Autism and Human Papillomavirus (HPV) E6: A Comprehensive Review

Objective: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social communication impairments, restricted interests, and repetitive behaviors. The etiology of ASD is complex, involving genetic and environmental factors. The HECT (Homologous to the E6-AP Carboxyl Terminus) family protein E6-associated protein (E6-AP), encoded by the UBE3A gene, is an ubiquitin ligase implicated in neurological disorders, including Angelman syndrome (AS) and potentially ASD. Dysregulation of E6-AP, influenced by environmental factors such as human papillomavirus (HPV) E6 protein, may contribute to neurodevelopmental abnormalities. Method : This review synthesizes current literature to explore the potential link between HPV E6 protein and E6-AP dysfunction in the context of ASD. We analyzed 32 peer-reviewed studies, including 12 original research articles, 10 reviews, and 10 meta-analyses, retrieved from PubMed and Google Scholar, focusing on E6-AP's roles in ubiquitin-mediated signaling pathways, its dysregulation in neurodevelopmental disorders, and the impact of HPV E6 on E6-AP function. Results: E6-AP is critical in regulating signaling pathways associated with tumorigenesis and neurodevelopment. Dysregulation of E6-AP, potentially induced by HPV E6, has been implicated in AS and, to a lesser extent, ASD. As visually demonstrated in Figure 1, these complex relationships between HPV, neurodevelopmental disorders, and E6 protein underscore the need for cross-disciplinary research. Current findings indicate that HPV E6 may disrupt E6-AP's ubiquitin ligase activity, potentially contributing to neurodevelopmental impairments observed in ASD. Conclusion: The potential link between HPV E6 and E6-AP dysfunction underscores a novel avenue for understanding environmental contributors to ASD. Given the complexity of ASD, further research is essential to elucidate E6-AP's role and to develop targeted therapeutic strategies. This review highlights the need for studies investigating HPV-related mechanisms in ASD to advance effective interventions and support systems.