👤 Fleur Kaptein

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

Dyslipidemia is an important risk factor in CKD. The liver clears triglyceride-rich lipoproteins (TRL) Uninephrectomy- and aging-induced CKD in normotensive Wistar rats and hypertensive Munich-Wistar-Frömter (MWF) rats. Compared with 22-week-old sex- and strain-matched rats, 48-week-old uninephrectomized Wistar-CKD and MWF-CKD rats showed proteinuria, increased plasma creatinine, and hypercholesterolemia (all Progressive CKD induces hepatic HS elongation, leading to increased interaction with PCSK9. This might reduce hepatic lipoprotein uptake and thereby induce dyslipidemia in CKD. Therefore, PCSK9/HS may be a novel target to control dyslipidemia. Show less

The effects of apolipoprotein (a), apolipoprotein-E, and apolipoprotein-A4 isoforms on quantitative lipoprotein(a) [Lp(a)] levels were assessed in a sample of 142 Dutch families consisting of two parents and their adolescent twin offspring. A total heritability of 95% was estimated for plasma Lp(a) concentrations. The largest part of this heritability was due to the apo(a) locus which explained 61% of the total variance in Lp(a) levels. The pattern of familial correlations for the residual part of the Lp(a) variance that could not be attributed to the apo(a) isoforms, suggested genetic influences on the residual variance. We addressed the question whether this residual genetic variance could be ascribed to the apoE or the apoA4 locus. A simultaneous analysis of all three loci showed that both the apoE and the apoA4 polymorphism did not contribute significantly to Lp(a) variation. Show less