CTLA-4 upregulation during HIV infection: association with anergy and possible target for therapeutic intervention.
Leng Q, Bentwich Z, Magen E, Kalinkovich A, Borkow G.
Ruth Ben-Ari Institute of Clinical Immunology and AIDS Center, Kaplan Medical Center, Hebrew University Hadassah Medical School, Rehovot 76100, Israel.
[I am more or less alone posting here these days. Perhaps not quite deserved. I believe that some excitement will start to build around MDX-010. Having one compound that may have an effect in both cancer- and HIV-treatments should generate some interest. Especially considering what biotech issues that appears to excite the investing public these days.
And as far the opportunites in cancer go. The data presented at ASCO do show substantial biological activity in a patient population, that is presently almost untreatable.
HIV is still too early to have an opinion on. But there are at least theoretical support and the mAb is now in the clinic.
There are not too many drugs around where it will be possible to counter an argument about a missed HIV primary endpoint with a "Yes, but it works in cancers (or vice versa). I think this is indeed exciting. The question is only how long it will take for others to find out.
Erik]
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. |
