HIV-1 ENVELOPE GLYCOPROTEIN GP120 DOWN-REGULATES CD4 EXPRESSION IN PRIMARY HUMAN MACROPHAGES THROUGH INDUCTION OF ENDOGENOUS TUMOR-NECROSIS-FACTOR-ALPHA

Among immunological abnormalities present in human immunodeficiency vi rus type 1 (HIV-I)infected individuals are dysregulation of cytokine p roduction and CD4 down-regulation in both T-helper cells and monocytes /macrophages. The HIV-I envelope glycoprotein 120 (gp120) has the abil ity to induce different cytokines in peripheral blood mononuclear cell s and in monocytes/macrophages in vitro which in some instances have b een reported to down-regulate macrophage CD4 expression. This study pr ovides evidence that HIV-I recombinant gp120 (rgp120) downregulates bo th surface and total CD4 expression in primary tissue culture-differen tiated macrophages (TCDM) at the level of transcription. The CD4 down- regulation observed in TCDM occurred between 6 and 12 hr after rgp120 treatment preceded by a peak of endogenous tumour necrosis factor-alph a (TNF-alpha) observed at 3-6 hr post-treatment. We demonstrate that t he TCDM CD4 down-regulation observed after rgp 120 treatment was inhib ited by the use of an anti-hu TNF-alpha monoclonal antibody (mAb), but not by mAb directed against other cytokines induced by rgp120, such a s interleukin-1 beta (IL-1 beta) and interferon-alpha (IFN-alpha). The present findings roughly parallel those observed both in the sera of patients and in the monocytes/macrophages isolated from HIV-positive i ndividuals, suggesting that gp120 by stimulating endogenous TNF-alpha production could be a good candidate for the CD4 down-regulation obser ved in the monocytes/macrophages of HIV-l-infected individuals. In con trast to CD4 down-regulation in HIV-infected lymphocytes, which result s from a direct effect of viral genes on CD4 expression, soluble facto rs such as cytokines induced during HIV infection might explain the mo nocyte/macrophage CD4 dysregulation observed in acquired immune defici ency syndrome.