The Architecture of Circulating Immune Cells Is Dysregulated in People Living With HIV on Long Term Antiretroviral Treatment and Relates With Markers of the HIV-1 Reservoir, Cytomegalovirus, and Microbial Translocation

Abstract

Long-term changes in the immune system of successfully treated people living with HIV (PLHIV) remain incompletely understood. In this study, we assessed 108 white blood cell (WBC) populations in a cohort of 211 PLHIV on stable antiretroviral therapy and in 56 HIV-uninfected controls using flow cytometry. We show that marked differences exist in T cell maturation and differentiation between PLHIV and HIV-uninfected controls: PLHIV had reduced percentages of CD4+ T cells and naïve T cells and increased percentages of CD8+ T cells, effector T cells, and T helper 17 (Th17) cells, together with increased Th17/regulatory T cell (Treg) ratios. PLHIV also exhibited altered B cell maturation with reduced percentages of memory B cells and increased numbers of plasmablasts. Determinants of the T and B cell composition in PLHIV included host factors (age, sex, and smoking), markers of the HIV reservoir, and CMV serostatus. Moreover, higher circulating Th17 percentages were associated with higher plasma concentrations of interleukin (IL) 6, soluble CD14, the gut homing chemokine CCL20, and intestinal fatty acid binding protein (IFABP). The changes in circulating lymphocytes translated into functional changes with reduced interferon (IFN)- γ responses of peripheral blood mononuclear cells to stimulation with Candida albicans and Mycobacterium tuberculosis. In conclusion, this comprehensive analysis confirms the importance of persistent abnormalities in the number and function of circulating immune cells in PLHIV on stable treatment.

Blood-Based Immune Profiling Combined with Machine Learning Discriminates Psoriatic Arthritis from Psoriasis Patients

“…In fact, including the patients' age did not improve the RF model performance. Age has been evaluated extensively in the past also using the same flow cytometry panels used in the current study [16,17]. Although aging influences the immune cell composition (e.g., young vs old), within the age-interval (mean age 44-56) of our study cohort, as expected and as analyzed, the outcome of the RF model was hardly influenced.…”

“…All antibodies were titrated and tested before use. Percentages of immune cell subsets were manually analyzed using Kaluza software version 2.1 (Beckman-Coulter, Brea, CA, USA) as described previously [16,17,19].…”

HIV-linked gut dysbiosis associates with cytokine production capacity in viral-suppressed people living with HIV

“…IL-1β and IL-6 and TNF) in PLHIV. 1 By comparing the cytokine production data of our HIV cohort to 173 samples from the 500FG cohort (different samples from our previous studies 1,36 ), we identified 24 cytokine abundances that were significantly different (Fig. 3a, Supplementary Table 10).…”

“…Despite long-term cART, the immune responses of PLHIV are known to be different than those of healthy controls 36 . In a previous study from our group 1 , PBMCs of PLHIV and healthy controls were stimulated ex vivo with 12 different microbial stimuli and the cytokine production capacity assessed, including monocyte-derived (IL-1β, IL-6 and TNF), lymphocyte-derived proinflammatory cytokines (IL-17, IL-22 and IFN-γ) and anti-inflammatory cytokines (IL-10 and IL-1 receptor antagonist, IL-1Ra) (Supplementary Table 9).…”

“…Cytokine production data for the 500FG cohort was obtained using the same method, and the measurements that overlapped with those in the HIV cohort are summarized in the Supplementary Table 9. For the comparison of cytokine production between PLHIV and HCs from 500FG, we used different samples compared with the previous studies 1,36 , so we conducted a re-analysis. A linear regression model was used, with correction for sex and age, using FDR < 0.05 as the significant threshold.…”