The role of 2'-5'-oligoadenylate synthetase (OAS) proteins in HIV infection: innate antiviral immunity, viral persistence, and therapeutic opportunities.

Human immunodeficiency virus type 1 (HIV-1) establishes persistent infection despite robust innate immune responses and effective antiretroviral therapy, highlighting the importance of host antiviral mechanisms in regulating viral replication and persistence. Among interferon-stimulated genes, 2'-5'-oligoadenylate synthetase 1 (OAS1) is a key antiviral effector that senses viral double-stranded RNA and activates the OAS-RNase L pathway. Beyond its canonical antiviral activity, emerging evidence implicates OAS1 in immune regulation, viral latency, neuroinflammation, and retroviral disease progression. This review examines the genomic organization, structural diversity, isoform-specific functions, genetic variation, and interferon-mediated regulation of the OAS protein family, emphasizing OAS1 in HIV infection. Experimental and clinical studies indicate that type I and type III interferons induce OAS1 in macrophages, dendritic cells, epithelial and endothelial cells, microglia, and lymphocytes, contributing to HIV restriction through RNase L activation and enhanced innate antiviral responses. OAS signalling may also support mucosal antiviral defence, regulate viral burden and chronic immune activation, influence interferon responsiveness during combination antiretroviral therapy, and contribute to central nervous system protection. Conversely, dysregulated OAS1 expression has been associated with HIV-associated neurocognitive disorders. Genetic polymorphisms and alternative splicing generate functional diversity in OAS1, potentially influencing antiviral activity, individual susceptibility, and clinical outcomes. Collectively, available evidence positions OAS1 as a multifunctional antiviral and immunoregulatory component of host defence that may influence multiple aspects of HIV pathogenesis. Further investigation into OAS1 activation, genetic variation, isoform-specific functions, and immune modulation may facilitate biomarker discovery and support the development of host-directed therapeutic strategies against persistent retroviral infections.