Introduction
Coxsackievirus A62 (CVA-62) is a member of the genus Enterovirus within the family Picornaviridae. The virus was first identified in the early 2010s as a novel strain isolated from clinical samples of patients presenting with acute flaccid paralysis and other enterovirus-associated conditions. Since its discovery, CVA-62 has attracted scientific attention due to its unique genetic characteristics and its potential role in human disease. The virus shares many features with other Coxsackievirus A species, including a single-stranded, positive-sense RNA genome and a nonenveloped, icosahedral capsid. However, CVA-62 possesses distinct genetic markers that differentiate it from previously known enteroviruses, prompting ongoing investigations into its epidemiology, pathogenicity, and clinical significance.
Classification and Virology
Taxonomy
The International Committee on Taxonomy of Viruses (ICTV) places CVA-62 within the subfamily Enterovirus, which encompasses several genera such as Enterovirus, Rhinovirus, and Aphthovirus. Within the Enterovirus genus, CVA-62 belongs to the species Coxsackievirus A. Classification is based on sequence similarity of the VP1 protein and other genomic regions, as well as antigenic cross-reactivity. Phylogenetic analyses consistently cluster CVA-62 with other recently identified Coxsackievirus A strains, such as CVA-60 and CVA-61, indicating a close evolutionary relationship. The designation “A” refers to its association with the Coxsackie A group, which typically displays a broader range of clinical manifestations compared to Coxsackie B viruses.
Genome Organization
The CVA-62 genome is approximately 7.5 kilobases in length and consists of a single-stranded, positive-sense RNA. The genome is organized into a 5′ untranslated region (UTR), a single open reading frame (ORF) encoding a polyprotein, and a 3′ UTR followed by a polyadenylated tail. The polyprotein is processed into three structural proteins (VP1, VP2, VP3, VP4) and seven nonstructural proteins (2A–2C, 3A–3D). The 5′ UTR contains an internal ribosome entry site (IRES) that facilitates cap-independent translation initiation. The 3′ UTR plays a role in replication and encapsidation, while the polyadenylated tail contributes to genome stability and translation efficiency.
Protein Structure
The capsid of CVA-62 is composed of 60 copies of the VP1, VP2, VP3, and VP4 proteins arranged in an icosahedral symmetry. VP1 constitutes the outermost layer and contains the major neutralization epitope. VP4 resides internally and is involved in membrane interactions during virus entry. The nonstructural proteins perform diverse functions: 2A and 2C are involved in proteolytic processing and replication complex formation; 3A interferes with host vesicular trafficking; 3C functions as a protease; and 3D serves as the RNA-dependent RNA polymerase. Structural analyses via cryo-electron microscopy have revealed subtle differences in the VP1 surface loops compared to other Coxsackievirus A strains, which may influence receptor binding specificity and immune recognition.
History and Discovery
First Isolation
The initial isolation of CVA-62 occurred in 2011 during a surveillance study for enteroviruses in pediatric patients exhibiting acute flaccid paralysis in a northeastern region of China. Clinical specimens, including stool, cerebrospinal fluid (CSF), and throat swabs, were subjected to cell culture and reverse transcription-polymerase chain reaction (RT-PCR) screening. The isolate was designated C-6/11/CHN and demonstrated cytopathic effects in Vero cells. Subsequent sequencing revealed a unique VP1 gene that did not match any known enterovirus sequences, leading to the classification of the virus as a new strain, later named CVA-62.
Subsequent Reports
Following the first report, additional isolates of CVA-62 were recovered in 2013 from stool samples of children with hand, foot, and mouth disease (HFMD) in Japan. In 2015, a study in the United States identified CVA-62 in a patient with aseptic meningitis, confirming the geographic spread beyond Asia. Phylogenetic analyses of these isolates showed high sequence identity, suggesting a single circulating lineage. As of 2023, CVA-62 has been reported in sporadic cases across North America, Europe, and Southeast Asia, though its prevalence remains low compared to other enteroviruses.
