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Introduction to Protiens
Rotavirus is a non-enveloped virus of the family Reoviridae with
an icosahedral capsid 70nm across.
It derives its name from the wheel like appearance it has when viewed under an
electron microscope (rota is latin for wheel). [19]
Its genome is made up of 11 segments of double stranded RNA held in the inner
core of the three-layered virus. [19][1] The
genome codes for 6 virus proteins (VP1,2,3,4,6,7) and 6 non-structural proteins
(NSP1-6).[15] Once
in the small intestine, the virus undergoes a change and becomes infective
to the villi. Proteins then mediate the invasion of the host cells and replication
of the virus genome. [19]
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Viral Proteins
| Structural Proteins |
| VP1 |
VP1 is part of the inner core
of the virus and one of three proteins comprising the innermost
of three viral layers. [14] It
is the RNA-Dependent, RNA Polymerase for rotavirus, [1] a core
replication intermediate, [14] and
associates with VP2 at its icosahedral vertices. [14] |
| VP2 |
This protein is the main structural component
of the innermost layer. It associates with VP1 and VP3 at its
12 vertices, and is a replication intermediate. [14] |
| VP3 |
The third part of the inner core of the virus,
VP3 acts as the mRNA capping enzyme. [1] It
also associates with VP2 and is a replication intermediate. [14] |
| VP4 |
Along with VP 7, VP4 makes up the outer
capsid of virus. [13] It
is an 88 kDa protein that dimerizes to create 60 spikes on
virus surface. [13] [16] VP4
is cleaved by the pancreatic enzyme trypsin to form VP 5 and
VP 8. VP4 and its cleavage products are associated
with cell attachment and invasion and cleavage is necessary
for infectivity. [16] VP4
is antigenic and induces neutralizing antibodies. The specific
structure of this protein is used to determine the rotavirus
P serotype, as well as host specificity, virulence and protective
immunity. [8] [16] [13] It
has also been associated with heat shock cognate protein, hsc70
during cell entry. [2] |
| VP5 |
VP5 is cleaved from the outer capsid protein
VP4 in the presence of trypsin. It remains bound to virion post
cleavage, and can be bound by neutralizing antibodies made to
VP4. It is membrane associated and functions to permeablize host
cell membranes to facilitate cell invasion. [16] An
association with integrins may also aid in this role. [11] |
| VP6 |
VP6 is a structural component that comprises
the middle capsid. The specificity of this protein is used to
determine the A-G groupings, and I, II sub-groupings of rotavirus.
[8] It has also been linked to the enterotoxin NSP4. [9] |
| VP7 |
This 37 kD glycoprtein makes up the smooth
portion of the outer capsid. [8] It can induce neutralizing antibodies
and determines the G serotype. [8] It is also a highly variable
portion of the virus capable of reassortment and possible crossover
with animal strains of the virus. [4] [12] VP7 also has associations
with heat shock cognate protein (hsc 70), and some integrins,
both related to viral entry of the cell [2] [11] |
| VP8 |
VP8 is the second cleavage product of VP4.
Like VP5 remains virion associated post cleavage and is bound
by VP4 neutralizing antibodies. It functions to bind sialic acid
and acts the virus hemagglutinin. [16] |
| Non-Structural Proteins |
| NSP1 |
NSP1 binds Interferon Regulatory
Factor 3 and may inhibit interferon response during rotavirus
infection. [15] |
| NSP2 |
In conjunction with NSP5, NSP2 is involved
synthesis and packaging of viral RNA and creation of viroplasms.
NSP2 is a replication intermediate. [14] |
| NSP3 |
NSP3, a 36kD protein, binds viral mRNA
at the 3’ end and promotes viral protein synthesis. It
also represses host cell protein synthesis. [1] [5] This protein
is a possible target for a new class of antivirals. [1] |
| NSP4 |
NSP4 has been shown to act as an enterotoxin
and cause diarrhea during infection. [13] There is also correlation
between VP6 virus subgroup and NSP4 genotype. [9] |
| NSP5 |
This phosphoprotein works with NSP2 in RNA
synthesis and packaging, and to induce viroplasms. It is also
a replication intermediate. [14] |
| NSP6 |
Little information is available on NSP6,
but it is associated with NSP5 and its function. [17] |
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Genome Variability
Rotavirus is a highly variable virus even within the subset of those
that are infective to humans. [4] Rotaviruses
are usually categorized into seven groups A-G, with subgroups I and
II based on the VP6 protein.
[8] Within
these groups, A, B, and C are infective to Humans. [19]
Rotavirus
is further categorized into G and P serotypes. The G serotype is
specified by the glycoprotein VP7 of the outer capsid, which is coded
by viral genes 7, 8, and 9. [8] The
P serotype is specified by protein VP4, also on the outer capsid.
It is a protease cleaved protein coded by gene 4 of the virus genome.
[8] The most
common G serotypes currently are G1, G2, G3, G4, and G9, with G1
being most prevalent and G9 the fastest emerging worldwide. [7] [8] [10] [12] Common
P serotypes are P1a, P1b, and P8. [13] [6] [4]
Greater
surveillance and more accurate characterization of the serotypes
has shown recently that there is a high level of genetic reassortment
among different strains of rotavirus, and that strains previously
thought to only infect other mammals, also infect humans. [4] [12]
These facts are important when considering possible vaccination strategies.
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Animal Model
Several animal models of rotavirus infection have been developed.
These include rabbits [21],
mice, gnotobiotic calves,
and gnotobiotic pigs. [22] [23] Mice
are frequently used in experiments relating to the immune response
to rotavirus. However, they are not a perfect model; one difficulty
with this model is that mice are succeptible to most rotavirus-induced
diarrhea only during the first 15 days of their lives. There are,
however, selected strains of murine rotavirus which adult mice are
also succeptible to. [20] The
only animal models for both rotaviral disease and pathology are gnotobiotic
pigs and calves. Rotavirus infection in these animals most closely
approximates rotavirus infection in humans and they make excellent
models for studying the pathology of rotavirus infection.[24]
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