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Katharyn Self
Spring 2015

Seoul Virus
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Seoul Virus (SEOV) is apart of the genus Hantavirus in the family

Bunyaviridae.(8). The genus Hantavirus is unique among other Bunyaviridae

viruses due to the fact they are not transmitted by insect vectors.(3) They are

instead transmitted by rodents and other insect eating animals. SEOV is carried

and spread by its natural host reservoir the Brown Norwegian Rat (Rattus

norvegicus), It is one of the three major pathogens that cause more than 200,000

annual cases of Hemorrhagic Fever with Renal Syndrome (HFRS) in China,

Korea, Russia, and Europe.(3) Very little is known about the mechanics of the

virus however, SEOV is currently listed as a major health concern in Asia and

has the capability to become a global concern due to the migration of rats (9).

Seoul Virus was first isolated along with other Hantaviruses in the early

1980s by a Korean virologist Dr. Ho Wang Lee and his collaborators, when they

were testing for different strains of Hantavirus. Seoul Virus was discovered in a

lung tissue sample taken from a Brown Norwegian Rat found in Seoul, South

Korea. The virus was aptly named after the location of discovery.(10)

Seoul virus, like other Hantaviruses is an enveloped single stranded

negative sense RNA virus with a tri-segmented genome. Each segment has an

open reading frame (ORF) located in the middle of two non-coding regions

(NCRs) at the 3 and 5 ends. Nucleocapsid proteins (N protein) surround each

genome segment. The ORF on the small (S) genome segment encodes N

protein. The medium (M) genome segment ORF encodes the glycoprotein

precursor, which is later made into glycoproteins: G1 and G2. The large (L)

genome segment ORF encodes for RNA dependent RNA polymerase (RdRp).(5)
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At the termini of the NCR regions there are complementary nucleotides that form

panhandle structures unique to the family Bunyaviridae. The panhandle structure

serves as the promoter for the virus. The virus particle is round and ranges from

100-120nm in diameter.(3) The lipid envelope surrounding the virion is about

5nm thick and is covered in 10nm long protrusions comprised of glycoproteins.

The virions are extremely hearty and are capable of surviving outside of a host in

excess of 10 days.(5).

The SEOV genome is thought to preform viral transcription like most other

negative sense segmented RNA genomes, in a process called cap snatching.

The Cap snatching process starts the initial transcription process by localizing

RdRp and N proteins to the cytoplasmic processing parts of the host cell called P

bodies. RdRp and N proteins then bind to degraded host cell mRNA. Then it is

speculated that the newly bound N protein and RdRp mRNAs are either

trafficked to the site of viral replication the ERGolgi intermediate compartment

(ERGIC) or, the P bodies maybe the site of replication. The science is still very

speculative. Then, the newly synthesized ribonucleoproteins (RNPs) are

transported by the host cells microtubule or actin filaments to the site of viral

assembly. RdRp uses the host mRNA at the point of viral replication to form

capped primers, 1015 bases long in order to transcribe viral mRNA. The

primers from the host cell have G residue on their 3 terminus that will then pair

with the first C of the AUC repeats located on the end of the viral RNA segment.

After bonding occurs, bases are added on, and the new RNA then slides back a

couple bases in order to realign with complementary nucleotides located on the

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3 terminus of the viral RNA. Repetition of the prime and realign cycle eventually

produces repeated sequences at the end of the terminal of the viral RNA located

in the new mRNA.(5)

Seoul virus also is speculated to undergo replication like other

Hantaviruses. The negative sense viral RNA serves as the template for the

formation of complementary RNA. Complementary RNA is then used as the

template for making more viral RNA. Complementary RNA is enclosed by N

protein like viral RNA and goes through a prime realign synthesis cycle as well.

