A pathogenic picornavirus acquires an envelope by hijacking cellular membranes

• Published in: Nature (London) 2013-04, Vol.496 (7445), p.367-371
• Main Authors: Feng, Zongdi, Hensley, Lucinda, McKnight, Kevin L., Hu, Fengyu, Madden, Victoria, Ping, LiFang, Jeong, Sook-Hyang, Walker, Christopher, Lanford, Robert E., Lemon, Stanley M.
• Format: Article
• Language: English
• Subjects: 631/250/590/1883; 631/326/421; 631/326/596/2557; 631/326/596/2558; Analysis; Animals; Antibodies, Neutralizing - immunology; Antibodies, Neutralizing - therapeutic use; Biosynthesis; Cell Line; Cell Membrane - metabolism; Cell membranes; Cercopithecus aethiops; Chloroform; Control; Endosomal Sorting Complexes Required for Transport - metabolism; Genetic aspects; Hepatitis A - blood; Hepatitis A - immunology; Hepatitis A - prevention & control; Hepatitis A - virology; Hepatitis A virus; Hepatitis A virus - chemistry; Hepatitis A virus - growth & development; Hepatitis A virus - immunology; Hepatitis A virus - metabolism; Hepatovirus; Host-Pathogen Interactions; Humanities and Social Sciences; Humans; Identification and classification; letter; Liver - virology; Macaca mulatta; Membranes; Microbiology; Molecular Sequence Data; multidisciplinary; Neutralization; Neutralization Tests; Pan troglodytes; Picornaviruses; Prophylaxis; Proteins; Science; Viral Envelope Proteins; Viral envelopes; Viruses
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature12029

Hepatitis A virus particles released from cells can hijack and become wrapped in host-derived membranes by using proteins that facilitate the budding of many enveloped viruses, calling into question the traditional distinction between enveloped and non-enveloped viruses. Viral envelopes made with host-cell proteins This study of hepatitis A virus (HAV) challenges a basic tenet in virology, the classic distinction between 'enveloped' and 'non-enveloped' viruses. HAV, a picornavirus consisting of a single-stranded RNA packaged in a protein shell, is classified as a non-enveloped virus, lacking a lipid-bilayer membrane. Stanley Lemon and colleagues now show that HAV particles released from cells can co-opt the ESCRT (endosomal sorting-complexes required for transport) machinery, becoming cloaked in host-derived membranes. HAV's hijacked envelope may facilitate the virus's spread within the liver, but could also explain how passive transfer of antibody works as post-exposure prophylaxis of hepatitis A, a phenomenon that has been known clinically for decades but has not been explained. Animal viruses are broadly categorized structurally by the presence or absence of an envelope composed of a lipid-bilayer membrane 1 , attributes that profoundly affect stability, transmission and immune recognition. Among those lacking an envelope, the Picornaviridae are a large and diverse family of positive-strand RNA viruses that includes hepatitis A virus (HAV), an ancient human pathogen that remains a common cause of enterically transmitted hepatitis 2 , 3 , 4 . HAV infects in a stealth-like manner and replicates efficiently in the liver 5 . Virus-specific antibodies appear only after 3–4 weeks of infection, and typically herald its resolution 3 , 4 . Although unexplained mechanistically, both anti-HAV antibody and inactivated whole-virus vaccines prevent disease when administered as late as 2 weeks after exposure 6 , when virus replication is well established in the liver 5 . Here we show that HAV released from cells is cloaked in host-derived membranes, thereby protecting the virion from antibody-mediated neutralization. These enveloped viruses (‘eHAV’) resemble exosomes 7 , small vesicles that are increasingly recognized to be important in intercellular communications. They are fully infectious, sensitive to extraction with chloroform, and circulate in the blood of infected humans. Their biogenesis is dependent on host proteins associated with endosomal-sorting complexes