Extended Interferon-Alpha Therapy Accelerates Telomere Length Loss in Human Peripheral Blood T Lymphocytes

BACKGROUND: Type I interferons have pleiotropic effects on host cells, including inhibiting telomerase in lymphocytes and antiviral activity. We tested the hypothesis that long-term interferon treatment would result in significant reduction in average telomere length in peripheral blood T lymphocytes. METHODS/PRINCIPAL FINDINGS: Using a flow cytometry-based telomere length assay on peripheral blood mononuclear cell samples from the Hepatitis-C Antiviral Long-term Treatment against Cirrhosis (HALT-C) study, we measured T cell telomere lengths at screening and at months 21 and 45 in 29 Hepatitis-C virus infected subjects. These subjects had failed to achieve a sustained virologic response following 24 weeks of pegylated-interferon-alpha plus ribavirin treatment and were subsequently randomized to either a no additional therapy group or a maintenance dose pegylated-IFNalpha group for an additional 3.5 years. Significant telomere loss in naive T cells occurred in the first 21 months in the interferon-alpha group. Telomere losses were similar in both groups during the final two years. Expansion of CD8(+)CD45RA(+)CD57(+) memory T cells and an inverse correlation of alanine aminotransferase levels with naive CD8(+) T cell telomere loss were observed in the control group but not in the interferon-alpha group. Telomere length at screening inversely correlated with Hepatitis-C viral load and body mass index. CONCLUSIONS/SIGNIFICANCE: Sustained interferon-alpha treatment increased telomere loss in naive T cells, and inhibited the accumulation of T cell memory expansions. The durability of this effect and consequences for immune senescence need to be defined

High cytotoxic and specific migratory potencies of senescent CD8+ CD57+ cells in HIV-infected and uninfected individuals

International audienceCD8+ CD57+ T lymphocytes, present at low levels in the peripheral blood of healthy individuals expand during HIV infection and remain elevated during chronic infection. Their role in the immune response remains unclear. We performed a large-scale gene array analysis (3158 genes) to characterize them and, interestingly, found no distinction in the transcriptional profiles of CD8+ CD57+ T lymphocytes from HIV-infected and uninfected subjects. In both groups, these cells showed specificity for multiple Ags and produced large amounts of IFN-gamma and TNF-alpha. The transcriptional profiles of CD8+ CD57+ and CD8+ CD57- cells, however, differed substantially. We propose that CD8+ CD57+ cells were Ag-driven effector cells with very high cytotoxic effector potential including perforin, granzymes, and granulysin, regardless of HIV status. At both the messenger and protein levels, they expressed more adhesion molecules and fewer chemokine receptors (CCR7 and CXCR4) than CD8+ CD57- cells but expressed preferentially CX3CR1. The lower expression level of genes involved in cell cycle regulation showed limited proliferation capacities of CD8+ CD57+ even in response to TCR and IL-2, IL-7, and IL-15 stimulation. CD8+ CD57+ T cells from both HIV and uninfected subjects maintain effective cytotoxic potentials but are destined to migrate to nonlymphoid tissues without further cycling

Metabolism and growth of juveniles of Litopenaeus vannamei: effect of salinity and dietary carbohydrate levels

The present study was designed to understand how carbohydrate (CBH) and protein metabolism are related in the penaeid shrimp Litopenaeus vannamei. With this information, we obtained a comprehensive schedule of the protein-carbohydrate metabolism including enzymatic, energetic, and functional aspects. We used salinity to determine its role as a modulator of the protein-carbohydrate metabolism in shrimp. Two experiments were designed. The first experiment evaluated the effect of CBH-salinity combinations in growth and survival, and hemolymph glucose, protein, and ammonia levels, digestive gland glycogen, osmotic pressure, and glutamate dehydrogenase (GDH) of L. vannamei juveniles acclimated during 18 days at a salinity of 15 parts per thousand and 40 parts per thousand. The second experiment was done to evaluate the effect of dietary CBH level on pre- and postprandial oxygen consumption, ammonia excretion, and the oxygen-nitrogen ratio (O/N) of juvenile L. vannamei in shrimps acclimated at 40 parts per thousand salinity. We also evaluated the ability of shrimp to carbohydrate: adaptation. We made phosphoenolpyruvate carboxykinase (PECPK) and hexokinase activity measurements after a change in dietary carbohydrate levels at different times during 10 days. The growth rate depended on the combination salinity-dietary CBH-protein level. The maximum growth rate was obtained in shrimps maintained at 15 parts per thousand salinity and with a diet containing low CBH and high protein. The protein in hemolymph is related to the dietary protein level

Affinity proteomics within rare diseases: a BIO-NMD study for blood biomarkers of muscular dystrophies

Despite the recent progress in the broad-scaled analysis of proteins in body fluids, there is still a lack in protein profiling approaches for biomarkers of rare diseases. Scarcity of samples is the main obstacle hindering attempts to apply discovery driven protein profiling in rare diseases. We addressed this challenge by combining samples collected within the BIO-NMD consortium from four geographically dispersed clinical sites to identify protein markers associated with muscular dystrophy using an antibody bead array platform with 384 antibodies. Based on concordance in statistical significance and confirmatory results obtained from analysis of both serum and plasma, we identified eleven proteins associated with muscular dystrophy, among which four proteins were elevated in blood from muscular dystrophy patients: carbonic anhydrase III (CA3) and myosin light chain 3 (MYL3), both specifically expressed in slow-twitch muscle fibers and mitochondrial malate dehydrogenase 2 (MDH2) and electron transfer flavoprotein A (ETFA). Using age-matched sub-cohorts, 9 protein profiles correlating with disease progression and severity were identified, which hold promise for the development of new clinical tools for management of dystrophinopathies