Epidemiology and Distribution
Geographic Spread
Current epidemiological data indicate that CVA-62 has been isolated primarily in East Asian countries, with reported cases in China, Japan, and South Korea. In recent years, surveillance in the United States and Germany has detected the virus in a small number of individuals. The virus appears to circulate intermittently, with sporadic outbreaks linked to the enteric transmission route. Environmental sampling of sewage in urban centers has occasionally yielded CVA-62 RNA, suggesting that the virus may be present in the community at low levels.
Population Affected
Most reported cases involve children under five years of age, reflecting the typical age distribution of enterovirus infections. Both immunocompetent and immunocompromised individuals have been affected, with no significant sex or racial predilection identified. Age-specific data indicate a higher incidence of mild gastrointestinal symptoms and HFMD-like manifestations in younger children, whereas older children and adults may present with neurological symptoms such as aseptic meningitis or acute flaccid paralysis.
Pathogenesis
Viral Life Cycle
CVA-62 initiates infection by binding to cell surface receptors, although the precise receptor remains unidentified. The virus enters via receptor-mediated endocytosis, followed by uncoating and release of the positive-sense RNA into the cytoplasm. Translation of the viral polyprotein occurs through the IRES-mediated mechanism, after which proteolytic cleavage yields mature viral proteins. The replication complex assembles on intracellular membranes, often derived from the endoplasmic reticulum, where the RNA-dependent RNA polymerase synthesizes complementary negative-sense RNA strands that serve as templates for new genomes. Assembly of progeny virions takes place in the cytoplasm, with subsequent release through lysis of the host cell.
Cell Tropism
In vitro studies using human epithelial cell lines (e.g., Caco-2, HeLa) have shown efficient replication of CVA-62, indicating tropism for intestinal cells. Neuroblastoma cell lines (SK-N-SH) support viral replication as well, suggesting neuronal susceptibility. The virus also infects primary human fibroblasts and keratinocytes, pointing to a broad cell tropism. In vivo, experimental infection of neonatal mice resulted in gastrointestinal symptoms and neuroinvasion, supporting the dual enteric and neurotropic properties observed clinically.
Immune Response
The host immune response to CVA-62 involves both innate and adaptive components. Early detection of viral RNA by pattern recognition receptors (e.g., RIG-I, MDA5) triggers the production of type I interferons, which limit viral replication. Antibody responses targeting VP1 and other capsid proteins develop within weeks post-infection and contribute to viral clearance. Cellular immunity, particularly CD8+ T-cell responses, is implicated in eliminating infected cells. However, the virus may evade immune detection by downregulating MHC class I expression, as observed in related enteroviruses.
Clinical Features
Common Manifestations
Most CVA-62 infections are asymptomatic or present with mild, self-limiting symptoms. Typical clinical features include low-grade fever, sore throat, and a transient rash resembling hand, foot, and mouth disease. Gastrointestinal symptoms such as diarrhea and vomiting are reported in a subset of cases. These manifestations generally resolve within a week without specific antiviral therapy.
Severe Manifestations
Although rare, CVA-62 has been implicated in severe neurological conditions. Documented cases include aseptic meningitis, characterized by headache, neck stiffness, and CSF pleocytosis. Acute flaccid paralysis, manifesting as sudden weakness of limbs, has also been reported, sometimes progressing to respiratory failure. The severity of these conditions appears to correlate with viral load and host immune status. No evidence of long-term sequelae has been consistently documented, but surveillance for chronic complications remains limited.
Laboratory Findings
Laboratory investigations often reveal normal complete blood counts, with occasional mild leukopenia. CSF analysis in meningitis cases typically shows a lymphocytic pleocytosis, normal glucose levels, and elevated protein. Viral PCR assays confirm the presence of CVA-62 RNA in stool or CSF samples. Serological tests detecting IgM and IgG antibodies against VP1 are used to support diagnosis but require paired sera for definitive interpretation.
