Abstract
Pathologically elevated immune activation and inflammation contribute to HIV disease progression and immunodeficiency, potentially mediated by elevated levels of prostaglandin E2, which suppress HIV-specific T cell responses. We have previously shown that a high dose of the cyclooxygenase-2 inhibitor celecoxib can reduce HIV-associated immune activation and improve IgG responses to T cell-dependent vaccines. In this follow-up study, we included 56 HIV-infected adults, 28 antiretroviral therapy (ART)-naïve and 28 on ART with undetectable plasma viremia but CD4 counts below 500 cells/μL. Patients in each of the two study groups were randomized to receive 90 mg qd of the cyclooxygenase-2 inhibitor etoricoxib for six months, two weeks or to a control arm, respectively. T cell activation status, HIV Gag-specific T cell responses and plasma inflammatory markers, tryptophan metabolism and thrombin generation were analyzed at baseline and after four months. In addition, patients received tetanus toxoid, conjugated pneumococcal and seasonal influenza vaccines, to which IgG responses were determined after four weeks. In ART-naïve patients, etoricoxib reduced the density of the activation marker CD38 in multiple CD8+ T cell subsets, improved Gag-specific T cell responses, and reduced in vitro plasma thrombin generation, while no effects were seen on plasma markers of inflammation or tryptophan metabolism. No significant immunological effects of etoricoxib were observed in ART-treated patients. Patients receiving long-term etoricoxib treatment had poorer tetanus toxoid and conjugated pneumococcal vaccine responses than those receiving short-course etoricoxib. Cyclooxygenase-2 inhibitors may attenuate harmful immune activation in HIV-infected patients without access to ART.
Highlights
Chronic, untreated HIV infection is characterized by a state of pathological immune activation and inflammation, which contributes to disease progression and immunodeficiency [1]
When plasma viremia is suppressed to near-undetectable levels by antiretroviral therapy (ART), immune activation is attenuated, but not to the level of the HIV-uninfected population [7, 8], and residual immune activation in patients on ART is associated with both mortality and impaired immune reconstitution [7, 9, 10]
We have previously shown that treatment with high-dose COX-2 inhibitors (COX-2i) for 12 weeks can reduce the expression of T cell activation markers in both untreated [31] and treated but viremic
Summary
Chronic, untreated HIV infection is characterized by a state of pathological immune activation and inflammation, which contributes to disease progression and immunodeficiency [1]. Expression of the activation marker CD38 on T cells predicts both progression to AIDS and mortality [2,3,4,5,6]. In the absence of ART, HIV-specific CD8+ T cell function is essential for viral control [13, 14], but this is progressively lost in most chronically infected patients [15] and not restored after ART initiation [16, 17]. Most cure strategies will likely rely on boosting HIV-specific CD8+ T cell function to eliminate the majority of latently infected cells and prevent viral rebound from any remaining reservoirs [19, 20]
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