Hantaan virus (HTNV) is the main cause of hemorrhagic fever with renal syndrome (HFRS) in East Asia. Hantaan virus is transmitted by the striped field mouse (Apodemus agrarius). In its natural reservoir, HTNV causes a persistent, asymptomatic 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 causes symptoms such as fever and headache, as well as the appearance of spots on the skin, hepatitis, and renal symptoms such as kidney swelling, excess protein in urine, blood in urine, decreased urine production, and kidney failure. Rarely, HTNV infection affects the pituitary gland and can cause empty sella syndrome. The case fatality rate from infection is up to 6.3%. The genome of HTNV is about 11.9 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. Hantaan virus 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 at the endoplasmic reticulum and bud from its surface to obtain their viral envelope. Progeny viruses are then transported by a cellular vesicle to the cell membrane, where they leave the cell by exocytosis. HTNV was discovered in 1976 then isolated in 1978 after being extracted from striped field mice. The virus was subsequently linked to a past outbreak among soldiers in the Korean War who were stationed near the Hantan river and for that was named after the river. Hantaan virus was the first hantavirus to be discovered, and the group is named after the virus. The vast majority of HFRS cases occur in China, where Hantaan virus is responsible for up to 70% of cases. Cases of HFRS caused by Hantaan virus also occur in South Korea, Russia, and Vietnam.
Genome The genome of Hantaan virus is about 11.8 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 1.7 kilobases (kb) in length, encodes the viral nucleoprotein. The medium segment, about 3.62 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 6.53 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 and range from 80 to 160 nm in diameter. 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.
Life cycle HTNV 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 complementary 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 endoplasmic reticulum. Viral RNPs are transported to the endoplasmic reticulum where they bud from the surface, thereby obtaining their envelope. Progeny viruses are then transported by a cellular vesicle to the cell membrane, where they leave the cell via exocytosis.
Evolution The most common way that hantaviruses evolve is through mutations of individual nucleotides being inserted, deleted, or substituted. Because Hantaan 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. In China, a recombinant strain of HTNV was discovered in which recombination had occurred with a different species of hantavirus. In another instance, an isolate from brown rats (Rattus norvegicus) was found to have reassorted with a virus in another species, Seoul virus.
Ecology
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