Background:
Persons with HIV have an increased risk of developing diabetes mellitus. The ratio of immature (Pro-insulin) relative to mature (C-peptide) insulin products (PI:C) in circulation serves as a biomarker of pancreatic β cell stress and predicts progression to type 1 or type 2 diabetes. In adults with HIV lower PI:C was observed in untreated persons compared to those on treatment or without HIV, suggesting immune dysregulation may preserve β cell function. Children with perinatal HIV (CPHIV) have higher rates of insulin resistance compared with healthy children, but whether β cell dysfunction contributes is unknown. We investigated PI:C ratios in CPHIV and their correlations with clinical and immune activation and exhaustion markers.
Methods:
We quantified plasma levels of proinsulin (TECO intact proinsulin ELISA) and C-peptide (TOSOH immunoassay) in 200 Kenyan children who were HIV unexposed (HU) and CPHIV who were treatment naïve (ART-) or virally suppressed on treatment (ART+) aged 0-5 years (‘0-5y’ n=28 ART-, 21 ART+, 36 HU) and 5-20 years (‘5-20y’ n=41 ART-, 28 ART+, 46 HU). We calculated PI:C and assessed correlations with HIV viral load, CD4%, CD4:CD8, monocyte (sCD14, sCD163), T cell (CD38+HLA-DR+), and systemic (CRP, IL-6) activation markers and immune checkpoints (ICPs: PD-1, CD160, TIM3) on memory T cells. Mann-Whitney and Spearman’s correlations were performed on GraphPad Prism.
Results:
Compared to HU, 0-5y ART- had lower proinsulin levels (p=0.005) and PI:C (p=0.004), whereas ART+ trended toward lower PI:C (p=0.06). In 5-20y, both ART- and ART+ had a higher C-peptide level (p=0.006 and p=0.04), and ART+ had lower PI:C (p=0.04). In both age groups in CPHIV, PI:C did not correlate with age, viral load, CD4 levels, or activation markers. However, in 0-5y CPHIV PI:C inversely correlated with PD-1 (p=0.05, r=-0.46) and TIM3 (p=0.01, r=-0.40) on memory CD4 T cells as well as PD-1 (p=0.03, r=-0.51) and CD160 (p=0.04, r=-0.32) on memory CD8 T cells. There were no significant correlations between PI:C with ICPs in older CPHIV.
Conclusions:
CPHIV had a lower PI:C compared with HU, stemming from lower proinsulin in younger CPHIV and higher C-peptide in older CPHIV. Clinical markers of HIV disease progression and inflammation were not associated with β cell stress in CPHIV. T cell exhaustion correlated with PI:C in younger CPHIV. Overall, our data show no evidence of β cell dysfunction in CPHIV and suggest ICPs may play a protective role against β cell stress in young CPHIV.