From Hepatitis to Encephalitis: Neuroinvasion and Antiviral Development in Rift Valley Fever Virus Infection

Rift Valley fever virus (RVFV) is a mosquito-borne zoonotic pathogen that causes substantial livestock losses and a range of severe human illnesses, including hemorrhagic disease, hepatitis, retinitis, vision loss, and delayed encephalitis. Despite its public health and One Health importance, no approved RVFV-specific antiviral therapy or licensed human vaccine is available. Therapeutic development is challenged by the progression of RVFV disease from acute viremia and hepatic injury to delayed neurologic and ocular complications, highlighting the need for countermeasures that protect both systemic organs and CNS tissues. This review examines RVFV antiviral development in the context of neuroinvasive disease. We summarize evidence on RVFV neuroinvasion and central nervous system injury, including route-dependent entry, blood–brain barrier interactions, immune responses, neuroinflammation, and neuronal damage. We then evaluate major antiviral strategies by mechanism, treatment timing, tissue exposure, and central nervous system relevance. Finally, we propose that future RVFV therapeutics are assessed not only by survival, viremia, and hepatic viral-load endpoints, but also by blood–brain barrier penetration, brain pharmacokinetics, efficacy in neuroinvasive models, delayed-treatment activity, and protection against encephalitis-associated injury. This framework may help prioritize antivirals that control both acute systemic disease and delayed neurological complications.