Abstract
Chronic inflammation is thought to be a major cause of morbidity and mortality in aging, but whether similar mechanisms underlie dysfunction in infection-associated chronic inflammation is unclear. Here, we profiled the immune proteome, and cellular composition and signaling states in a cohort of aging individuals versus a set of HIV patients on long-term antiretroviral therapy therapy or hepatitis C virus (HCV) patients before and after sofosbuvir treatment. We found shared alterations in aging-associated and infection-associated chronic inflammation including T cell memory inflation, up-regulation of intracellular signaling pathways of inflammation, and diminished sensitivity to cytokines in lymphocytes and myeloid cells. In the HIV cohort, these dysregulations were evident despite viral suppression for over 10 y. Viral clearance in the HCV cohort partially restored cellular sensitivity to interferon-α, but many immune system alterations persisted for at least 1 y posttreatment. Our findings indicate that in the HIV and HCV cohorts, a broad remodeling and degradation of the immune system can persist for a year or more, even after the removal or drastic reduction of the pathogen load and that this shares some features of chronic inflammation in aging.
Highlights
Chronic inflammation is thought to be a major cause of morbidity and mortality in aging, but whether similar mechanisms underlie dysfunction in infection-associated chronic inflammation is unclear
Three independent cohorts were analyzed in this study (SI Appendix, Tables S1–S3): 1) year two (2009) of the Stanford-Ellison longitudinal cohort on aging [12,13,14, 17,18,19, 30,31,32] consisting of 89 generally healthy and ambulatory individuals (n = 60 older individuals age 61–90, n = 29 young controls age 22–33); 2) an HIV cohort consisting of 69 individuals (n = 24 HIV-infected individuals age 26–78, n = 45 HIVuninfected controls age 25–78); and 3) an hepatitis C virus (HCV) cohort consisting of 25 individuals (n = 14 HCV-infected individuals age 29–71, n = 11 HCV-uninfected controls age 18–74)
We analyzed the abundance of major PBMC populations (SI Appendix, Fig. S1) including T cells, B cells, myeloid cells, and natural killer cells (NKs) cells, each cell type’s signal transducer and activator of transcription 1 (STAT1), STAT3, and STAT5 baseline signaling states, and each cell type’s sensitivity to ex vivo cytokine stimulation
Summary
Chronic inflammation is thought to be a major cause of morbidity and mortality in aging, but whether similar mechanisms underlie dysfunction in infection-associated chronic inflammation is unclear. It remains unclear whether common molecular mechanisms underlie dysfunction in both agingassociated and infection-associated chronic inflammation, and if any of these functional alterations are reversible upon the removal of the inflammatory driver To address these questions, we analyzed three independent cohorts: 1) an aging cohort enriched for older individuals 61–90 y old; 2) a cohort of virologically suppressed, HIV-infected individuals on combination antiretroviral therapy (cART); and 3) a cohort of HCV-infected individuals prior to initiating treatment with the direct-acting antiviral (DAA) sofosbuvir—an NS5B nucleoside polymerase inhibitor which leads to viral clearance in a matter of weeks [15, 16]. Our findings suggest a broad and persistent functional remodeling and deterioration of the human immune system despite removal of a chronic pathogenic burden that shares features of chronic inflammation in aging
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
