CMV+ Serostatus Associates Negatively with CD4:CD8 Ratio Normalization in Controlled HIV-Infected Patients on cART.

Cytomegalovirus (CMV) infection is common among HIV-infected patients but its repercussion on the course of CD4+ and CD8+ T cells after cART initiation remains elusive. The French Dat'AIDS cohort enrolled 5,688 patients on first-line cART, from which we selected patients who achieved HIV suppression for at least 12 months without modification of cART, and for whom CMV serostatus was available. Five hundred and three patients fulfilled the selection criteria (74% male, median age 43 yrs, 15.5% CDC stage C), of whom 444 (88.3%) were seropositive for CMV (CMV+). Multivariate analyses using mixed-linear models adjusted for the time from HIV suppression, sex, age, transmission risk group, duration of HIV follow-up, the interaction between time from HIV suppression and CMV+ serology, and the nadir CD4 count revealed a negative correlation between CMV+ and CD4:CD8 ratio (coeff. = -0.16; p = 0.001). This correlation was also observed among patients displaying optimal CD4 recovery (≥500 cells/mm3 at M12; coeff. = -0.24; p = 0.002). Hence, CMV+ serostatus antagonizes normalization of the CD4:CD8 ratio, although further analyses of the impact of co-morbidities that associate with CMV serostatus, like HCV infection, are needed to elucidate this antagonism formally. However, this might reflect a premature T cell senescence, thus advocating for a close monitoring of T cells in CMV co-infected patients. In addition, our results raise the question of the benefit of treatment for asymptomatic CMV co-infection in HIV-infected patients.

Impact of hepatitis C virus coinfection on T-cell dynamics in long-term HIV-suppressors under combined antiretroviral therapy.

OBJECTIVE: The objective of this study is to evaluate the impact of hepatitis C virus (HCV) serostatus on the evolution of CD8 cells and CD4 : CD8 ratio in HIV-infected patients on combined antiretroviral therapy (cART) who achieve sustained undetectable viral load (HIV-pVL). DESIGN AND METHODS: A longitudinal study performed in an outpatient HIV-unit following 1495 HIV-infected patients. Data of patients on cART achieving undetectable HIV-pVL for at least 3 years were collected retrospectively from our medical e-database NADIS from January 1997 to April 2005, a period defined in order to select patients who were naive of hepatitis treatment. T-cell counts were assessed every 6 months from HIV-suppression over the study period. RESULTS: Two hundred and twenty-six HIV mono-infected (group 1) and 130 HCV-coinfected patients (group 2; genotype prevalence: 42% HCV-G1, 26% HCV-G3, 11% HCV-G4 and 21% HCV-G2) fulfilled the selection criteria. cART regimens were comparable between the groups, as were CD4 and CD8 cell counts at the first undetectable HIV-pVL. After 3 years, both groups displayed similar CD4 cell reconstitution, although CD4 percentage was higher in group 1 (30.3 ±â€Š1.1 vs. 27 ±â€Š1.1%; P < 0.001). HIV suppression led to a significant drop of median CD8 cell counts in group 1 (P = 0.027), but not in group 2, which displayed higher CD8 cell counts all through the follow-up (mean diff. = 135.71 ±â€Š26.89 cells/µl, P < 0.001). Moreover, the fraction of patients reaching CD4 : CD8 ratio ≥ 1 was lower in group 2 (14 vs. 27.7%; P < 0.05). CONCLUSION: Despite sustained HIV suppression under cART, HCV coinfection was found to hamper CD8 downregulation. Further studies will determine the impact of treatment with direct-acting antiviral agents on the CD8 pool, and the advantage of systematic HCV-targeted therapy for HIV/HCV-coinfected patients.

Nuclear protein 1 promotes pancreatic cancer development and protects cells from stress by inhibiting apoptosis.

Pancreatic ductal adenocarcinoma (PDAC) has the lowest survival rate of all cancers and shows remarkable resistance to cell stress. Nuclear protein 1 (Nupr1), which mediates stress response in the pancreas, is frequently upregulated in pancreatic cancer. Here, we report that Nupr1 plays an essential role in pancreatic tumorigenesis. In a mouse model of pancreatic cancer with constitutively expressed oncogenic Kras(G12D), we found that loss of Nupr1 protected from the development of pancreatic intraepithelial neoplasias (PanINs). Further, in cultured pancreatic cells, nutrient deprivation activated Nupr1 expression, which we found to be required for cell survival. We found that Nupr1 protected cells from stress-induced death by inhibiting apoptosis through a pathway dependent on transcription factor RelB and immediate early response 3 (IER3). NUPR1, RELB, and IER3 proteins were coexpressed in mouse PanINs from Kras(G12D)-expressing pancreas. Moreover, pancreas-specific deletion of Relb in a Kras(G12D) background resulted in delayed in PanIN development associated with a lack of IER3 expression. Thus, efficient PanIN formation was dependent on the expression of Nupr1 and Relb, with likely involvement of IER3. Finally, in patients with PDAC, expression of NUPR1, RELB, and IER3 was significantly correlated with a poor prognosis. Cumulatively, these results reveal a NUPR1/RELB/IER3 stress-related pathway that is required for oncogenic Kras(G12D)-dependent transformation of the pancreas.