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Volume 272, Number 31, Issue of August 1, 1997 pp. 19441-19450
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Transduction of Activation Signal That Follows HIV-1 Binding to CD4 and CD4 Dimerization Involves the Immunoglobulin CDR3-like Region in Domain 1 of CD4

(Received for publication, January 14, 1997, and in revised form, May 23, 1997)

Laurence Briant , Nathalie Signoret ^¶ , Muriel Gaubin ^** , Véronique Robert-Hebmann , Xin Zhang , Ramachandran Murali , Mark I. Greene , Dominique Piatier-Tonneau ^** and Christian Devaux

From the  Laboratoire d'Immunologie des Infections Retrovirales, CNRS ERS155, Institut de Biologie, 34060 Montpellier, France, the ^¶ Centre d'Immunologie de Marseille Luminy, 13288 Marseille, France, the ^** Génétique Moléculaire et Biologie du Développement, CNRS UPR 420, 94801 Villejuif , France, and the  Department of Pharmacology, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6082

The role of CD4 during the human immunodeficiency virus type 1 (HIV-1) life cycle in T cells is not restricted to binding functions. HIV-1 binding to CD4 also triggers signals that lead to nuclear translocation of NF-B and are important to the productive infection process. In addition to its cytoplasmic tail, in the ectodomain, the immunoglobulin (Ig) CDR3-like region of CD4 domain 1 seemed to play a role in this cascade of signals. We demonstrate in this work that the structural integrity of the CDR3-like loop is required for signal transduction. Substitutions of negatively charged residues by positively charged residues within the CDR3-like loop either inhibited NF-B translocation after HIV-1 and gp120-anti-gp120 immune complexes binding to E91K,E92K mutants or induced its constitutive activation for E87K,D88K mutants. Moreover, A2.01-3B cells expressing the E91K,E92K mutant exhibited a lower HIV-1_Lai replication. These cells, however, expressed p56^lck, demonstrated NF-B translocation upon PMA stimulation, bound HIV-1_Lai envelope glycoprotein with high affinity, and contained HIV-1 DNA 24 h after exposure to virus. E91K, E92K, and E87K,D88K mutant CD4 molecules were unable to bind a CD4 synthetic aromatically modified exocyclic, CDR3.AME-(82-89), that mimics the CDR3-like loop structure and binds to native cell surface CD4. This result together with molecular modeling studies indicates that the CDR3.AME-(82-89) analog binds to the CDR3-like loop of CD4 and strongly suggests that this region represents a site for CD4 dimerization. The negative charges on the CDR3-like loop thus appear critical for CD4-mediated signal transduction most likely related to CD4 dimer formation.

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