In the picornaviruses, a provirion is first formed that is
(Fig. 1.6). Cleavage is required to potentiate the fusion activ-
composed of the viral RNA complexed with three viral pro-
ity present at the N terminus of HA2. As a second example,
teins, called VP0, VP1, and VP3. During maturation to form
alphaviruses produce two envelope glycoproteins that form
the virion, VP0 is cleaved to VP2 and VP4. No protease
a heterodimer and one of the glycoproteins is produced as
has been found that performs this cleavage, and it has been
a precursor, as described before. The heterodimer contain-
postulated that the virion RNA may catalyze it. Cleavage to
ing the uncleaved precursor is quite stable, so that a parti-
produce VP4, which is found within the interior of the cap-
cle containing uncleaved heterodimer is not infectious. The
sid shell, as illustrated schematically in Fig. 2.9, is required
cleaved heterodimer, which is required for virus entry, is
for the virus to be infectious. As described in Chapter 1,
much less stable and dissociates readily during infection.
VP4 appears to be required for entry of the virus into the
Thus, in contrast to the poliovirus maturation cleavage, the
cell. This maturation cleavage has another important conse-
alphavirus cleavage makes the virion less stable rather than
quence. Whereas the provirion is quite unstable, the mature
more stable. Maturation cleavages also occur in the envelope
virion is very stable. The poliovirus virion will survive treat-
glycoproteins of retroviruses, paramyxoviruses, flaviviruses,
ment with proteolytic enzymes and detergents, and survives
and coronaviruses.
exposure to the acidic pH of less than 2 that is present in the
stomach. Only on binding to its receptor (Figs. 1.5 and 2.9)
Neutralization of Charge on the
is poliovirus destabilized such that VP4 can be released for
Virion Genome
entry of the viral RNA into the host cell.
Similarly, the insect nodaviruses first assemble as a pro-
DNA or RNA has a high net negative charge, and there
capsid containing the RNA and 180 copies of a single pro-
is a need for counterions to neutralize this charge in order
tein species called α (44 kDa). Over a period of many hours,
to form a virion. In many viruses, positively charged poly-
spontaneous cleavage of α occurs to form β (40 kDa) and γ
mers are incorporated that neutralize half or so of the nucleic
(4 kDa). This cleavage is required for the particle to be infec-
acid charge. The DNA in the virions of the polyomaviruses
tious. These events in nodaviruses have been well studied
is complexed with cellular histones. The viral genomes in
because it has been possible to assemble particles in vitro,
these viruses have been referred to as minichromosomes.
and the structures of both cleaved and uncleaved particles
In contrast, the adenoviruses encode their own basic pro-
have been solved to atomic resolution.
teins that complex with the genome in the core of the virion.
Rotaviruses, which form a genus in the family Reoviridae,
Another strategy is used by the herpesviruses, which incor-
must be activated by cleavage with trypsin after release from
porate polyamines into the virion. Herpes simplex virus has
an infected cell in order to be infectious. Trypsin is present
been estimated to incorporate 70,000 molecules of spermi-
in the gut, where the viruses replicate, and activation occurs
dine and 40,000 molecules of spermine, which would be suf-
normally during the infection cycle of the virus in animals.
ficient to neutralize about 40% of the DNA charge. Among
When the viruses are grown in cultured cells, however,
RNA viruses, the nucleocapsid proteins are often quite basic
trypsin must be supplied exogenously.
and neutralize part of the charge on the RNA. As one exam-
A different type of cleavage event occurs during assembly
ple, the N-terminal 110 amino acids of the capsid protein of
of retroviruses and adenoviruses, as well as of a number of
Sindbis virus have a net positive charge of 29. The positive
other viruses. During assembly of retroviruses, the Gag and
charges within this domain of the 240 capsid proteins in a
Gag­Pol precursor polyproteins are incorporated, together
nucleocapsid would be sufficient to neutralize about 60%
with the viral RNA, into a precursor nucleocapsid. These
of the charge on the RNA genome. This charged domain is
polyproteins must be cleaved into several pieces by a pro-
thought to penetrate into the interior of the nucleocapsid and
tease present in the polyprotein if the virus is to be infec-
complex with the viral RNA.
tious. These cleavages often visibly alter the structure of the
particle as seen in the electron microscope (Fig. 2.21). An
analogous situation occurs in adenoviruses, where a viral
protease processes a protein precursor in the core of the
immature virion.
Virions differ greatly in stability, and these differences
In most enveloped viruses, one of the envelope proteins is
are often correlated with the means by which viruses infect
produced as a precursor whose cleavage is required to acti-
new hosts. Viruses that must persist in the extracellular
vate the infectivity of the virus. This cleavage may occur
environment for considerable periods, for example, must
prior to budding, catalyzed by a host enzyme called furin, or
be more stable than viruses that pass quickly from one host
may occur after release of the virus, catalyzed by other host
to the next. As an example of such requirements, consider
enzymes. The example of the hemagglutinin of influenza
the closely related polioviruses and rhinoviruses, members
virus was described in Chapter 1. This protein is produced as
of two different genera of the family Picornaviridae. These
a precursor called HA0, which is cleaved to HA1 and HA2
viruses shared a common ancestor in the not too distant
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