Abacavir and cardiovascular risk in HIV-infected patients: does T-lymphocyte hyperactivation exert a pathogenic role?

n/

Carotid intima media thickness with no cardiovascular disease in HIV-infected patients correlates with a hyperactivated/pro-apoptotic T-cell phenotype

Background HIV-infected patients may be at increased risk of cardiovascular disease (CVD), and present higher carotid intima media thickness (IMT) compared with healthy controls. Besides clinical and metabolic factors, atherosclerosis in HIV is influenced by immune and inflammatory parameters. Given that T-cell activation correlates with CVD and HIV accounts for heightened T-cell hyperactivation, we hypothesized that early IMT increases associate to T-cell hyperactivation

HIV-infected long-term nonprogressors display a unique correlative pattern between the interleukin-7/interleukin-7 receptor circuit and T-cell homeostasis.

none15MARCHETTI G; RIVA A; CESARI M; BELLISTRI' GM; GIANELLI E; CASABIANCA A; ORLANDI C; MAGNANI M.; MERONI L; D'ARMINIO MONFORTE A; MUSSINI C; COSSARIZZA A; GALLI M; GORI A; ELVIS STUDY GROUPMarchetti, G; Riva, A; Cesari, M; Bellistri', Gm; Gianelli, E; Casabianca, Anna; Orlandi, C; Magnani, Mauro; Meroni, L; D'ARMINIO MONFORTE, A; Mussini, C; Cossarizza, A; Galli, M; Gori, A; ELVIS STUDY, Grou

Microbial translocation predicts disease progression of HIV-infected antiretroviral-naive patients with high CD4+ cell count

Objectives: We investigated the significance of microbial translocation measured on average 3 years after HIV seroconversion in driving disease progression in HIV(+) untreated patients with high CD4(+) cell count. Design: We included ICONA patients with documented last HIV-negative and first HIV-positive test, at least one plasma sample stored while antiretroviral therapy (ART)-naive and CD4(+) cell count greater than 200 cells/mu l. Methods: Microbial translocation [lipopolysaccharide (LPS), sCD14 and EndoCAb] and immune activation (IL-6 and TNF-alpha) were measured. Correlation between immune activation, microbial translocation, CD4(+) and plasma HIV-RNA was evaluated by linear regression and nonparametric Spearman's rho. The independent predictive value of these markers on time to progression to the combined endpoint of AIDS, death, CD4(+) cell count less than 200 cells/mu l or start of antiretroviral therapy (ART) was assessed using survival analysis. Results: We analysed 1488 biomarker measures from 379 patients. A median of 3.1 years after the estimated seroconversion date [interquartile range (IQR) 1.6-5.4], median (IQR) markers values were LPS, 110 pg/ml (IQR 75-215), sCD14, 3.3 mu g/ml (2.2-4.8), IL-6, 1.1 pg/ml (0.6-1.9) and TNF-alpha, 2.4 pg/ml (1.8-3.4). Two hundred and sixty progression events were recorded over a median of 1.6 years from the first sample (2% AIDS, 84% ART initiation, 12% CD4(+) cell count less than 200 cells/mu l and 2% death). LPS was the only biomarker associated with this primary composite outcome independently of age, HIV-RNA and CD4(+) (relative hazard = 1.40 per log(e) higher, 95% confidence interval 1.18-1.66, P<0.001). Conclusion: Circulating LPS in the first years of chronic HIV infection is a strong predictor of disease progression independent of CD4(+) cell count and HIV viraemia and may be considered a candidate biomarker for HIV monitoring and evaluation in clinical trials

HIV-infected long-term nonprogressors display a unique correlative pattern between the interleukin-7/interleukin-7 receptor circuit and T-cell homeostasis.

BACKGROUND:We hypothesized that there may be a correlation between the interleukin-7 (IL-7)/IL-7 receptor (IL-7R) regulatory system and parameters of T-cell homeostasis in HIV-infected long-term nonprogressors (LTNPs) as compared with patients with disease progression.METHODS:The possibility of a correlation between T-cell homeostatic parameters and IL-7/IL-7R was investigated in 22 LTNPs (CD4 count > or =500 cells/microL for >10 years) vs. HIV-positive patients at different disease stages [12 early: CD4 count > or =400 cells/microL ; 15 late (AIDS-presenters): CD4 count < or =150 cells/microL ].RESULTS:Compared with early-stage HIV-positive patients, LTNPs displayed a higher circulating IL-7 concentration (P=0.05), which was positively associated with higher IL-7Ralpha expression and a higher T-cell receptor excision circle (TREC) content specifically within CD4 cells (P<0.05). Compared with late-stage disease patients, early-stage disease patients displayed a lower IL-7 concentration (P<0.01) and higher percentages of IL-7Ralpha+ CD4 and CD8 cells (P=0.05). IL-7 was positively correlated with the percentage of TREC+ CD4 cells (P<0.01), which translated into a higher percentage of naïve CD4 cells in early-stage disease patients than in late-stage disease patients; however, the CD4 cells in early-stage disease patients were less enriched in recent thymic emigrants (RTEs) compared with LTNPs (P<0.05). In late-stage AIDS-developing patients, substantially increased IL-7 was correlated with a decreased percentage of IL-7Ralpha+ CD4 cells (P=0.01), which resulted in these patients having a significantly lower percentage of naïve T cells (P<0.01) and a significantly lower content of TREC (P<0.01) than the other patients.CONCLUSIONS:The maintenance of high CD4 cell counts in LTNPs was associated with a specific IL-7/IL-7R pattern characterized by increased IL-7 and highest IL-7Ralpha-expressing CD4 cells relative to other patients. Compared with patients with late-stage disease, LTNPs displayed a phenotypically naïve, less activated CD4 cell pool highly enriched in RTEs, suggesting the existence of a compensatory IL-7-mediated pathway specifically sustaining peripheral CD4 counts