Persistent monocyte activation and altered cytokine responses are reported in PWH despite ART. How prior HIV-1 infection status and timing of ART initiation relate to monocyte pattern-recognition rece Show more
Persistent monocyte activation and altered cytokine responses are reported in PWH despite ART. How prior HIV-1 infection status and timing of ART initiation relate to monocyte pattern-recognition receptor crosstalk between TLR8 and RLRs remains uncertain. We conducted a comparative cohort study in adult males enrolled from two Dutch HIV-cohorts. Participants included HIV-negative participants, PWH who initiated ART during chronic HIV infection, and PWH who initiated ART during acute HIV infection, with sampling at 24 and 156 weeks after ART initiation for the acute group. PBMCs were stimulated with an RLR agonist, a TLR8 agonist, or both. Monocyte surface markers were assessed by flow cytometry and pro-inflammatory cytokines were analysed with qPCR and ELISA. Across groups, RLR stimulation induced IL-12p70 and IL-27, TLR8 stimulation induced IL-6 and IL-12p70 and combined TLR8 + RLR co-stimulation synergistically increased IL-12p70 and IL-27 while restricting IL-6. Compared with controls, CHI showed reduced IL-12p70 and IL-27 and higher IL-6. In AHI at 24 weeks, cytokine patterns and co-stimulation effects resembled HIV-negative participants; by 156 weeks, responses were attenuated and approximated CHI. In this male cohort, TLR8-RLR crosstalk was preserved early after ART initiation during acute infection but diminished over time, approaching profiles observed in chronically treated infection. These observations emphasise a potential early window after ART initiation for interventions aiming to preserve monocyte function and motivate studies to characterise underlying mechanisms. Funding for this study was obtained through a ZonMW/Aidsfonds grant NL4Cure: Bridging shock and kill strategies (446002508). Show less
Genome-wide association studies (GWAS) have been highly informative in discovering disease-associated loci but are not designed to capture all structural variations in the human genome. Using long-rea Show more
Genome-wide association studies (GWAS) have been highly informative in discovering disease-associated loci but are not designed to capture all structural variations in the human genome. Using long-read sequencing data, we discovered widespread structural variation within SINE-VNTR- Show less