Persistent immune activation and altered gut integrity over time in a longitudinal study of Ugandan youth with perinatally acquired HIV

Frontiers in Immunology

Immunology

Grace A. McComsey¹  Sahera Dirajlal-Fargo¹  Cissy Kityo²  Christine Karungi²  Rashidah Nazzinda²  Victor Musiime³  Nicholas Funderburg⁴  Kate Ailstock⁴  Monika Strah⁵  Abdus Sattar⁵ 

[1] Division of Pediatrics, University Hospitals Cleveland Medical Center, Cleveland, OH, United States;Division of Infectious Diseases, Rainbow Babies and Children’s Hospital, Cleveland, OH, United States;School of Medicine and Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, United States;Joint Clinical Research Centre, Kampala, Uganda;Joint Clinical Research Centre, Kampala, Uganda;Makerere University, Kampala, Uganda;School of Health and Rehabilitation Sciences, Ohio State University School of Health and Rehabilitation Sciences, Columbus, OH, United States;School of Medicine and Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, United States;

关键词: inflammation;    immune activation;    gut integrity;    microbial translocation;    children;    HIV;    sub-Saharan Africa;   

DOI  :  10.3389/fimmu.2023.1165964

 received in 2023-02-14, accepted in 2023-03-14,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionPerinatally acquired HIV infection (PHIV) occurs during a critical window of immune development. We investigated changes in systemic inflammation and immune activation in adolescents with PHIV and those without HIV (HIV-) in Uganda.MethodsA prospective observational cohort study was performed in 2017-2021 in Uganda. All participants were between 10-18 years of age and without active co-infections. PHIVs were on ART with HIV-1 RNA level ≤400 copies/mL. We measured plasma and cellular markers of monocyte activation, T-cell activation (expression of CD38 and HLA-DR on CD4+ and CD8+), oxidized LDL, markers of gut integrity and fungal translocation. Groups were compared using Wilcoxon rank sum tests. Changes from baseline were examined with 97.5% confidence intervals on relative fold change. P values were adjusted for false discovery rate.ResultsWe enrolled 101 PHIV and 96 HIV-; among these, 89 PHIV and 79 HIV- also had measurements at 96 weeks. At baseline, median (Q1, Q3) age was 13 yrs (11,15), and 52% were females. In PHIV, median CD4+ cell counts were 988 cells/µL (638, 1308), ART duration was 10 yrs (8, 11), and 85% had viral load <50 copies/mL throughout the study, 53% of participants had a regimen switch between visits, 85% of whom switched to 3TC, TDF and DTG. Over 96 weeks, while hsCRP decreased by 40% in PHIV (p=0.12), I-FABP and BDG both increased by 19 and 38% respectively (p=0.08 and ≤0.01) and did not change in HIV- (p≥0.33). At baseline, PHIVs had higher monocyte activation (sCD14) (p=0.01) and elevated frequencies of non-classical monocytes (p<0.01) compared to HIV- which remained stable over time in PHIV but increased by 34% and 80% respectively in HIV-. At both time points, PHIVs had higher T cell activation (p ≤ 0.03: CD4+/CD8+ T cells expressing HLA-DR and CD38). Only in PHIV, at both timepoints, oxidized LDL was inversely associated with activated T cells(p<0.01). Switching to dolutegravir at week 96 was significantly associated an elevated level of sCD163 (β=0.4, 95% CI=0.14,0.57, p<0.01), without changes in other markers.ConclusionUgandan PHIV with viral suppression have some improvement in markers of inflammation over time, however T-cell activation remains elevated. Gut integrity and translocation worsened only in PHIV over time. A deeper understanding of the mechanisms causing immune activation in ART treated African PHIV is crucial.

【 授权许可】

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Copyright © 2023 Dirajlal-Fargo, Strah, Ailstock, Sattar, Karungi, Nazzinda, Kityo, Musiime, Funderburg and McComsey