However, it initially binds a triphosphorylated G to a C residue in viral RNA. The

triphosphorylated G is then split by the protein RdRp making a

monophosphorylated 5 terminal of complementary RNA. The mechanism is

repeated to produce more viral RNA from a complementary RNA template. It is

not yet known exactly where replication takes place. The theory is that Virus

replication takes place in viral factories attached to ERGolgi intermediate

compartment (ERGIC) or the Golgi. The viruses then bud into the Golgi where

they then are transported by recycling endosomes to the cell membrane to be

released out of the cell.(5)

Information regarding the life cycle of an SEOV virion and other

Hantaviruses in a host cell is still very speculative and generalized. Many of the

mechanisms have yet to be determined. However, scientific inferences and

strong educated guesses can be made based on the genomic structure,

similarities to other viruses, and experimental data. The main pathway a SEOV
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virion is thought to use in order to enter a host cell is by attachment to the

integrin receptor V3 on an endothelial cell. This binding then signals the cells

receptor to pull the virion closer to its cell membrane where a clathrin-coated pit

forms around it. The cell then takes the virion wrapped in clathrin-coated cellular

membrane into the cell. This process is called clathrin-dependent endocytosis.

Upon entry to the host cell, the clathrin-coated vesicle containing the virion is

broken down. The virion then gets trafficked into an early stage endosome, which

then matures to a late stage endosome, where the cellular receptor is then

detached. This causes the pH in the endosome to drop, catalyzing a structural

change in the G2 and G1 glycoproteins on the virion thus allowing for fusion of

viral and endosomal membranes to take place. This fusion results in viral genetic

material called viral ribonucleoproteins (RNPs) to be released into the cytoplasm

and transported to the site of replication. There is some disagreement as to

where transcription takes place, as stated above. Some theories include

transcription-taking place when the RNPs are released from the endosome, the

RNPs might also be transported to the ERGolgi intermediate compartment

(ERGIC) to then be transcribed or, the virion is transported directly to the Golgi

complex from the endosome before or after fusion occurs.

Norwegian Brown Rats serve as the natural reservoir for SEOV. The virus

is passed from rat to rat and from rat to human through aerosolized rat fecal

matter. (3). Rats who are infected with SEOV are asymptomatic and continually

shed virus particles through their urine, feces, and saliva.(5). SEOV can be

maintained and transmitted in the rats because it is able to suppress their innate
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immune function by causing the upregulation of transforming growth factor 1,

which produces regulatory T cells. This causes a nonexistent inflammatory

response that is evidently seen in the main site of viral replication, the lung tissue

of the rat. However, some studies have noted inflammation in the spleen.(2)

In humans SEOV causes a milder form of HFRS with the inclusion of liver

complications. There are about 200,000 cases of HFRS is Asia, China, Russia,

and Europe and SEOV causes about 25%. The mortality rate among people who

contract Seoul virus is 1-5%. Yet, there is still no globally accepted vaccine and

vaccines given to people in high-risk areas had little success. The only way to

prevent SEOV is through avoidance measures. SEOV can be avoided by

avoiding high populations of rats. The people most at risk for contracting SEOV

are: farmers, field biologists, lab techs, sanitation workers, and ship yard

workers. There is also no treatment for SEOV; usually intensive supportive care

at a hospital is required.

The virus predominantly infects vascular endothelial cells.(2) Which along

with immune responses produced by the patient, contribute to the observed

symptoms of: high fever, lower stomach pains, backache, nausea and vomiting,

malfunctioning kidneys, low platelet counts that result in spontaneous bleeding

and hemorrhages, bloody vomit, bloody urine, and bruising may occur in soft

areas of the body. (encyclopedia) Symptoms of HFRS typically start between 1

and 6 weeks after exposure to SEOV. There are considered to be 5 stages of

HFRS that may or may not be distinct; febrile which consists of non-specific flu

like symptoms, hypotensive shock where vomiting is common, oliguric involves

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kidney impairment and hypervolemia, the diuretic stage where kidney function

improves and patients start to feel better, and convalescent stage where

dehydration is still common but the body is almost recovered.

SEOV is a virus that causes a serious disease that has the capability to be

spread worldwide. However, the specific mechanics of the virus are poorly

understood. More research needs to be conducted in order to figure out exact

mechanisms in order to make a successful vaccine and treatment. I believe an

experiment could possibly be done to determine what the attachment protein is

for SEOV, and maybe there would be a way to synthesize an inhibitory drug.