Immune modulatory effects of cyclooxygenase type 2 inhibitors in HIV patients on combination antiretroviral treatment.
OBJECTIVE
To examine the immune modulating effects of cyclooxygenase type 2 (COX-2) inhibitors (COX-2i) in HIV-infected patients on combination antiretroviral treatment (CART).


METHODS
In-depth substudy from an approved, open, controlled, randomized study comparing the immune modulating effects of CART in combination with COX-2i after 12 weeks.


METHODS
Patients (n = 38) on long-term CART with stable viral load (VL) < 50,000 copies/ml and CD4+ T-cell counts > 100/microl were randomized to CART and rofecoxib 25 mg bid (n = 12) or celecoxib 400 mg bid (n = 12), or CART only without placebo (n = 14). Routine clinical chemistry, CD4+ and CD8+ counts and VL were safety parameters. Immunological parameters included C-reactive protein, beta2-microglobulin, Ig isotypes and IgG subclasses as well as several T-lymphocyte subsets. Non-parametric analyses were used throughout.


RESULTS
Prestudy experiments showed higher median intracellular expression of COX-2 in CD4+ (P = 0.048) and possibly CD8+ (P = 0.09) T cells from patients on CART compared with uninfected controls. In the clinical study, increased CD4+ T-cell counts were observed only in patients on COX-2i with VL < 50 copies/ml (P = 0.02). Decreased expression of CD38+ on CD8+ T cells and subsets as well as reductions in IgA and IgM (P < 0.03) were most pronounced in patients on COX-2i who had detectable VL (n = 6). COX-2i treatment enhanced the perforin content particularly in the differentiated CD27-/CD8+ T-cell subsets compared with controls (P = 0.05).


CONCLUSIONS
COX-2i together with CART improved markers for persistent immune activation, particularly in patients with viraemia, as well as enhanced perforin expression, and thereby strengthened COX-2 as a potential therapeutic target in HIV infection.
Kvale
Dag
D
Department of Infectious Diseases, Ullevål University Hospital, Oslo, Norway. dag.kvale@medisin.uio.no
Ormaasen
Vidar
V
Kran
Anne-Marte Bakken
AM
Johansson
Carl Christian
CC
Aukrust
Pål
P
Aandahl
Einar Martin
EM
Frøland
Stig S
SS
Taskén
Kjetil
K
D051997:ADP-ribosyl Cyclase 1 / Q000097:blood; D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D015415:Biomarkers / Q000097:blood; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000097:blood; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects; D018655:Lymphocyte Count; D008297:Male; D008562:Membrane Glycoproteins / Q000097:blood; D008875:Middle Aged; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D016176:T-Lymphocyte Subsets / Q000378:metabolism; D016896:Treatment Outcome; D019562:Viral Load
D019380:Anti-HIV Agents; D015415:Biomarkers; D052246:Cyclooxygenase 2 Inhibitors; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; D051546:Cyclooxygenase 2; D051997:ADP-ribosyl Cyclase 1