Background
HIV disease in children differs from that seen in adults. The objective of this study was to test the association between HIV reservoir size and the development of antiviral immunity between childhood, adolescence and young adulthood in terms of a) expression of co-inhibitory receptors; and b) expression of plasma cytokines.
Methods
Expression of co-inhibitory receptors was measured by flow cytometry. Levels of 33 plasma cytokines and chemokines were assessed using the Meso Scale Discovery platform. Total HIV DNA was measured by qRT-PCR and inducible HIV RNA levels were measured following prostratin stimulation. HIV-specific cell-mediated immune responses were measured using IFN-g ELISPOT.
Results
The study was conducted on 65 participants of the EPIC4 Cohort (47.4% male) who were stratified as children (<10 yrs; n=15), adolescents (10-18 yrs; n=34) or young adults (>18; n=16). Median viral load was <40 RNA copies/mL plasma (range=<40-8473 copies). Frequencies of CD4+ T cells expressing PD-1 or TIGIT and of CD8+ T cells expressing PD-1, TIGIT or CD160 significantly increased with age. Total HIV DNA and inducible HIV RNA levels were positively correlated with frequencies of PD-1+ (p≤0.033) and TIGIT+ (p≤0.032) CD4+ T cells and of PD-1+ (p<0.001), TIGIT+ (p≤0.080) and CD160+ (p≤0.021) CD8+ T cells (Figure). Children clustered separately from adolescents and young adults in PCA whether reservoir size or HIV-specific cell-mediated immune responses were included. Unbiased PCA showed that global variability in the plasma cytokine profile on the first PC (27.4% variability) was significantly (p<0.05) associated with age at sample collection, while the second PC (15.04% variability) was linked to HIV reservoir size. Plasma levels of TGF-b and TH2 cytokines (e.g., IL-4) were significantly elevated in children <10. A subset of older participants (>10 years) with high TGF-b levels did not exhibit high levels of inducible HIV RNA. Conversely, older participants with reduced levels of TGF-b showed higher levels of IL-17A, IFN-g, total HIV DNA and inducible HIV RNA.
Conclusions
Expression of a set of co-inhibitory receptors (PD-1, TIGIT, CD160) and evolution of cytokine profiles were associated with age and with total and inducible HIV reservoir size in children and adolescents living with vertically-acquired HIV. This study highlights major longitudinal shifts in mobilization of immune pathways that could inform the differential pathology of pediatric HIV disease.
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