Coxsackievirus A6 (CVA6) has recently emerged as a major cause of hand, foot and mouth disease in children worldwide but no vaccine is available against CVA6 infections. Here, we demonstrate the isolation of two forms of stable CVA6 particles-procapsid and A-particle-with excellent biochemical stability and natural antigenicity to serve as vaccine candidates. Despite the presence (in A-particle) or absence (in procapsid) of capsid-RNA interactions, the two CVA6 particles have essentially identical atomic capsid structures resembling the uncoating intermediates of other enteroviruses. Our near-atomic resolution structure of CVA6 A-particle complexed with a neutralizing antibody maps an immune-dominant neutralizing epitope to the surface loops of VP1. The structure-guided cell-based inhibition studies further demonstrate that these loops could serve as excellent targets for designing anti-CVA6 vaccines.

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g Varicella-zoster virus (VZV) is the causative agent of chickenpox and herpes zoster (shingles). After the primary infection, the virus remains latent in sensory ganglia and reactivates upon weakening of the cellular immune system due to various conditions, erupting from sensory neurons and infecting the corresponding skin tissue. The current varicella vaccine is highly attenuated in the skin and yet retains its neurovirulence and may reactivate and damage sensory neurons. The factors involved in neuronal invasion and establishment of latency are still elusive. Previously, we constructed a library of whole-gene deletion mutants carrying a bacterial artificial chromosome sequence and a luciferase marker in order to perform a comprehensive VZV genome functional analysis. Here, screening of dispensable gene deletion mutants in differentiated neuronal cells led to the identification of ORF7 as the first known, likely a main, VZV neurotropic factor. ORF7 is a virion component localized to the Golgi compartment in infected cells, whose deletion causes loss of polykaryon formation in epithelial cell culture. Interestingly, ORF7 deletion completely abolishes viral spread in human nervous tissue ex vivo and in an in vivo mouse model. This finding adds to our previous report that ORF7 is also a skin-tropic factor. The results of our investigation will not only lead to a better understanding of VZV neurotropism but could also contribute to the development of a neuroattenuated vaccine candidate against shingles or a vector for delivery of other antigens. V aricella-zoster virus (VZV), upon encountering a naïve host, causes a primary infection commonly known as chickenpox (varicella) (1, 4, 5). The disease is generally considered mild and self-resolving even in the absence of treatment (2), although occasionally it has severe and lethal consequences (9, 23). The virus reaches sensory nerve ganglia, where it remains latent for life, unless temporary or permanent immunosuppressive conditions within the host facilitate its reactivation as shingles or herpes zoster (HZ) affecting thoracic, cranial, or lumbosacral dermatomes. Many patients report excruciating and relentless pain during HZ episodes (16,34,36,44). The reactivation is sometimes associated with postherpetic neuralgia (PHN), a severe pain along the affected sensory nerves that can linger for years even after the herpetic rash resolves (4). The drug treatments available to date against VZV-elicited diseases are useful only in alleviating some of the symptoms and in shortening the disease duration but cannot clear the virus or prevent establishment of latency (27,30). PHN is difficult to manage, especially in the elderly, who frequently suffer from other age-related conditions, and the use of the standard PHN treatment, including tricyclic antidepressants, anticonvulsants, and opioids, can be hazardous (16,36).Chickenpox was a ubiquitous childhood disease before the anti-VZV vaccination was mandated in 1995 in the United States. Since then, the numbers of hospitalizati...

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