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However, no vaccine or anti-viral agent is currently available for CVA16

However, no vaccine or anti-viral agent is currently available for CVA16. anti-viral agent TCS PIM-1 1 is currently available for CVA16. Here, the functions and working mechanisms of two CVA16-specific neutralizing monoclonal antibodies (MAbs), 9B5 and 8C4, are comprehensively investigated. Both 9B5 and 8C4 display potent neutralization in vitro and prophylactic and therapeutic efficacy in a mouse model of CVA16 contamination. Mechanistically, 9B5 exerts neutralization primarily through inhibiting CVA16 attachment to cell surface via blockade of CVA16 binding to its attachment receptor, heparan sulfate, whereas 8C4 functions mainly at the post-attachment stage of CVA16 access by interfering with the conversation between CVA16 and its uncoating receptor SCARB2. Cryo-EM studies show that 9B5 and 8C4 target unique epitopes located at the 5-fold and 3-fold protrusions of CVA16 capsids, respectively, and exhibit differential binding preference to three forms of naturally occurring CVA16 particles. Moreover, 9B5 and 8C4 are compatible in formulating an antibody cocktail which displays the ability to prevent computer virus escape seen with individual MAbs. Together, our work elucidates the functional and structural basis of CVA16 antibody-mediated neutralization and protection, providing important information for design and development of effective CVA16 vaccines and antibody therapies. Subject terms: Structural biology, Virology Coxsackievirus A16 (CVA-16) causes hand, food and mouth disease in infants and young children, however, currently you will find neither anti-virals nor vaccines available for treatment. Here, Zhang et al. characterize two CVA16-specific neutralizing monoclonal antibodies, 9B5 and 8C4. They provide evidence for their prophylactic and therapeutic application in vivo in mice and perform CryoEM to show that both antibodies target different epitopes around the viral capsid. Introduction Coxsackievirus A16 (CVA16), a member of the within the family1,2, is one of the major causative brokers of hand, foot and mouth disease (HFMD) prevalent in infants and young children3C6. CVA16 contamination TCS PIM-1 1 may result in moderate and self-limiting symptoms7 as well as severe clinical outcomes such as encephalitis, myocarditis, pneumonitis, and even death8C10. TCS PIM-1 1 In addition, CVA16 often co-circulates with other HFMD-causing agents such as human enterovirus A71 (EV71), coxsackievirus A6 (CVA6), and coxsackievirus A10 (CVA10), leading to co-infection and viral genetic recombination11C13, which make it more challenging to prevent and control HFMD as a whole. Like other enteroviruses (EVs), CVA16 is usually a nonenveloped computer virus of ~30?nm in diameter with a single-stranded, positive-sense RNA genome of ~7.4?kb in length packaged in a protein shell termed capsid14. The viral genome encodes a large polyprotein precursor, which is Mouse monoclonal to ROR1 usually subsequently processed into structural protein P1 and nonstructural proteins P2 and P314. P1 can be further cleaved by a viral protease to yield capsid subunit proteins VP0, VP1, and VP3, among which VP0 may undergo autocleavage to produce VP2 and VP414. CVA16 prepared from infected cell cultures is present mainly in two particle forms, including the mature virion (also termed full particle) TCS PIM-1 1 made up of infectious viral RNA genome and the vacant particle (also termed procapsid) lacking viral RNA genome15C17. The capsids of CVA16 full particle and vacant particle are structurally comparable, both made of 60 copies TCS PIM-1 1 of protomers arranged in symmetry, however, each protomer in the full particle consists of four subunits, including VP1, VP2, VP3, and VP4, whereas the one in the vacant particle comprises VP1, VP3, and uncleaved VP015C17. For most EVs, their mature virions are in the native/compact state, whereas their vacant particles appear relatively expanded17C20. However, vacant particles in compact state have also been reported for CVA16 and hepatitis A computer virus16,21. CVA16 interacts with its host receptors to gain access into susceptible cells. Specifically, CVA16 utilizes cell surface heparan sulfate (HS) glycosaminoglycans as its.