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

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Abstract

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 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.

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Rawat, P., Brummel, S. S., Singh, K. K., Kim, J., Frazer, K. A., Nichols, S., … Spector, S. A. (2021). Genomics Links Inflammation with Neurocognitive Impairment in Children Living with Human Immunodeficiency Virus Type-1. Journal of Infectious Diseases, 224(5), 870–880. https://doi.org/10.1093/infdis/jiaa792

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