Sin Nombre virus

Sin Nombre virus (SNV) is the most common cause of hantavirus pulmonary syndrome (HPS) in North America. Sin Nombre virus is transmitted mainly by the western deer mouse (Peromyscus sonoriensis). In its natural reservoir, SNV causes an asymptomatic, persistent infection and is spread through excretions, fighting, and grooming. Humans can become infected by inhaling aerosols that contain rodent saliva, urine, or feces, as well as through bites and scratches. In humans, infection leads to HPS, an illness characterized by an early phase of mild and moderate symptoms such as fever, headache, and fatigue, followed by sudden respiratory failure. The case fatality rate from infection is 30 to 50 percent. The genome of SNV is about 12.3 kilobases (kb) in length and segmented into three negative-sense, single-stranded RNA (-ssRNA) strands. The small strand encodes the viral nucleoprotein, the medium strand encodes the viral spike protein, which attaches to cell receptors for entry into cells, and the long strand encodes the viral RNA-dependent RNA polymerase (RdRp), which replicates and transcribes the genome. Genome segments are encased in nucleoproteins to form ribonucleoprotein (RNP) complexes that are surrounded by a viral envelope that contains spikes emanating from its surface. SNV replicates first by binding to the surface of cells with its envelope spikes. Virus particles, called virions, are then taken into the cell by endosomes, where a drop in pH causes the viral envelope to fuse with the endosome, which releases viral RNA into the host cell. RdRp then transcribes the genome for translation by host cell ribosomes and produces copies of the genome for progeny viruses. New virions are assembled near the cell membrane, where virions bud from the cell membrane and use it to obtain their viral envelope and leave the cell. SNV was first discovered in 1993 when it caused an outbreak of disease in the Four Corners region of the US. This outbreak was historically significant since it marked the first time that pathogenic hantaviruses were discovered in the Americas as well as the discovery of HPS. Since its discovery, SNV has caused hundreds of cases of HPS in the US and Canada, where it is responsible for most HPS cases. Most cases of HPS caused by SNV occur in the western parts of the US and Canada.

Genome The genome of Sin Nombre virus is about 12.3 thousand nucleotides in length and segmented into three negative-sense, single-stranded RNA (-ssRNA) strands. The segments form into circles via non-covalent bonding of the ends of the genome. The small segment, about 2.06 kilobases (kb) in length, encodes the viral nucleoprotein and a non-structural protein that inhibits interferon production. The medium segment, about 3.7 kb in length, encodes a glycoprotein precursor that is cleaved into the two spike proteins Gn and Gc during virion assembly. The large segment, about 6.56 kb in length, encodes the viral RNA-dependent RNA polymerase (RdRp), which is responsible for transcribing and replicating the genome. The ends of each segment contain untranslated terminal regions (UTRs) that are involved in the replication and transcription of the genome.

Structure

Virions are mostly spherical or pleomorphic in shape, with an average diameter of 112 nanometers (nm). They contain a lipid envelope covered in spike proteins made of the two viral glycoproteins, Gn and Gc. The spike proteins extend about 10 nm out from the surface and are tetrameric, consisting of four copies each of Gn and Gc with helical symmetry, in which Gn forms the stalk of the spike and Gc the head. Spikes are arranged on the surface in a lattice pattern. Inside the envelope are the three genome segments, which are encased in nucleoproteins to form a ribonucleoprotein (RNP) complex. Attached to each RNP complex is a copy of RdRp. For some SNV strains, virions may be roughly tubular in shape, with an average diameter of 85 nm and an average length of 180 nm.

Life cycle SNV primarily infects endothelial cells and macrophages. It enters cells by using β3-integrins as receptors. Virions are taken into a cell via an endosome. Once pH is lowered, the viral envelope fuses with the endosome, which releases viral RNA into the host cell's cytoplasm. The small segment is transcribed by RdRp first, then the medium segment, and lastly the large segment. Once the genome has been transcribed, RdRp snatches caps from host messenger RNA (mRNA) to create viral mRNA that is primed for translation by host ribosomes to produce viral proteins. For replication of the genome, a complementary positive-sense strand is produced by RdRp. Copies of the genome are made from this complementery strand. Progeny RNA strands are then encapsidated by nucleoproteins. During replication, the glycoprotein is cleaved in the endoplasmic reticulum by the host signal peptidase during translation. This produces Gn at the N-terminus and Gc at the C-terminus of the protein. Spike proteins are expressed on the surface of the cell membrane. Viral RNPs are transmitted to the cell membrane where they bud from the surface, thereby obtaining their envelope as the new progeny virions leave the cell.

Evolution The most common way that hantaviruses evolve is through mutations of individual nucleotides being inserted, deleted, or substituted. Because Sin Nombre virus has a segmented genome, it is possible for recombination and reassortment of segments to occur, whereby segments from different lineages mix in a single host cell and produce hybrid progeny. This has been observed for SNV in the US, mainly in exchanges of the S and M segments. Diploid progeny are also possible, in which virions may possess two of the same segment from two parent viruses.

Ecology

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