HIV-1 envelope glycoprotein gp120 down-regulates CD4 expression in primary human macrophages through induction of endogenous tumour necrosis factor-alpha.
Among immunological abnormalities present in human immunodeficiency virus type 1 (HIV-1)-infected individuals are dysregulation of cytokine production and CD4 down-regulation in both T-helper cells and monocytes/macrophages. The HIV-1 envelope glycoprotein 120 (gp120) has the ability to induce different cytokines in peripheral blood mononuclear cells and in monocytes/macrophages in vitro which in some instances have been reported to down-regulate macrophage CD4 expression. This study provides evidence that HIV-1 recombinant gp120 (rgp120) down-regulates both surface and total CD4 expression in primary tissue culture-differentiated 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-alpha (TNF-alpha) observed at 3-6 hr post-treatment. We demonstrate that the TCDM CD4 down-regulation observed after rgp120 treatment was inhibited by the use of an anti-huTNF-alpha monoclonal antibody (mAb), but not by mAb directed against other cytokines induced by rgp120, such as 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 individuals, suggesting that gp120 by stimulating endogenous TNF-alpha production could be a good candidate for the CD4 down-regulation observed in the monocytes/macrophages of HIV-1-infected individuals. In contrast to CD4 down-regulation in HIV-infected lymphocytes, which results from a direct effect of viral genes on CD4 expression, soluble factors such as cytokines induced during HIV infection might explain the monocyte/macrophage CD4 dysregulation observed in acquired immune deficiency syndrome.
Karsten
V
V
I.N.S.E.R.M. Unit 74, Louis Pasteur University, Strasbourg, France.
Gordon
S
S
Kirn
A
A
Herbein
G
G
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001483:Base Sequence; D015704:CD4 Antigens / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D015536:Down-Regulation; D005434:Flow Cytometry; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology*; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000494:pharmacology; D013268:Stimulation, Chemical; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D017931:DNA Primers; D015699:HIV Envelope Protein gp120; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha