Recognition of a highly conserved region of human immunodeficiency virus type 1 gp120 by an HLA-Cw4-restricted cytotoxic T-lymphocyte clone.
Human immunodeficiency virus type 1 (HIV-1) isolates exhibit extensive sequence variation, particularly in the gp120 subunit of the envelope glycoprotein, and the degree of this variation has raised questions as to whether conserved regions of the HIV-1 envelope can be recognized by the host immune response. A CD8+ cytotoxic T-lymphocyte (CTL) clone specific for the HIV-1 envelope was derived by culturing peripheral blood mononuclear cells from an HIV-1 seropositive subject in the presence of a CD3-specific monoclonal antibody, interleukin-2, and irradiated allogeneic peripheral blood mononuclear cells. Lysis of target cells was restricted by an HLA-C molecule, Cw4, which has not been previously shown to present viral antigen to CTL. Mapping of the specificity of this CTL clone by using synthetic HIV-1 peptides localized the epitope to an 8-amino-acid region of gp120 (amino acids 376 to 383) which is conserved among approximately 90% of sequenced viral isolates. Examination of the recognition of variant peptides by this CTL clone demonstrated that a single, nonconservative amino acid substitution within the 8-amino-acid minimal epitope could abrogate lysis of targets incubated with the variant peptide. The identification of a CTL epitope in a highly conserved region of gp120 documents the ability of cellular immune responses of infected persons to respond to relatively invariant portions of this highly variable envelope glycoprotein. However, the ability of even a single-amino-acid change in gp120 to abolish lysis by CTL supports the hypothesis that sequence variation in HIV-1 may serve as a mechanism of immune escape. In addition, the identification of an HLA-C molecule presenting viral antigen to CTL supports a functional role for these molecules.
Johnson
R P
RP
Infectious Disease Unit, Massachusetts General Hospital, Boston 02114.
Trocha
A
A
Buchanan
T M
TM
Walker
B D
BD
D000595:Amino Acid Sequence; D000918:Antibody Specificity; D016827:CD8 Antigens / Q000276:immunology; D002999:Clone Cells; D017124:Conserved Sequence / Q000235:genetics / Q000276:immunology*; D004252:DNA Mutational Analysis; D000939:Epitopes / Q000276:immunology; D014644:Genetic Variation; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000276:immunology*; D006679:HIV Seropositivity / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D015236:HLA-C Antigens / Q000276:immunology*; D006801:Humans; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000276:immunology; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D016827:CD8 Antigens; D000939:Epitopes; D015699:HIV Envelope Protein gp120; D015236:HLA-C Antigens; C039966:HLA-C*04 antigen; D009842:Oligopeptides