Multibranched peptide constructs derived from the V3 loop of envelope glycoprotein gp120 inhibit human immunodeficiency virus type 1 infection through interaction with CD4.
The V3 loop of the gp120 of human immunodeficiency virus type 1 (HIV-1) is assumed to be involved in HIV-1-mediated membrane fusion. V3-derived peptides have been shown either to enhance or to prevent HIV-1 infection. Multibranched peptide constructs (MBPCs) derived from the V3 North American/European consensus sequence were designed to sort out these conflicting findings. At 5 microM, MBPC1 (8-branched GPGRAF) totally, and MBPC2 ([RKSIHIGPGRAFYT]4) partially, inhibited HIV-1LAI infection, whereas the GPGRAF monomer had only a limited effect. A peptide of the entire V3 consensus loop and a control MBPC had no detectable activity. The 5 microM MBPC1 HIV-1-inhibiting concentration was not cytotoxic, nor did it alter T lymphocyte allogeneic, antigen-, or mitogen-induced reactivities, and it was about 5- to 50-fold lower (MBPC2 and MBPC1, respectively) than that resulting in 50% cell death. Analysis of MBPC immunoreactivity showed that MBPC2, but not MBPC1, strongly reacted with human HIV-1 positive sera. Only MBPC2 elicited significant antibody responses in rabbits. The V3-derived MBPCs bound to CD4+ cells, as determined by immunofluorescence analysis. The binding was inhibited either by soluble CD4 or by CD4 monoclonal antibody (mAb) MT151, which recognizes the CDR3 region of the D1 domain of CD4, but not by other CD4 mAbs Leu3a, OKT4A, Q4021, 13B8-2, 5A8, RFT4, nor by the CD26 mAb BA5. Therefore, it appears likely that MBPCs inhibit HIV-1 infection by interacting with the CDR3 region of CD4 or with a region in its vicinity.
Laboratoire de Biologie et Génétique des Pathologies Immunitaires, CNRS URA 1463, Paris, France.
A
A
Benjouad
F
F
Chapuis
E
E
Fenouillet
J C
JC
Gluckman
D000595:Amino Acid Sequence; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D015704:CD4 Antigens / Q000187:drug effects*; D002455:Cell Division; D002460:Cell Line; D003429:Cross Reactions; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000472:pathogenicity; D006801:Humans; D008214:Lymphocytes / Q000166:cytology; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000494:pharmacology*; D010455:Peptides / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D011485:Protein Binding; D011817:Rabbits
D000998:Antiviral Agents; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; C059762:HIV envelope protein gp120 (305-321); D010446:Peptide Fragments; D010455:Peptides