Narrative review discusses Risk Group 4 zoonotic virus infection and viral RNA persistence in hosts.

RNA viruses are historically characterized by acute, strictly transient infections, with few exceptions. However, the emerging phenomenon of viral RNA persistence is fundamentally challenging this paradigm. Accumulating data across non-retroviral RNA viruses including several families of Risk Group 4 (RG4) pathogens demonstrate that viral genetic material can persist within the host long after clinical recovery and the clearance of systemic viremia. The current review explores this new frontier in infectious diseases, synthesizing recent evidence for viral RNA persistence in RG4 zoonotic viruses and its profound clinical and public health implications, from post-acute sequelae and fatal recrudescence to the risk of re-igniting outbreaks. We further attempt to integrate findings from disease-susceptible hosts with those from natural reservoir hosts and propose a hypothetical, central role of viral RNA persistence in the maintenance and transmission of zoonotic RNA viruses, an idea we refer to as “the Latency Hypothesis”. These updates underscore the critical need to elucidate the molecular mechanisms underlying persistence and to develop targeted medical countermeasures.