CTLA-4 upregulation during HIV infection: association with anergy and possible target for therapeutic intervention.
OBJECTIVE
To study the role of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) during HIV infection.


METHODS
Intracellular CTLA-4 expression, determined by flow-cytometry, and proliferative responses to HIV antigens, were studied in peripheral blood mononuclear cells (PBMC) from 93 HIV-1-infected [HIV(+)] patients and 40 HIV-1 seronegative controls.


RESULTS
The proportions of CTLA-4 expressing CD4+ T cells were: (1) significantly higher in HIV(+) patients, 10.95 +/- 0.66%, than in controls, 6 +/- 0.45% (P < 0.0001); (2) inversely correlated to CD4+ counts (r = -0.67, P < 0.005, n = 16, drug-naive patients; r = -0.57, P < 0.0001, n = 77, HAART-treated patients); and (3) positively correlated to proportion of activated (HLA-DR+CD3+) (r = 0.53, P < 0.0001) and memory (CD45RO+CD4+) T cells (r = 0.46, P < 0.001). CD28 median fluorescence intensity in CTLA-4- cells was twice that in CTLA-4+ cells (140 +/- 5.3 versus 70 +/- 2.28, P < 0.00001), whereas cells low in CD28 and CD4, expressed more CTLA-4 (P < 0.0001). Higher proportion of CTLA-4+CD4+ cells expressed CCR5 and Ki-67, in comparison with CTLA-4-CD4+ cells, (65 +/- 11.9 and 25 +/- 7.5% versus 27 +/- 8.9 and 3.7 +/- 2%, P < 0.0001 and P < 0.01, respectively). Among HAART-treated patients, with viral load below detectable levels, CD4+ cells increase was inversely correlated to %CTLA-4+CD4+ cells (r = -0.5, P = 0.003, n = 39). Proliferation of PBMC to anti-CD3, gp-120 depleted HIV-1 antigen or HIV-1 p24 stimulation was inversely correlated with CTLA-4 levels (r = -0.68, P = 0.0035; r = -0.38,P = 0.04; and r = -0.43, P = 0.028, respectively).


CONCLUSIONS
(1) CTLA-4 is upregulated during HIV infection and may therefore account for CD4 T-cell decline and anergy in HIV-1 infection. (2) Increased levels of CTLA-4 may undermine immune responses and in the HAART-treated patient-immune reconstitution. (3) Blocking of CTLA-4 may offer a novel approach for immune-based therapy in HIV infection.
Leng
Qibin
Q
Ruth Ben-Ari Institute of Clinical Immunology and AIDS Center, Kaplan Medical Center, Hebrew University Hadassah Medical School, Rehovot 76100, Israel.
Bentwich
Zvi
Z
Magen
Eli
E
Kalinkovich
Alexander
A
Borkow
Gadi
G
D000069594:Abatacept; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000096:biosynthesis*; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D060908:CTLA-4 Antigen; D002455:Cell Division; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000276:immunology*; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy / Q000276:immunology* / Q000503:physiopathology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D018796:Immunoconjugates; D019394:Ki-67 Antigen / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology; D019713:Receptors, CCR5 / Q000096:biosynthesis; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D015854:Up-Regulation
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018106:CD28 Antigens; D017252:CD3 Complex; D015704:CD4 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018796:Immunoconjugates; D019394:Ki-67 Antigen; D019713:Receptors, CCR5; D015375:Receptors, Interleukin-2; D000069594:Abatacept