Differential neutralization of human immunodeficiency virus (HIV) replication in autologous CD4 T cells by HIV-specific cytotoxic T lymphocytes.
Defining the antiviral efficacy of CD8 T cells is important for immunogen design, and yet most current assays do not measure the ability of responses to neutralize infectious virus. Here we show that human immunodeficiency virus (HIV)-specific cytotoxic T-lymphocyte (CTL) clones and cell lines derived from infected persons and targeting diverse epitopes differ by over 1,000-fold in their ability to retard infectious virus replication in autologous CD4 T cells during a 7-day period in vitro, despite comparable activity as assessed by gamma interferon (IFN-gamma) enzyme-linked immunospot (ELISPOT) assay. Cell lines derived from peripheral blood mononuclear cells stimulated in vitro with peptides representing targeted Gag epitopes consistently neutralized HIV better than Env-specific lines from the same person, although ineffective inhibition of virus replication is not a universal characteristic of Env-specific responses at the clonal level. Gag-specific cell lines were of higher avidity than Env-specific lines, although avidity did not correlate with the ability of Gag- or Env-specific lines to contain HIV replication. The greatest inhibition was observed with cell lines restricted by the protective HLA alleles B*27 and B*57, but stimulation with targeted Gag epitopes resulted in greater inhibition than did stimulation with targeted Env epitopes even in non-B*27/B*57 subjects. These results assessing functional virus neutralization by HIV-specific CD8 T cells indicate that there are marked epitope- and allele-specific differences in virus neutralization by in vitro-expanded CD8 T cells, a finding not revealed by standard IFN-gamma ELISPOT assay currently in use in vaccine trials, which may be of critical importance in immunogen design and testing of candidate AIDS vaccines.
Chen
Huabiao
H
Ragon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129, USA.
Piechocka-Trocha
Alicja
A
Miura
Toshiyuki
T
Brockman
Mark A
MA
Julg
Boris D
BD
Baker
Brett M
BM
Rothchild
Alissa C
AC
Block
Brian L
BL
Schneidewind
Arne
A
Koibuchi
Tomohiko
T
Pereyra
Florencia
F
Allen
Todd M
TM
Walker
Bruce D
BD
D000483:Alleles; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006678:HIV / Q000276:immunology*; D006680:HLA Antigens / Q000235:genetics; D006801:Humans; D008213:Lymphocyte Activation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D006680:HLA Antigens