Background:
The protective role of trained innate immunity in various infections is well known, but its impact on HIV control has not been investigated. We hypothesized that trained monocytes, as induced by b-glucan, are crucial in orchestrating a beneficial antiviral immune response associated with long-term spontaneous HIV control.
Methods:
1895 people living with HIV, among which 114 HIV controllers (HIC) classified as Elite controller (EC), viremic controllers (VC) and transient controllers (TC), were included (2000HIV study – NTC03994835). First degree family members (FAM) of HIV controllers and non-HIV controllers (non-HIC) were part of the 2000HIV-trained study (NCT04968717). We analyzed multi-omics data consisting of: 1) cytokine/chemokine production upon stimulation, 2) circulating concentrations of b-glucans, 3) trained immunity induction through the exposure of monocytes to b-glucan and restimulation with LPS, 4) genome-wide association study (GWAS), 5) single-cell and bulk RNA seq expression in PBMCs, 6) epigenomic profile using H3K4me3 ChiP- and ATAC-seq.
Results:
Monocytes of HIC and their FAM showed increased production of IL-1b, IL-6 and MCP-1 upon viral and bacterial stimulation compared to non-HIC and their FAM, respectively. Difference in monocytes responsiveness was stronger in ECs but not different between TCs and non-HIC. b-glucan induced trained immunity responses in all groups, yet upregulation of TNF and IL-6 production was highest in HIC and their FAM. Genetic data (GWAS) showed no link between SNPs associated with HIV control and monocyte responsiveness of HIC. Interestingly, HIC and their relatives displayed higher circulating concentrations of b-glucan, suggesting a trained phenotype in their monocytes. scRNA-seq demonstrated that monocytes of HIC displayed upregulation of type I IFN and antigen processing and presentation genes, as well as downregulation of genes associated with chronic inflammation and regulation of DNA transcription. Moreover, changes in gene expression levels and cytokine production of HIC, more prominently in EC, were sustained by changes in chromatin accessibility in innate immune genes, among which NF-kB and type I IFN were reported.
Conclusions:
Monocyte responsiveness is increased in HIV controllers and their relatives, which is associated with trained immunity and related epigenetic regulation. These traits are stronger in EC compared to transient controllers, suggesting the importance of a trained program in monocytes in maintaining HIV control
