Multiple effector functions mediated by human immunodeficiency virus-specific CD4(+) T-cell clones.
Mounting evidence suggests that human immunodeficiency virus type 1 (HIV-1) Gag-specific T helper cells contribute to effective antiviral control, but their functional characteristics and the precise epitopes targeted by this response remain to be defined. In this study, we generated CD4(+) T-cell clones specific for Gag from HIV-1-infected persons with vigorous Gag-specific responses detectable in peripheral blood mononuclear cells. Multiple peptides containing T helper epitopes were identified, including a minimal peptide, VHAGPIAG (amino acids 218 to 226), in the cyclophilin binding domain of Gag. Peptide recognition by all clones examined induced cell proliferation, gamma interferon (IFN-gamma) secretion, and cytolytic activity. Cytolysis was abrogated by concanamycin A and EGTA but not brefeldin A or anti-Fas antibody, implying a perforin-mediated mechanism of cell lysis. Additionally, serine esterase release into the extracellular medium, a marker for cytolytic granules, was demonstrated in an antigen-specific, dose-dependent fashion. These data indicate that T helper cells can target multiple regions of the p24 Gag protein and suggest that cytolytic activity may be a component of the antiviral effect of these cells.
Norris
P J
PJ
Partners AIDS Research Center and Infectious Disease Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Sumaroka
M
M
Brander
C
C
Moffett
H F
HF
Boswell
S L
SL
Nguyen
T
T
Sykulev
Y
Y
Walker
B D
BD
Rosenberg
E S
ES
D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000906:Antibodies / Q000494:pharmacology; D020126:Brefeldin A / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D002999:Clone Cells; D021983:Cyclophilins / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004533:Egtazic Acid / Q000494:pharmacology; D000939:Epitopes / Q000276:immunology; D016655:HIV Core Protein p24 / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D015497:HIV-1; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D018942:Macrolides; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D011485:Protein Binding; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology; D019014:fas Receptor / Q000276:immunology
D000900:Anti-Bacterial Agents; D000906:Antibodies; D000939:Epitopes; D016655:HIV Core Protein p24; D018942:Macrolides; D019014:fas Receptor; D020126:Brefeldin A; D004533:Egtazic Acid; C036978:concanamycin A; D007371:Interferon-gamma; D021983:Cyclophilins