Epidemiologic and Virologic Investigation of Hand, Foot, and Mouth Disease, Southern Vietnam, 2005

Tú, Phan Văn; Thảo, Nguyễn Thị; Perera, David; Truong, Khanh Huu; Tien, Nguyen Thi Kim; Thuong, Tang Chi; How, Ooi Mong; Cardosa, Mary Jane; McMinn, Peter C.

doi:10.3201/eid1311.070632

Cited by 314 publications

(225 citation statements)

References 30 publications

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“…12 Tu PV et al reported that there were 411 HFMD cases in Vietnam in 2005, among which 214 were identified as CA16-induced (52%) while 173 were EV71 (42%). 13 It has also been reported that an outbreak of HFMD in Odisha, India in 2009 was caused by CA16 (78 cases).…”

Section: Hfmd Outbreaks Caused By Ca16mentioning

confidence: 97%

“…The first outbreak of HFMD caused by CA16 was described in Toronto in 1957. 8 CA16 infection was responsible for HFMD outbreaks in Sydney, Australia in 1991, 9 in England and Wales in 1994, 10 in Taiwan in 2002-2003, 11 in Singapore in 2002, 2005 and 2007, 12 in Vietnam in 2005, 13 and in Odisha, India in 2009. 14 In Mainland China, CA16 was the predominant pathogen causing HFMD in 2007 in Beijing 15 and in 2009 in Guangzhou.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Coxsackievirus A16

Mao

Wang²,

Yao³

et al. 2013

Human Vaccines & Immunotherapeutics

149

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Section: Hfmd Outbreaks Caused By Ca16mentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Coxsackievirus A16

Mao

Wang²,

Yao³

et al. 2013

Human Vaccines & Immunotherapeutics

149

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“…In particular, EV-A71 is often associated with neurological complications and is responsible for the majority of fatalities (4)(5)(6). There has been a significant increase in EV-A71 epidemic activity across the AsiaPacific region since 1997 (7)(8)(9)(10)(11)(12). Unfortunately, no approved antiviral therapeutics are currently available for the treatment of EV-A71 infection, and treatment remains limited to supportive care.…”

mentioning

confidence: 99%

In Vitro Assessment of Combinations of Enterovirus Inhibitors against Enterovirus 71

Wang

Yuan

et al. 2016

Antimicrob Agents Chemother

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Enterovirus 71 (EV-A71) is a major causative pathogen of hand, foot, and mouth disease (HFMD) epidemics. No antiviral therapies are currently available for treating EV-A71 infections. Here, we selected five reported enterovirus inhibitors (suramin, itraconazole [ITZ], GW5074, rupintrivir, and favipiravir) with different mechanisms of action to test their abilities to inhibit EV-A71 replication alone and in combination. All selected compounds have anti-EV-A71 activities in cell culture. The combination of rupintrivir and ITZ or favipiravir was synergistic, while the combination of rupintrivir and suramin was additive. The combination of suramin and favipiravir exerted a strong synergistic antiviral effect. The observed synergy was not due to cytotoxicity, as there was no significant increase in cytotoxicity when compounds were used in combinations at the tested doses. To investigate the potential inhibitory mechanism of favipiravir against enterovirus, two favipiravir-resistant EV-A71 variants were independently selected, and both of them carried an S121N mutation in the finger subdomain of the 3D polymerase. Reverse engineering of this 3D S121N mutation into an infectious clone of EV-A71 confirmed the resistant phenotype. Moreover, viruses resistant to ITZ or favipiravir remained susceptible to other inhibitors. Most notably, combined with ITZ, rupintrivir prevented the development of ITZ-resistant variants. Taken together, these results provide a rational basis for the design of combination regimens for use in the treatment of EV-A71 infections.

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“…Since its first isolation from the stool of an infant with encephalitis in California in 1969 (1), EV71 has been recognized as a major cause of hand, foot, and mouth disease (HFMD), which is associated with severe neurological symptoms in a small proportion of cases (2). There has been a significant increase in EV71 epidemic activity throughout the Asia-Pacific region since 1997 (3)(4)(5)(6)(7). No approved antiviral therapeutics are currently available for clinical treatment of EV71 infections, and approval is still pending for three EV71 vaccine candidates which completed phase III clinical trials in 2013 (8).…”

mentioning

confidence: 99%

Identification of Positively Charged Residues in Enterovirus 71 Capsid Protein VP1 Essential for Production of Infectious Particles

Yuan

Wang

et al. 2016

J Virol

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Enterovirus 71 (EV71), a positive-stranded RNA virus, is the major cause of hand, foot, and mouth disease (HFMD) in children, which can cause severe central nervous system disease and death. The capsids of EV71 consist of 60 copies of each of four viral structural proteins (VP1 to VP4), with VP1, VP2, and VP3 exposed on the surface and VP4 arranged internally. VP1 plays a central role in particle assembly and cell entry. To gain insight into the role of positively charged residues in VP1 function in these processes, a charged-to-alanine scanning analysis was performed using an infectious cDNA clone of EV71. Twenty-seven mutants containing single charged-to-alanine changes were tested. Sixteen of them were not viable, seven mutants were replication defective, and the remaining four mutants were replication competent. By selecting revertants, second-site mutations which could at least partially restore viral infectivity were identified within VP1 for four defective mutations and two lethal mutations. The resulting residue pairs represent a network of intra-and intermolecular interactions of the VP1 protein which could serve as a potential novel drug target. Interestingly, mutation K215A in the VP1 GH loop led to a significant increase in thermal stability, demonstrating that conditional thermostable mutants can be generated by altering the charge characteristics of VP1. Moreover, all mutants were sensitive to the EV71 entry inhibitor suramin, which binds to the virus particle via the negatively charged naphthalenetrisulfonic acid group, suggesting that single charged-to-alanine mutation is not sufficient for suramin resistance. Taken together, these data highlight the importance of positively charged residues in VP1 for production of infectious particles. IMPORTANCEInfection with EV71 is more often associated with neurological complications in children and is responsible for the majority of fatalities. No licensed vaccines or antiviral therapies are currently available for the prevention or treatment of EV71 infection. Understanding the determinants of virion assembly and entry will facilitate vaccine development and drug discovery. Here, we identified 23 out of 27 positively charged residues in VP1 which impaired or blocked the production of infectious particles. The defect could be rescued by second-site mutations within the VP1 protein. Our findings highlight the importance of positively charged residues in VP1 during infectious particle production and reveal a potential strategy for blocking EV71 infections by inhibiting intra-or intermolecular interactions of the VP1 protein. Enterovirus 71 (EV71) is a nonenveloped icosahedral RNA virus belonging to genus Enterovirus within the family Picornaviridae. Since its first isolation from the stool of an infant with encephalitis in California in 1969 (1), EV71 has been recognized as a major cause of hand, foot, and mouth disease (HFMD), which is associated with severe neurological symptoms in a small proportion of cases (2). There has been a significant incre...

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Epidemiologic and Virologic Investigation of Hand, Foot, and Mouth Disease, Southern Vietnam, 2005

Abstract: Human enterovirus 71, but not coxsackievirus A16, is strongly associated with acute neurologic disease.

Cited by 314 publications

References 30 publications

Coxsackievirus A16

Coxsackievirus A16

In Vitro Assessment of Combinations of Enterovirus Inhibitors against Enterovirus 71

Identification of Positively Charged Residues in Enterovirus 71 Capsid Protein VP1 Essential for Production of Infectious Particles

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