Background
Inflammation persists under antiretroviral therapy (ART) in HIV infection. Soluble mediators of inflammation play major roles in immune function, reservoir persistence and rebound post-analytical treatment interruption (ATI). Interactions between cytokines/chemokines and/or metabolites with reservoir size and viral rebound dynamics are not fully known. We evaluated associations between host and microbial-derived metabolites or cytokines/chemokines and reservoir size on ART and post-ATI viral rebound in a pediatric HIV model.
Methods
Eight infant rhesus macaques (3 male, 5 female) were orally infected with SIVmac251 at 4 weeks of age, initiated on ART 4 weeks after infection, and underwent ATI after 60 weeks of ART. Plasma samples were collected at pre/early ART and late ART for cytokine/chemokine quantification using multiplex assay and untargeted metabolomics by high performance liquid chromatography and mass spectrometry. SIV reservoir was evaluated at late ART, and viral load was quantified post-ATI to determine area under the curve (AUC) of rebound.
Results
Longitudinal metabolite modulation was driven by lipid and amino acid pathways, with pre/early ART segregating from later timepoints. Cytokines clustered into two groups, with similar timepoint delineation. At pre/early ART, IL-15 and fatty acids were negatively associated while non-essential amino acids were positively associated with late ART levels of SIV DNA in CD4+ T cells. Comparing cytokines and metabolites at late ART with SIV DNA at late ART, we found a negative correlation with ITAC and a positive correlation with modified amino acids. Branched-chain amino acids (BCAAs) at late ART were positively associated with viral rebound AUC post-ATI, while a negative association was found between viral rebound AUC and interferons, interferon-induced cytokines/chemokines and IL-7 measured at late ART.
Conclusions
Cytokine modulation of CD4+ T cells and NK/CD8+ T cell effector function may explain the observed associations with reservoir size and viral rebound. While less studied, metabolites also influence immune cells; for example, the non-essential amino acids glycine/serine are associated with T cell proliferation and BCAAs similarly support proliferation of activated T cells. These effects may cause both reservoir expansion and fuel viremia off ART. Validation of a direct role of these pathways and immune modulators in seeding and maintenance of the SIV reservoir could lead to new approaches for HIV cure.
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