Identification of CD4 and major histocompatibility complex functional peptide sites and their homology with oligopeptides from human immunodeficiency virus type 1 glycoprotein gp120: role in AIDS pathogenesis.
CD4 molecules interact with class II major histocompatibility complex molecules as a critical costimulatory signal in CD4+ cell immune activation. CD4 also recognizes a specific region of the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein gp120 forming a binding site for early stages of HIV-1 infection. We designed two software packages, AUTOMAT and CRITIC, which allowed us to identify similarities between regions of HIV-1 proteins and immunoregulatory protein sequences stored in data banks. In this report we have characterized (i) a pentapeptide, SLWDQ, found in both CD4 and HIV-1 gp120, which surprisingly had remained undetected in these two well-studied molecules until now, and (ii) an HLA sequence corresponding to the putative functional site of H2 I-A. We found that a region of gp120 (residues 254-263) known to be similar to a sequence in HLA class II beta chain overlaps this functional region. We showed experimentally that these two CD4 and HLA peptide segments inhibit CD4+ cell immune activation. There is strong inhibition (50% up to 80%) of immune activation by SLWDQ-containing gp120 segments and a lesser inhibition by the gp120 HLA-homologous segment. In addition, we found that SLWDQ induced in HIV-1-infected individuals a humoral (antibody) and cellular (cytotoxic T lymphocyte) immune reaction. We propose that these HIV-1 gp120 segments, together with the known CD4-binding region, may contribute to the HIV-1-induced immunosuppression by two mechanisms affecting CD4-HLA interaction during T-cell immune activation: autoimmune reaction toward CD4 and direct interference with the CD4-HLA costimulatory signal inducing CD4+ cell anergy with, as a consequence, generation of immunosuppression.
Zagury
J F
JF
Université Pierre et Marie Curie, Paris, France.
Bernard
J
J
Achour
A
A
Astgen
A
A
Lachgar
A
A
Fall
L
L
Carelli
C
C
Issing
W
W
Mbika
J P
JP
Picard
O
O
D000163:Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000503:physiopathology*; D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000737:chemistry / Q000378:metabolism*; D015704:CD4 Antigens / Q000737:chemistry / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic; D004797:Enzyme-Linked Immunosorbent Assay; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000378:metabolism*; D015497:HIV-1 / Q000472:pathogenicity / Q000502:physiology*; D006680:HLA Antigens / Q000737:chemistry / Q000378:metabolism*; D006681:HLA-D Antigens / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009000:Monocytes / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013601:T-Lymphocytes / Q000276:immunology*
D015703:Antigens, CD; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D006680:HLA Antigens; D006681:HLA-D Antigens