MECHANISMS OF DOWN-MODULATION AND RELEASE OF TUMOR-NECROSIS-FACTOR RECEPTOR-INDUCED BY HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 IN HUMAN MONOCYTES

Infection of human monocytes with human immunodeficiency virus type 1 (HIV-1 LAI) triggers the release of both the cytokine tumour necrosis factor alpha (TNF-alpha) and its soluble receptor (TNFsr), In the pres ent study, the authors have investigated the cellular events implicate d in the modulation of expression and shedding of the monocyte TNF rec eptor induced by HIV-1 LAI, Release of TNFsr75 was triggered at an ear ly step of interaction of the virus particles with the monocyte, invol ving the envelope glycoprotein gp120, HIV-1 LAI induced an upregulatio n of TNFr75 mRNA, whereas TNFr55 mRNA was not detectable, TNFsr75 rele ase required exocytosis, proteolytic cleavage by serine protease(s), b ut was independent of prior endocytosis of the receptor, Early sheddin g of TNFr75 accounted for the almost total but transient disappearance of the membrane TNF receptor P75, observed 60 min after activation wi th HIV-1 LAI, whereas internalization was minimal, Endogenous TNF-alph a had no role in the disappearance of its own receptor, Complete and s table restoration of TNFr expression at the cell membrane, dependent o n de novo protein synthesis, occurred after 5 h, followed by massive T NFsr75 release, These results demonstrate that interaction of human mo nocytes with HIV-1 LAI triggers at an early stage a cascade of cellula r events that lead to profound remodeling of the cell TNFr pool, Under standing the mechanisms of these receptor movements is of importance t o document the central role of the TNF system in HIV infection, (C) 19 97 Academic Press Limited.