, Centre de Recherches de Vitry/Alfortville, 13 quai Jules Guesde, 94403 Vitry sur Seine, France

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/BaL and by three primary HIV-1 isolates, HIV-1/DAS, HIV-1/PAR and HIV-1/THI. Production of tumour necrosis factor- (TNF-), interleukin-6 (IL-6) and IL-1 was monitored between days 3 and 26 after MDM infection. TNF- and IL-6 were 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 viral replication. IL-1 was not found at the same time points. TNF- mRNA expression occurred around the peak of both TNF- levels and supernatant RT activities. In HIV-1/THI-infected macrophage cultures no endogenously produced TNF- was observed, despite high levels of HIV-1 in MDM. This result demonstrates that a primary isolate may replicate independently of TNF- in MDM. To investigate the relationship between TNF- and viral replication we used a TNF- synthesis inhibitor, RP 55778. Treatment throughout the course of cell culture resulted in a significant decrease in both TNF- levels and 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- to the RP 55778-treated cell cultures from day 14 post-infection. No effect of RP 55778 was observed in MDM cultures infected with the primary isolate HIV-1/THI, whose replication is independent of TNF- production and therefore remained unchanged after RP 55778 treatment. 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- production at the time of viral replication.

Received 24 September 1993; accepted 3 January 1994.

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