High viral burden in the presence of major HIV-specific CD8(+) T cell expansions: evidence for impaired CTL effector function.
To investigate the effect of HIV-specific CD8(+) T cells on viral plasma load and disease progression, we enumerated HLA-A2-, B8- and B57-restricted CD8(+) T cells directed against several HIV epitopes in a total of 54 patients by the use of tetrameric HLA-peptide complexes. In patients with high CD4(+) T cell numbers, HIV-specific tetramer(+) cells inversely correlated with viral load. Patients with CD4(+) T cell numbers below 400/microl blood, however, carried high viral load despite frequently having high tetramer(+) T cell numbers. This lack of correlation between viral load and tetramer(+) cells did not result from viral escape variants, as in only 4 of 13 patients, low frequencies of viruses with mutated epitopes were observed. In 15 patients we measured CD8(+) T cell antigen responsiveness to HIV peptide stimulation in vitro. FACS analyses showed differential IFN-gamma production of the tetramer(+) cells, and this proportion of IFN-gamma-producing tetramer(+) cells correlated with AIDS-free survival and with T cell maturation to the CD27(-) effector stage. These data show that most HIV-infected patients have sustained HIV-specific T cell expansions but many of these cells seem not to be functional, leaving the patient with high numbers of non-functional virus-specific CD8(+) T cells in the face of high viral burden.
Department of Clinical Viro-Immunology, CLB Sanquin Blood Supply Foundation & Laboratory for Clinical and Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands. S_Kostense@clb.nl
S
S
Kostense
G S
GS
Ogg
E H
EH
Manting
G
G
Gillespie
J
J
Joling
K
K
Vandenberghe
E Z
EZ
Veenhof
D
D
van Baarle
S
S
Jurriaans
M R
MR
Klein
F
F
Miedema
D018791:CD4 Lymphocyte Count; D002478:Cells, Cultured; D018450:Disease Progression; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D015693:Gene Products, nef / Q000276:immunology; D015488:HIV Antigens / Q000235:genetics / Q000276:immunology*; D016655:HIV Core Protein p24 / Q000235:genetics / Q000276:immunology; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D006680:HLA Antigens / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation; D009154:Mutation; D010641:Phenotype; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019562:Viral Load; D054311:nef Gene Products, Human Immunodeficiency Virus
D000939:Epitopes; D015693:Gene Products, nef; D015488:HIV Antigens; D016655:HIV Core Protein p24; D006680:HLA Antigens; D054311:nef Gene Products, Human Immunodeficiency Virus; D007371:Interferon-gamma