Endogenous Retroviruses and Alcohol Use Disorder - Project Summary/Abstract Alcohol use disorder (AUD) is characterized by uncontrollable alcohol consumption due to physical and psychological dependence. It poses a significant public health issue, affecting approximately 14.1 million Americans and resulting in an annual economic burden of $249 billion. Despite the alarming rise in deaths and economic costs, pharmacological treatment options for AUD have advanced only minimally since 2004, underscoring the urgent need for novel therapeutic targets. Increased interferon signaling and activation of inflammatory pathways have been established in both individuals with AUD and alcohol-preferring animals. However, the mechanisms to reverse or modify these neuroimmune abnormalities remain inadequately understood. Thus, there is a critical need to identify new neurobiological factors for potential intervention. Endogenous retroviruses (ERVs) represent a promising area of investigation due to their roles in modulating immune responses and contributing to inflammation. Comprising 8% of the human genome, ERVs consist of more than 400,000 distinct elements derived from ancient retroviral infections integrated into human genomes. These sequences can disrupt host cell functions and may reactivate in response to various environmental triggers, including alcohol. Our proposed ERV-AUD model suggests that, although typically silenced, specific ERVs can be transcriptionally activated by alcohol exposure, leading to inflammatory immune dysregulation in AUD. We aim to investigate the role of ERV expression and ERV genotypes in the pathophysiology of AUD through our innovative ERVcaller platform, which enables precise genotyping and expression quantification of individual ERVs. Utilizing existing RNA sequencing and genome sequencing datasets from AUD patients, we will pursue two Specific Aims: (1) to identify distinct ERVs whose expression correlates with AUD, and (2) to identify ERV variants (rather than SNPs in ERV sequences) whose genotypes are associated with AUD. Leveraging large datasets, innovative analytic tools, and high-performance computing resources, our analyses will enable comprehensive genome-wide assessments of the full spectrum of the ERV landscape. Anticipated outcomes include the identification of transcriptionally activated ERV transcripts and associated ERV variants that could serve as novel biomarkers for AUD. This research has the potential to inform future therapeutic strategies by elucidating ERV-related inflammatory pathways for targeted treatments, including repurposing FDA-approved anti-retroviral or anti-inflammatory drugs, or developing new agents aimed at mitigating ERV- driven inflammation in AUD patients. Establishing the connection between ERVs and AUD will provide focus and supportive data for subsequent in-depth studies at the R01 level.
