Prenatal Alcohol Exposure and Fetal Alcohol Spectrum Disorder

Univ Of North Carolina Chapel Hill, Chapel Hill NC

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Abstract

the direct impact of alcohol (and its metabolic byproducts) on viral replication of Kaposi’s sarcoma herpesvirus (KSHV). Our preliminary findings show alcohol and alcohol biproducts accelerate KSHV reactivation. Greater viral reactivation is correlated with higher levels of circulating viruses, and an increased risk to develop KSHV-associated malignancies. KSHV is one of the eight identified oncogenic viruses. KSHV is the etiological agent of three human cancers, Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL) and Multicentric Castleman’s disease (MCD). Like all herpesviruses, once infected KSHV establishes a lifelong infection. To investigate the relationship between alcohol consumption in the background of persistent KSHV infection, we seek to study the alcohol induced epigenetic modifications to the KSHV episomes and alcohol enhanced extracellular vesicle (EV) production in increasing viral spread. Based on our data, we hypothesize that alcohol exposure sensitizes latently infected cells to a more rapid reactivation of lytic replication via alternations to the viral episomes epigenetic modifications. DNA chromatin remodeling of the viral genome will promote transcription of lytic transcripts and subsequent lytic proteins. Alcohol consumption also augments the release of cellular extracellular vesicles (EVs). Viral-mediated EV release not only boosts paracrine delivery of key viral RNAs and proteins but can dictate cellular products are packaged within the excretory vesicles to enhance immune escape and drive non-specific cellular uptake. Thus, alcohol-enhanced EV delivery from latently infected cells may further sensitize neighboring cells to future promotion of more viral infection. We propose to study the role of alcohol enhanced EV production on the viral lifecycle and mechanism of viral spread. We propose a unique transdisciplinary approach to obtain innovative data defining the consequences of a modifiable risk factor, alcohol consumption, on disease progression. Our findings can be applied in future studies to related herpesviruses, such as EBV, which infects most of the world population, thereby increasing our understanding of the likelihood of alcohol-induced consequences to persistent oncogenic viral infections.