Our objective was to evaluate the association of plasma inflammatory biomarkers with MetS in an older population of treated HIV-infected (HIV(+)) as compared to age-matched HIV-negative (HIV(-)) adults. This was done in a retrospective observational study. Plasma concentrations of complement component 3 (C3), cystatin C, fibroblast growth factor 1, interleukin 6, oxidized LDL, soluble RAGE, soluble CD163, soluble CD14, and osteopontin were measured in 79 HIV(+) participants on combination antiretroviral treatment (cART) with a suppressed HIV viral load and 47 HIV(-) participants with a median age of 59 (range 50 to 79). Outcomes were individual MetS components (hypertension, type II diabetes, dyslipidemia, and obesity) and MetS. Covariates were screened for inclusion in multivariable models. Odds ratios are reported per 50 mg/dl increase in C3. In the HIV(+) group, higher C3 levels were associated with MetS (OR 3.19, p = 0.004), obesity (OR 2.02, p = 0.01), type II diabetes (OR 1.93, p = 0.02), and at a trend level with dyslipidemia (OR 1.87, p = 0.07) and hypertension (OR 1.66, p = 0.09). C3 levels were significantly higher in HIV(+) participants with MetS compared to those without MetS (p = 0.002). C3 was higher among HIV(+) patients with three or four MetS components as compared to those with one or two (p = 0.04) and those with none (p = 0.002). No associations were found between C3 and the outcomes for HIV(-) participants. C3 is strongly associated with both MetS and MetS components in an older HIV(+) sample on cART compared to HIV(-) controls. C3 warrants further investigation as a marker of cardiometabolic risk among persons aging with HIV.

Background

We identified host single-nucleotide variants (SNVs) associated with neurocognitive impairment (NCI) in perinatally HIV-infected (PHIV) children.

Methods

Whole-exome sequencing (WES) was performed on 217 PHIV with cognitive score for age (CSA) < 70 and 247 CSA ≥ 70 (discovery cohort [DC]). SNVs identified in DC were evaluated in 2 validation cohorts (VC). Logistic regression was used to estimate adjusted odds ratios (ORs) for NCI. A human microglia NLRP3 inflammasome assay characterized the role of identified genes.

Results

Twenty-nine SNVs in 24 genes reaching P ≤ .002 and OR ≥ 1.5 comparing CSA < 70 to CSA ≥ 70 were identified in the DC, of which 3 SNVs were identified in VCs for further study. Combining the 3 cohorts, SNV in CCRL2 (rs3204849) was associated with decreased odds of NCI (P < .0001); RETREG1/FAM134B (rs61733811) and YWHAH (rs73884247) were associated with increased risk of NCI (P < .0001 and P < .001, respectively). Knockdown of CCRL2 led to decreased microglial release of IL-1β following exposure to ssRNA40 while knockdown of RETREG1 and YWHAH resulted in increased IL-1β release.

Conclusions

Using WES and 2 VCs, and gene silencing of microglia we identified 3 genetic variants associated with NCI and inflammation in HIV-infected children.