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

Abstract

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.

Are we closer to better understanding risk factors for insulin resistance among children and adolescents with perinatally acquired HIV?

“…Antiretroviral-associated adverse effects have traditionally been linked to metabolic complications, including newer regimens using integrase strand transfer inhibitors (INSTIs), which have been associated with weight gain [13,14]. Although a significant proportion of the PHIV in this study (85%) switched to a regimen including an INSTI, dolutegravir [15], it is reassuring that there were no identified associations between the type of ART received and HOMA-IR. Future studies with larger cohorts and longer follow-up durations will need to be pursued to confirm that INSTIs, which are widely recommended as first-line ART, do not indeed increase the risk of insulin resistance and other metabolic complications.…”

“…Although we know that youth and adults with HIV are at a greater risk for metabolic and cardiovascular complications compared with those without HIV, we have yet to uncover the complex underpinnings of the relationships between inflammation, immune activation, and metabolic complications. We would be remiss if we did not acknowledge the wealth of data regarding inflammation, immune activation, metabolic measures, and intestinal integrity that the authors have contributed to the literature from this observational cohort of PHIV and HIV-children in Kampala, Uganda [15][16][17][18]. This cohort of youth with PHIV, like many others with HIV, has evidence of increased immune activation that persists over time, which may be associated with intestinal integrity and microbial translocation.…”

Factors associated with insulin resistance in a longitudinal study of Ugandan youth with and without HIV

“…Specifically, higher insulin resistance, as measured by HOMA-IR or oral glucose tolerance test in HIV, has been associated with classical monocyte subsets and monocyte activation [12,38] and with bacterial translocation [39][40][41] but not gut barrier dysfunction [42]. We have previously published that this Ugandan cohort with PHIV has increased T cell activation and evidence of a leaky gut compared with children without HIV, which worsened over time [43,44]; however, in this analysis, none of the markers of systemic inflammation, immune activation, gut integrity, or translocation were associated with HOMA-IR in PHIV. The lack of associations between the inflammatory and gut markers may be due to type II errors, as few children reached the cut-off of insulin resistance and may not reflect true associations.…”

Immune activation and inflammation in lactating women on combination antiretroviral therapy: role of gut dysfunction and gut microbiota imbalance

“…HIV-infected individuals in our study showed activation of innate immunity, indicated by persistently high plasma sCD14 levels, a biomarker for innate immune activation including monocytes and macrophages ( 46 ), and an independent predictor for mortality in HIV-infected individuals on cART ( 47 , 48 ). Elevated sCD14 levels were also found in HIV-infected European and African children as well as African and Chinese adults ( 2 , 3 , 8 , 13 , 36 , 43 , 44 , 46 , 49 , 50 ). We did not determine the source of monocyte activation in our population but our results are consistent with HIV-induced microbial translocation potentially driving monocyte/macrophage activation as demonstrated in another study ( 47 ).…”

“…The introduction of combination antiretroviral therapy (cART) has reduced the burden of HIV in SSA with a significant reduction in morbidity and mortality. However, chronic persistent low-level viremia due to residual HIV remains a significant contributor to microbial translocation, chronic monocyte activation, and inflammation in this population ( 2 – 4 ). Understanding the relationship between these biological systems contributes to the global effort of interventions toward the mitigation of HIV-associated morbidities.…”