Genomics Links Inflammation with Neurocognitive Impairment in Children Living with Human Immunodeficiency Virus Type-1.

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 NCI (cognitive score for age (CSA) <70 and 247 CSA > 70 (Discovery Cohort [DC]). SNVs identified in DC were evaluated in two 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 29 SNVs in 24 genes reaching p ≤0.002 and OR ≥1.5 comparing CSA <70 to CSA ≥70 were identified in the DC of which three SNVs were identified in VC1 and VC2 for further study. Combining the three cohorts, a SNV in CCRL2 (rs3204849) was associated with decreased odds of NCI (p<0.0001) whereas RETREG1/FAM134B (rs61733811) and YWHAH (rs73884247) were associated with increased risk of NCI (p<0.0001 and P<0.001, 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 two VCs, and gene silencing of microglia we identified three genetic variants that are associated with NCI and inflammation in HIV-infected children.