An Exploratory Trial of Cyclooxygenase Type 2 Inhibitor in HIV-1 Infection: Downregulated Immune Activation and Improved T Cell-Dependent Vaccine Responses

Abstract

Chronic HIV infection is characterized by chronic immune activation and dysfunctional T cells with elevated intracellular cyclic AMP (cAMP), which inhibits the T cell activation capability. cAMP may be induced by prostaglandin E 2 following lipopolysaccharide (LPS)-induced upregulation of cyclooxygenase type 2 (COX-2) in monocytes due to the elevated LPS levels in patients with chronic HIV infection. This hypothesis was tested using celecoxib, a COX-2 inhibitor, for 12 weeks in HIV-infected patients without antiretroviral treatment in a prospective, open, randomized exploratory trial. Thirty-one patients were randomized in the trial; 27 completed the study, including 13 patients on celecoxib. Celecoxib reduced chronic immune activation in terms of CD38 density on CD8 ؉ T cells (؊24%; P ‫؍‬ 0.04), IgA levels (P ‫؍‬ 0.04), and a combined score for inflammatory markers (P < 0.05). Celecoxib further reduced the inhibitory surface receptor programmed death 1 (PD-1) on CD8 ؉ T cells (P ‫؍‬ 0.01), including PD-1 on the HIV Gag-specific subset (P ‫؍‬ 0.02), enhanced the number of CD3 ؉ CD4 ؉ CD25 ؉ CD127 lo/؊ Treg or activated cells (P ‫؍‬ 0.02), and improved humoral memory recall responses to a T cell-dependent vaccine (P ‫؍‬ 0.04). HIV RNA (P ‫؍‬ 0.06) and D dimers (P ‫؍‬ 0.07) tended to increase in the controls, whereas interleukin-6 (IL-6) possibly decreased in the treatment arm (P ‫؍‬ 0.10). In conclusion, celecoxib downmodulated the immune activation related to clinical progression of chronic HIV infection and improved T cell-dependent functions in vivo.

Immune activation and HIV-specific T cell responses are modulated by a cyclooxygenase-2 inhibitor in untreated HIV-infected individuals: An exploratory clinical trial

“…In keeping with this, we have previously observed improved IgG recall responses after tetanus toxoid vaccination in ART-naïve, HIV-infected patients receiving high-dose celecoxib [31]. However, in the current study long-term COX-2i therapy was associated with the poorest IgG responses to both tetanus toxoid and conjugated pneumococcal vaccines.…”

Persistent immune activation in chronic HIV infection

“…In cART-treated patients, selective COX-2 inhibitors were associated with increased T-cell proliferation [94], a nonsignificant reduction in T-cell activation, and increased perforin-containing CD8 T cells [42]. A recent RCT of high-dose celecoxib in untreated HIV-infected patients ( n = 31) reported a significant reduction in immune activation levels [43]. …”

Immune activation and HIV persistence

“…In a recent randomized, open-label study, untreated HIV-infected individuals were randomized to receive a cyclooxygenase type 2 (COX-2) inhibitor (celecoxib) for 12 weeks [54]. Administration of the COX-2 inhibitor decreased levels of immune activation (defined as CD38 density on CD8+ T cells) as well as PD-1 density on CD8+ T cells.…”