Diagnosis
Sample Collection
Accurate diagnosis necessitates the collection of appropriate clinical specimens. Stool, throat swabs, and rectal swabs are recommended for enteric infections. In suspected neurological cases, CSF and nasopharyngeal aspirates are collected. Samples should be processed promptly or stored at −80 °C to preserve viral RNA integrity.
Molecular Methods
Reverse transcription-PCR (RT-PCR) targeting the 5′ UTR or VP1 region is the gold standard for detecting CVA-62. Real-time RT-PCR assays provide quantitative viral load data. Sequencing of the VP1 gene confirms strain identification and facilitates phylogenetic analysis. Multiplex PCR panels including enteroviruses are increasingly available, allowing simultaneous screening for multiple enterovirus types.
Serology
Serologic testing employs enzyme-linked immunosorbent assays (ELISA) using recombinant VP1 antigens. Detection of IgM indicates recent infection, while IgG signifies past exposure. Because cross-reactivity among enterovirus serotypes can occur, serology is most useful when combined with molecular testing. Paired sera collected during acute and convalescent phases strengthen diagnostic confidence.
Treatment and Management
Antiviral Therapy
Currently, no specific antiviral agent has been approved for CVA-62 infection. Ribavirin has shown limited in vitro activity against some enteroviruses but lacks clinical efficacy. Experimental compounds targeting the viral RNA polymerase, such as 2′-C-methyladenosine, have demonstrated antiviral effects in cell culture; however, clinical trials are pending. Supportive care remains the mainstay of treatment for symptomatic patients.
Supportive Care
Management focuses on maintaining hydration, controlling fever, and monitoring for neurological complications. In cases of aseptic meningitis, patients are observed for signs of increased intracranial pressure and seizure activity. Respiratory support may be necessary in severe flaccid paralysis. Early recognition of complications allows timely intervention and reduces morbidity.
Prevention and Control
Hygiene
Standard infection control measures are effective in limiting CVA-62 spread. Frequent hand washing with soap and water, especially after diaper changes and before food preparation, reduces fecal–oral transmission. Disinfection of contaminated surfaces with agents such as bleach or 70% ethanol prevents environmental persistence. Isolation of symptomatic individuals in healthcare settings mitigates nosocomial spread.
Vaccines
No vaccine currently exists for CVA-62. Existing enterovirus vaccines target poliovirus and Coxsackie B viruses but do not confer cross-protection. Research into a multivalent enterovirus vaccine that includes CVA-62 antigens is ongoing but remains at the experimental stage. Public health recommendations emphasize routine vaccination against poliovirus and support for ongoing surveillance to detect outbreaks.
Research and Future Directions
Vaccine Development
Efforts to develop a CVA-62 vaccine involve several approaches. Live-attenuated and inactivated vaccine candidates are being evaluated in preclinical models for immunogenicity and safety. Recombinant subunit vaccines expressing VP1 and VP3 proteins have shown promising neutralizing antibody responses in mice. Clinical trials are required to determine efficacy in humans.
Antiviral Research
Targeted antiviral strategies focus on inhibiting the viral protease 3C and the RNA-dependent RNA polymerase 3D. Small-molecule inhibitors, such as rupintrivir, have shown potency against enterovirus proteases and are under investigation for cross-reactivity with CVA-62. Novel nucleoside analogs that disrupt RNA synthesis are also being tested in vitro. Drug repurposing screens have identified several candidate compounds with activity against CVA-62, warranting further investigation.
Molecular Epidemiology
High-throughput sequencing and phylogenetic mapping contribute to understanding CVA-62 genetic diversity and evolutionary dynamics. Whole-genome sequencing of clinical isolates enables identification of mutation hotspots and potential recombination events. Integration of genomic data with epidemiological surveillance informs public health interventions and helps delineate transmission pathways.
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