Search

The destruction of CD4 T cells in human immunodeficiency virus (HIV) infection is associated with activation of apoptotic programs, partly mediated by death receptors. The role of CD95L/CD95 in depletion of patients' CD4 T cells is well documented, but the possible contribution of the tumor necrosis factor/tumor necrosis factor receptor (TNF/TNFR) pathway has not been examined. In this study, we found that both TNFR1 and TNFR2 induced marked apoptosis in peripheral T cells from HIV-infected persons, involving both CD4 and CD8 T cells. Longitudinal follow-up of HIV+ patients suggests an association between the in vivo evolution of CD4 T-cell numbers and variations in susceptibility to TNFR-induced apoptosis. Analysis of molecular mechanisms involved showed that it was not related to altered ex vivo expression of TNFR1-associated death domain, receptor interacting protein, or TNFR-associated factor 2. Susceptibility to TNFR-mediated apoptosis was rather related to Bcl-2 expression, because patients' T cells expressing high levels of Bcl-2 were completely protected from TNFR1- and TNFR2-induced cell death, whereas T cells expressing normal levels of Bcl-2 were not protected in patients in contrast to controls. Early recruitment of caspase-8 and caspase-3 is needed to transduce the apoptotic signals, and expression of both caspases in their active form was detected in blood T cells from HIV+ patients, whereas it was hardly detected in controls. Moreover, ligation of TNFRs induced increased activation of both caspases in patients' T cells. Together these data demonstrate that exacerbated TNFR-mediated cell death of T cells from HIV-infected individuals is associated with both alteration of Bcl-2 expression and activation of caspase-8 and caspase-3 and may contribute to the pathogenesis of acquired immunodeficiency syndrome.

Primary effusion lymphoma (PEL) is a rare high-grade B-cell non-Hodgkin lymphoma associated with Kaposi sarcoma-associated Herpesvirus/Human Herpesvirus 8 (KSHV/HHV-8) infection, and mostly observed in the course of HIV infection. The prognosis is poor with reported median survival time shorter than 6 months. To date, no prognostic factor has been identified in this subset of lymphoma. We described here the largest series of HIV-infected patients with PEL, including 30 cases diagnosed in six French centers over a 15-year time period. Prognosis analysis was performed using a Cox proportional hazard regression model. Statistically significant covariates were further analyzed in a forward, stepwise multivariate model. After a median follow-up of 3.2 years (range, 10 months-8.2 years), 9 patients (30%) were still alive, and 8 of them remained progression free. The overall median survival was 5.5 months and the 1-year overall survival rate was 36.7%. Fourteen patients (47%) achieved complete remission, with a 1-year disease-free survival rate at 78.6%. In multivariate analysis, only a performance status > 2 [hazard ratio 6.27, 95% confidence intervals (CI),1.91–20.58] and the absence of highly active antiretroviral therapy (HAART) before PEL diagnosis [hazard ratio 0.28, 95% CI, 0.10–0.77] were found to be independent predictors for shorter survival. Based on a retrospective series of 30 patients, two prognostic factors were identified as being independently associated with impaired clinical outcome in HIV-related PEL, (i) a poor performance status and (ii) the absence of HAART prior to PEL diagnosis.