Viral and Host Factors in Herpetic Diseases

In adults, herpes simplex virus (HSV) causes ocular diseases ranging from mild to sight-threatening. In addition, HSV causes cold sores, genital sores, encephalitis, and is implicated in the genesis of neurodegenerative disease and Alzheimer’s. The lifecycle of HSV comprises an acute infection at mucosal sites (e.g. the cornea) when all virus genes are expressed, and latency in neurons, when viral gene expression is limited. Most clinical and preclinical studies of HSV use adults in both humans and animal models. Neonatal HSV (nHSV) infections, however, result in traumatic manifestations and occur following exposure to HSV-1 or HSV-2 either during parturition or the early postnatal period. Infected newborns develop skin, eye, and mouth (SEM) disease, or disseminated infections and encephalitis. Without treatment, mortality is high (≤ 57%), largely due to difficulties diagnosing nHSV which is often mistaken for sepsis. Surviving infants develop long-term sequelae including anterior and posterior segment ocular disorders, neurodevelopmental disabilities, blindness, spastic quadriplegia, and seizures, incurring significant emotional and economic burden. Acyclovir (ACV) is the standard of care, but initiation of ACV therapy requires clinical suspicion. Even aggressive ACV treatment of generalized nHSV infection leaves ~70% with neurosensory and ophthalmic sequelae. It is imperative, therefore, to develop new options for prevention and treatment of nHSV in this vulnerable, and understudied population. nHSV transmission and risk patterns are counterintuitive. HSV vertical transmission risk is lowest (<1% of cases) from mothers with long-standing pre-existing genital infections, even with proven recurrence during birth. >85% of cases arise from a primary maternal infection during birth, and ~15% of cases follow postnatal infection from the community following birth to a seronegative mother. This risk pattern is consistent with the hypothesis that protection is conferred through transfer of maternal antibodies. These antibodies cross the placenta and supplement the underdeveloped fetal and neonatal immune system to protect against congenital infections. These antibodies also pass in the breast milk. We have shown that maternal antibodies access fetal and neonatal neural tissues with surprising efficiency and prevent nHSV in mice. We have developed a novel mouse model wherein we study not only morbidity, mortality and viral burden, but also behavioral pathologies (testing vision, anxiety, learning and memory) observed in humans following nHSV. Our overarching goal, is to explore use of an experimental vaccine (dl5-29), and a therapeutic monoclonal antibody (mAb) (CH42) expressed by an AAV vector to prevent damage to the visual system and CNS following nHSV. Our data also implicate a role for perturbation of the autophagy pathway in the development of corneal and CNS diseases and we will assess how novel autophagy-modulating therapeutics may ameliorate the sequelae of nHSV. Overall, these translational studies will study an area problem of high clinical significance — the development novel interventions targeted to improve neonatal health outcomes following HSV infections.