HCV monoinfection and HIV/HCV coinfection enhance T-cell immune senescence in injecting drug users early during infection

Background: Injecting drug users (IDU) are at premature risk of developing multimorbidity and mortality from causes commonly observed in the elderly. Ageing of the immune system (immune-senescence) can lead to premature morbidity and mortality and can be accelerated by chronic viral infections. Here we investigated the impact of HCV monoinfection and HIV/HCV coinfection on immune parameters in (ex-) IDU. We analyzed telomere length and expression of activation, differentiation and exhaustion markers on T cells at baseline (t = 1) and at follow-up (t = 2) (median interval 16.9 years) in IDU who were: HCV mono-infected (n = 21); HIV/HCV coinfected (n = 23) or multiple exposed but uninfected (MEU) (n = 8). Results: The median time interval between t = 1 and t = 2 was 16.9 years. Telomere length within CD4(+) and CD8(+) T cells decreased significantly over time in all IDU groups (p <= 0.012). CD4(+) T-cell telomere length in HCV mono-infected IDU was significantly reduced compared to healthy donors at t = 1 (p <0.008). HIV/HCV coinfected IDU had reduced CD4(+) and CD8(+) T-cell telomere lengths (p <= 0.002) to healthy donors i at t = 1. This was related to persistent levels of immune activation but not due to increased differentiation of T cells over time. Telomere length decrease was observed within all T-cell subsets, but mainly found in immature T cells (CD27(+)CD57(+)) (p <= 0.015). Conclusions: HCV mono-infection and HIV/HCV coinfection enhance T-cell immune-senescence. Our data suggest that this occurred early during infection, which warrants early treatment for both HCV and HIV to reduce immune senescence in later lif

Associations of faecal microbiota with influenza-like illness in participants aged 60 years or older:an observational study

Background People aged 60 years or older are at high risk for respiratory infections, one of the leading causes of mortality worldwide. Vaccination is the main way to protect against these infections; however, vaccination is less effective in older adults than in younger adults due to ageing of the immune system, so innovative strategies that improve vaccine responses could provide a major public health benefit. The gut microbiota regulates host immune homoeostasis and response against pathogens, but human studies showing the effects of the gut microbiota on respiratory infections in older adults are sparse. We aimed to investigate the composition of the microbiota in relation to respiratory infections and local and systemic immune markers in older adults during an influenza season. Methods In this observational study, participants were selected from an influenza-like illness (ILI) prospective surveillance cohort in which community-dwelling adults aged 60 years and older in the Netherlands were recruited through their general practitioner or the Civil Registry. Inclusion criteria have been described elsewhere. Participants completed questionnaires and self-reported symptoms. To measure microbiota composition, faecal samples were collected from participants registering an ILI event, with a follow-up (recovery) sample collected 7-9 weeks after the ILI event, and from asymptomatic participants not reporting any event throughout the season. We tested associations between microbiota profiles and a set of health-related variables, patient characteristics, and local and systemic immune markers. We cultured identified bacterial biomarkers for ILI with CaCo-2 cells in an in vitro intestinal epithelial model and measured the induced immune response. This study is registered with http://www.trialregister.nl, NL4666. Findings Between Oct 1, 2014, and April 30, 2015, 2425 older adults were recruited into the ILI surveillance cohort. From Oct 1, 2014, to June 15, 2015, faecal samples were collected from 397 participants, of whom 213 (54%) reported an ILI event once throughout the season and 184 (46%) did not. 192 ILI participants recovered and provided follow-up samples. Microbiota composition was altered during an ILI event. The Bacteroidetes (mean relative abundance 17.51% [SD 11.41] in the ILI group and 14.19% [10.02] in the control group; adjusted p=0.014) and the Proteobacteria (3.40% [8.10] in the ILI group and 1.57% [3.69] in the control group; adjusted p=0.015) were more abundant in the ILI group than in the control group. The abundance of Ruminococcus torques was positively associated with ILI and the abundance of Escherichia/Shigella, negatively correlated with alpha diversity, and negatively co-occurred with beneficial taxa, including butyrate producers. R torques was associated with pro-inflammatory profiles, both locally in faeces and systemically in blood. ILI-associated taxa (R torques and Escherichia coli) had symbiotic effects on the cellular immune response when cultured together in an in vitro model. Interpretation The abundances of specific bacteria could be used as potential biomarkers for susceptibility to respiratory infections and as targets for intervention in the ageing population. Copyright (C) 2020 The Author(s). Published by Elsevier Ltd

Altered EBV viral load setpoint after HIV seroconversion is in accordance with lack of predictive value of EBV load for the occurrence of AIDS-related non-Hodgkin lymphoma

In contrast to the situation in the post-transplant setting, in HIV-infected individuals an elevated EBV load is not predictive of EBV-related malignancies. To study whether a high EBV load is already a normal situation early in HIV infection and is not related to a decrease in immune function over time, we investigated EBV load and EBV-specific CD8(+) T cells similar to1 year before and I year after HIV seroconversion. EBV load significantly increased after HIV seroconversion from 205 to 1002 copies/10(6) PBMC (p <0.001), whereas no further increase in EBV load was observed between 1 and 5 years after HIV seroconversion (median, 1827-2478 copies/10(6) PBMC; p = 0.530). Interestingly, the absolute number of EBV lytic epitope, RAKFKQLL-specific CD8(+) T cells increased over HIV seroconversion (4.78 to 9.54/mul; p = 0.011). Furthermore, the fraction of CD27-negative effector, RAK-specific CD8(+) T cells tended to increase (from 12.2 to 17.31% CD27(-); p = 0.051), in accordance with Ag-driven differentiation. In conclusion, both virological and immunological data support the idea that a new EBV viral setpoint is reached early in HIV infection, probably by EBV reactivation, as suggested by the preferential increase in EBV lytic epitope-specific CD8(+) T cells. These data may thus help to explain the lack of predictive value of EBV load for the occurrence of AIDS-related lymphom

Novel method for detection of virus-specific CD41+ T cells indicates a decreased EBV-specific CD4+ T cell response in untreated HIV-infected subjects

A lower function of EBV-specific CD8(+) T cells in HIV-infected subjects could be related to a lack of specific CD4(+) T cell help. Therefore, we studied EBV-specific CD4(+) T cells in both healthy donors and untreated or highly active antiretroviral therapy (HAART)-treated HIV-seropositive homosexual men. To this end, PBMC were stimulated with overlapping peptide pools from a latent and a lytic EBV protein, EBV nuclear antigen (EBNA)1 and EBV lytic-switch protein ZEBRA (BZLF1), respectively. EBV-specific CD4(+) T cell frequencies measured directly ex vivo were low. To measure EBV-specific memory CD4(+) T cells, capable of both expansion and IFN-gamma production upon antigenic challenge, we developed a specific and reproducible assay, combining ex vivo expansion of specific T cells with flow cytometric analysis of IFN-gamma production. Untreated HIV-infected individuals had a lower CD4(+) T cell response to both EBNA1 and BZLF1 as compared to healthy EBV carriers and HAART-treated HIV-positive subjects. This suggests loss of EBV-specific CD4(+) T cells due to HIV infection, while HAART might restore this response. In addition, we found an increase in the EBNA1-specific CD8(+) T cell response in HAART-treated subjects. Interestingly, numbers of EBV-specific CD4(+) and CD8(+) T cells were inversely correlated with EBV viral load, suggesting an important role also for EBV-specific CD4(+) T cells in the control of EBV infectio