Important properties of the coronaviruses are listed in Table 1.

Table1. Important Properties of Coronaviruses

Structure and Composition

 Coronaviruses are enveloped, 120- to 160-nm particles that contain an unsegmented genome of single-stranded positive sense RNA (27–32 kb), the largest genome among RNA viruses. The genomes are polyadenylated at the 3′ end. Isolated genomic RNA is infectious. The helical nucleocapsid is 9–11 nm in diameter. There are 20-nm-long club- or petal shaped projections that are widely spaced on the outer sur face of the envelope, suggestive of a solar corona (Figure 1). The viral structural proteins include a 50–60 kDa phosphorylated nucleocapsid (N) protein, a 20–35 kDa membrane (M) glycoprotein that serves as a matrix protein embedded in the envelope lipid bilayer and interacting with the nucleocapsid, and the spike (S; 180–220 kDa) glycoprotein that makes up the petal-shaped peplomers. Some viruses, including human coronavirus OC43 (HCoV-OC43), contain a third glycoprotein (HE; 65 kDa) that causes hemagglutination and has acetylesterase activity.

Fig1. Human coronavirus OC43. Note the characteristic large, widely spaced spikes that form a “corona” around the virion (297,000×). (Courtesy of FA Murphy and EL Palmer.)

The genome organizations of a representative coronavirus is shown in Figure 2. The gene order for the proteins encoded by all coronaviruses is Pol-S-E-M-N-3′. Several open reading frames encoding nonstructural proteins and the HE protein differ in number and gene order among coronaviruses. The SARS virus contains a comparatively large number of interspersed genes for nonstructural proteins at the 3′ end of the genome.

Fig2. Genomic organization of coronaviruses. The SARS coronavirus (SARS-CoV) genome is about 29.7 kb. Boxes shaded in yellow represent open reading frames (ORFs) encoding structural proteins; boxes shaded in lavender encode nonstructural proteins. The separate ORFs within each gene are translated from a single mRNA species. S, spike; E, envelope; M, transmembrane; N, nucleocapsid. The ORF1 cleavage products are designated nsp1–16 and include a phosphatase, cysteine proteinases, an RNA-dependent RNA polymerase, a helicase, and an endoribonuclease. (Adapted with permission from Lai MMC, Perlman S, Anderson LJ: Coronaviridae. In Knipe DM, Howley PM [editors in-chief]. Fields Virology, 5th ed. Lippincott Williams and Wilkins, 2007.)

Classification

The Coronaviridae is one of two families, along with Arteriviridae, within the order Nidovirales. Characteristics used to classify Coronaviridae include particle morphology, unique RNA replication strategy, genome organization, and nucleotide sequence homology. There are two subfamilies (Coronavirinae and Torovirinae) and six genera (Alphacoronavirus, Betacoronavirus, Gammacoronavirus, Deltacoronavirus, Bafinivirus, and Torovirus) in the Coronaviridae family. The first two and the last genera contain viruses able to infect humans. The toroviruses are widespread in ungulates and appear to be associated with diarrheal disease.

There are six coronaviruses that can infect humans, the alpha coronaviruses 229E and NL63 and the beta coronaviruses OC43, HKU1, SARS-CoV, and MERS-CoV. There are many coronaviruses that infect animals, with most infecting one or a few species.

Coronavirus Replication Because human coronaviruses do not grow well in cell culture, details of viral replication have come from studies with mouse hepatitis virus, which is closely related to human strain OC43 (Figure 3). The replication cycle takes place in the cytoplasm of cells.

Fig3. Coronavirus replication cycle. Virions bind to specific receptor glycoproteins or glycans via the spike protein. Penetration and uncoating occur by S protein-mediated fusion of the viral envelope with the plasma membrane or endosomal membranes. Gene 1 of viral genomic RNA is translated into a polyprotein, which is processed to yield the transcriptase–replicase complex. Genomic RNA is used as a template to synthesize negative-stranded RNAs, which are used to synthesize full-length genomic RNA and subgenomic mRNAs. Each mRNA is translated to yield only the protein encoded by the 5′ end of the mRNA, including nonstructural proteins. The N protein and newly synthesized genomic RNA assemble to form helical nucleocapsids. Membrane glycoprotein M is inserted in the endoplasmic reticulum (ER) and anchored in the Golgi apparatus. Nucleocapsid (N plus genomic RNA) binds to M protein at the budding compartment (ERGIC). E and M proteins interact to trigger the budding of virions, enclosing the nucleocapsid. S and HE glycoproteins are glycosylated and trimerized, associate with M protein, and are incorporated into the maturing virus particles. Virions are released by exocytosis-like fusion of vesicles with the plasma membrane. Virions may remain adsorbed to the plasma membranes of infected cells. The entire cycle of coronavirus replication occurs in the cytoplasm. (Reproduced with permission from Lai MMC, Perlman S, Anderson LJ: Coronaviridae. In Knipe DM, Howley PM [editors-in-chief]. Fields Virology, 5th ed. Lippincott Williams and Wilkins, 2007.)

The virus attaches to receptors on target cells by the glycoprotein spikes on the viral envelope (either by S or HE). The receptor for human coronavirus 229E is aminopeptidase N, whereas a functional receptor for SARS-CoV is angiotensin converting enzyme 2. The receptor for MERS-CoV is dipeptyl peptidase 4, also known as CD26. Multiple isoforms of the carcinoembryonic antigen-related glycoprotein family serve as receptors for mouse coronavirus. The particle is then internalized, probably by absorptive endocytosis. The S glycoprotein may cause fusion of the viral envelope with the cell membrane.

The first event after uncoating is translation of the viral genomic RNA to produce a virus-specific RNA-dependent RNA polymerase. The viral polymerase transcribes a full length complementary (minus-strand) RNA that serves as the template for a nested set of five to seven subgenomic mRNAs. Only the 5′ terminal gene sequence of each mRNA is translated. Full-length genomic RNA copies are also transcribed off the complementary RNA.

Newly synthesized genomic RNA molecules interact in the cytoplasm with the nucleocapsid protein to form helical nucleocapsids. There is a preferred binding site for N protein within the leader RNA. The nucleocapsids bud through membranes of the rough endoplasmic reticulum and the Golgi apparatus in areas that contain the viral glycoproteins. Mature virions may then be transported in vesicles to the cell periphery for exit or may be released upon cell lysis.

Virions are apparently not formed by budding at the plasma membrane. Large numbers of particles may be seen on the exterior of infected cells and are presumably adsorbed to it after virion release. Certain coronaviruses induce cell fusion; this is mediated by the S glycoprotein and requires pH 6.5 or higher. Some coronaviruses establish persistent infections of cells rather than being cytocidal.

Coronaviruses exhibit a high frequency of mutation during each round of replication, including the generation of a high incidence of deletion mutations. Coronaviruses undergo a high frequency of recombination during replication; this is unusual for an RNA virus with a nonsegmented genome and may contribute to the evolution of new virus strains.

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