Impaired function of circulating HIV-specific CD8(+) T cells in chronic human immunodeficiency virus infection.
The functional status of circulating human immunodeficiency (HIV)-specific CD8 T cells in chronically infected subjects was evaluated. By flow cytometry, only 5 of 7 subjects had detectable CD8 T cells that produced IFN-gamma after stimulation with HIV-infected primary CD4 T cells. In 2 subjects, the frequency of IFN-gamma-producing cells increased 4-fold when IL-2 was added to the culture medium; in another subject, IFN-gamma-producing cells could be detected only after IL-2 was added. IFN-gamma-producing cells ranged from 0.4% to 3% of CD8 T cells. Major histocompatibility complex-peptide tetramer staining, which identifies antigen-specific T cells irrespective of function, was used to evaluate the proportion of HIV-specific CD8 T cells that may be nonfunctional in vivo. CD8 T cells binding to tetramers complexed to HIV gag epitope SLYNTVATL and reverse transcriptase epitope YTAFTIPSI were identified in 9 of 15 and 5 of 12 HLA-A2-expressing seropositive subjects at frequencies of 0.1% to 1.1% and 0.1 to 0.7%, respectively. Freshly isolated tetramer-positive cells expressed a mixed pattern of memory and effector markers. On average, IFN-gamma was produced by less than 25% of tetramer-positive CD8 T cells after stimulation with the relevant gag or reverse transcriptase peptide. In all subjects tested, freshly isolated CD8 T cells were not cytolytic against peptide-pulsed B lymphoblastoid cell line or primary HIV-infected CD4 T-cell targets. Exposure to IL-2 enhanced the cytotoxicity of CD8 T cells against primary HIV-infected CD4 targets in 2 of 2 subjects tested. These results suggest that a significant proportion of HIV-specific CD8 T cells may be functionally compromised in vivo and that some function can be restored by exposure to IL-2.
Shankar
P
P
Center for Blood Research, Harvard Medical School, and the New England Medical Center, Tufts University School of Medicine, Boston, MA, USA. shankar@cbr.med.harvard.edu
Russo
M
M
Harnisch
B
B
Patterson
M
M
Skolnik
P
P
Lieberman
J
J
D000595:Amino Acid Sequence; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology*; D002478:Cells, Cultured; D002908:Chronic Disease; D003602:Cytotoxicity, Immunologic; D000939:Epitopes / Q000276:immunology; D005434:Flow Cytometry; D015683:Gene Products, gag / Q000737:chemistry / Q000276:immunology; D006678:HIV / Q000276:immunology*; D015658:HIV Infections / Q000097:blood / Q000276:immunology*; D015789:HLA-A2 Antigen / Q000097:blood; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000494:pharmacology; D007700:Kinetics; D008213:Lymphocyte Activation
D000939:Epitopes; D015683:Gene Products, gag; D015789:HLA-A2 Antigen; D007376:Interleukin-2; D007371:Interferon-gamma