Multiancestry Genome-Wide Association Study Identifies Variants in a Zinc Finger Gene Cluster as Novel Regulators of HIV Control

BACKGROUND: Human immunodeficiency virus 1 (HIV-1) remains a global health challenge, emphasizing the need to identify new host factors that influence pathogenesis to serve as drug targets. Identifying genetic determinants of HIV-1 control across diverse populations remains a top priority. METHODS: We conducted a multiancestry genome-wide association study (GWAS) of HIV-1 set-point viral load (spVL) leveraging genotype and viral load data from 10 723 individuals with HIV-1. To prioritize candidate genes and mechanisms, we integrated GWAS findings with transcriptome-wide association study (TWAS) and expression quantitative trait loci (eQTL) data. RESULTS: We implicate the potential role of zinc finger proteins in pathogenesis through identification of a novel signal in the zinc finger protein 586 (ZNF586) gene on chromosome 19, which is predicted to regulate RNA polymerase II transcription. The top variant, (rs35962362-G) is intronic to the ZNF586 gene, and is associated with an approximate 0.1 log increase in spVL per mutant allele. Our subsequent TWAS along with interrogation of eQTL data suggest that increased ZNF586 expression is associated with increased spVL in whole blood. CONCLUSIONS: Our findings suggest ZNF586 as a novel host factor for HIV-1 control and highlight the role of zinc finger proteins as potential contributors to viral persistence. Although ZNF586 has not previously been linked to HIV-1 pathogenesis, its potential role in maintaining retroviral latency and modulating genomic regulation warrants further investigation.