REPRESSION OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 LONG TERMINAL REPEAT-DRIVEN GENE-EXPRESSION BY BINDING OF THE VIRUS TO ITS PRIMARY CELLULAR RECEPTOR, THE CD4 MOLECULE

We have previously postulated that the binding of the human immunodefi ciency virus type 1 (HIV-1) to cell surface CD4 induces signal transdu ction pathways that down-modulate production of progeny virions in acu tely infected T cells (M. Tremblay, S. Meloche, S. Gratton, M. A. Wain berg, and R.-P. Sekaly, EMBO J. 13:774-783, 1994). To evaluate the pos sibility that CD4 cross-linking might indeed affect viral gene express ion, we have introduced a molecular construct made of the luciferase r eporter gene placed under the control of the regulatory elements of HI V-1 in several CD4-positive T-cell lines. We found that cross-linking of CD4 with defective HIV-1 particles and heat-inactivated viruses inh ibits long terminal repeat-dependent luciferase expression. Experiment s revealed that the gp120-CD4 interaction was necessary to repress HIV -1 long terminal repeat-dependent luciferase activity. The cytoplasmic domain of CD4 was also found to be required for this effect to occur. The virus-mediated signal transduction was shown to be mediated via p 56(lck)-dependent and -independent pathways. These results indicate th at the earliest event in the HIV-1 replicative cycle, namely, the bind ing of the virus to its cellular receptor, can lead to signal transduc tion culminating in down-modulation of viral gene expression. Thus we propose that defective viruses could regulate the pathogenesis of HIV disease as they constitute the vast majority of circulating HIV-1 part icles.