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A systematic exploration of the VH2/Vκ12–13 variable domains of the anti-CD4 monoclonal antibody (mAb) 13B8.2 was performed by the Spot method to screen for paratope-derived peptides (PDPs) demonstrating CD4 binding ability. Nine peptides, named CB1 to CB9, were identified, synthesized in a cyclic and soluble form and tested for binding to recombinant soluble CD4. Among them, CB1, CB2 and CB8 showed high anti-CD4 activity. Competition studies for CD4 binding indicated that PDPs CB1, CB8, and the parental mAb 13B8.2 recognized the same complementarity determining region (CDR)3-like loop region. PDP CB1 was shown to mimic the biological properties of 13B8.2 mAb in two independent cellular assays, demonstrating inhibitory activities in the micromolar range on antigen presentation and human immunodeficiency virus promoter activation. Our results indicate that the bioactive CDR-H1 PDP CB1 has retained a significant part of the parental 13B8.2 mAb properties and might be a lead for the design of anti-CD4 peptidomimetics of clinical interest.

Human immunodeficiency virus type-1 envelope glycoprotein (gp120 env ) binding to cell surface CD4 receptor triggers a broad range of intracellular effects leading to T cell activation and cell cycle entry. Among these effects we and others previously reported on the nuclear translocation of the nuclear factor-UB (NF-U UB) transcription factor. The present work further investigates the signal transduction pathways involved in gp120 env -induced NF-UB activation. We demonstrate that gp120 env ^CD4 interaction stimulates the hyperphosphorylation of IUB-K inhibitory protein. Conversely, overexpression of a dominant-negative IUB-K K transgene mutated at S32 and S36 residues, abolishes gp120 env -induced NF-UB activation. IUB kinases (IKKs) activity was found to be selectively enhanced following CD4 engagement with gp120 env and to mediate the phosphorylation of IUB-K while co-transfection experiments using dominant-negative forms of IKKs inhibited gp120 env - induced NF-UB activation. Taken together, these results confirm that IKKs complex play a key role in gp120 env -induced NF-UB activation. fl 2002 Published by Elsevier Science B.V. on be- half of the Federation of European Biochemical Societies.

Human T-cell leukemia virus type I (HTLV-I) bZIP factor (HBZ) is a viral basic leucine zipper protein that was originally described as a partner of cAMP response element binding protein-2 and as a repressor of HTLV-I viral transcription. In addition, HBZ is able to interact with the activator protein-1 (AP-1) transcription factors c-Jun and JunB, the interaction with c-Jun leading to a transcriptional repression of AP-1-regulated genes. Here we show that HBZ also interacts with JunD in vitro and in vivo, and that this association occurs via the bZIP domain of the two proteins. Moreover, we show that HBZ can activate JunD-dependent transcription and that its amino-terminus is required.