D1
A1
B1
A2
E1
F1
C1
N
D2
C
E2
F2
C2
Cys 122
His 54
B2
Glu 71
A
B
N
C
C
N
C
FIGURE 1.19 Divergent structures of viral proteases. (A) Ribbon diagram of human rhinovirus 3Cpro. The β strands
are shown in blue and the helical secondary structure is shown in yellow. The side chains that make up the catalytic triad
are shown: Cys-146 (with the sulfur atom shown in yellow), His-40, and Glu-71 (with the atoms of the charged carboxyl
group shown in red). The N termini and C termini are indicated "N" and "C," respectively, in red. From Matthews et
al. (1994) with permission. (B) Ribbon diagram of the papain-like protease of adenovirus complexed with its 11 amino
acid cofactor (red arrow at bottom). The protein trace is colored from N terminus to C terminus as the visible spectrum
from red to violet. The locations of the amino acids making up the catalytic triad (Cys-122, His-54, and Glu-71) are
indicated with dots. From Ding et al. (1996), with permission. (C) The HIV protease, a dimer of identical subunits,
is shown complexed with a nonamino acid inhibitor in the active site. One monomer is colored from red to green
(N terminus to C terminus) while the second one is colored from green to dark blue. Adapted from Rutenber et al. (1993)
with permission.
assembly of viruses will be discussed in Chapter 2, after the
replication cycle. The term nonpermissive usually refers to
structure of viruses is described.
a cell in which no progeny virus are produced. A cell may
be nonpermissive because it lacks receptors for the virus
or because it lacks factors required by the virus after entry.
EFFECTS OF VIRUS INFECTION ON THE HOST CELL
In the latter case, an abortive infection may occur in which
virus replication begins but does not result in the production
Cells can be described as permissive, semipermissive,
of progeny virus. The term semipermissive usually refers
or nonpermissive for virus replication. Semipermissive or
to a cell in which a small yield of progeny virus may be
nonpermissive cells lack factors required for a complete
produced.
Several types of viral infection cycle can be distinguished.
by different mechanisms. In what is here referred to as a per-
The infection may be lytic, latent, persistent, or chronic. In
sistent infection, an infected cell lives and produces progeny
some cases, virus infection results in the transformation of
virus indefinitely. The retroviruses represent the best studied
a cell.
case of persistent infection. During infection by retroviruses,
the DNA copy of the genome is integrated into the host cell
genome. Continual transcription of the genome and assem-
Lytic Infection or Latent Infection
bly of progeny virus, which bud from the cell surface, occur
In a lytic infection, the virus replicates to high titer, host
without apparent ill effects on the host cell. The infected
cell macromolecular synthesis is shut down, and the host cell
cell retains its normal functions and can divide. However,
dies. Bacterial cells are usually actively lysed by the elabora-
although infection by most retroviruses does not lead to cell
tion of a specific lysis product during bacteriophage infec-
death, active replication of HIV can result in cell death.
tion. Animal viruses, in contrast, usually cause cell death by
Chronic infection is a property of a group of cells or
inducing apoptosis or programmed cell death. Apoptosis is
of an organism in which lytic infection is established in
a suicide pathway in which the mitochrondria cease to func-
many cells, but many potentially susceptible cells escape
tion, the cell destroys its DNA, and the cell fragments into
the infection at any particular time, for whatever reason.
small vesicles (Chapter 10). Cell death may also be due to
The infection is not cleared and the continual appearance
necrosis, a generalized loss of cell integrity caused by virus
of susceptible cells in the population leads to the continued
interference with activities necessary for the upkeep of the
presence of replicating virus. One well-known example of a
cell. Membrane integrity is lost during necrotic cell death
chronic infection in humans is HIV, in which the infection
and cytoplasmic contents leak out of the cell. Apoptosis is a
cannot be cleared by the immune system and the virus con-
normal event in animals and does not result in an inflamma-
tinues to replicate. AIDS results when the immune system is
tory response. In contrast, necrosis does result in an inflam-
finally overwhelmed by the virus. Hepatitis B and hepatitis
matory response.
C viruses are also well known for their ability to establish
During lytic infection, profound changes in the condition
chronic liver infections that can persist for life.
of the cell occur well before it dies and fragments. These
changes may result in alterations that are observable in the
Transfor mation of Cells
light microscope, such as changes in the morphology of the
cell, the formation of vacuoles within the cell, or the fusion
The normal outcome of the infection of a cell by a virus
of cells to form syncytia. Such changes are given the name
is the death of the cell and the release of progeny virus. The
cytopathic effect, or CPE. CPE is often an early sign that the
major exceptions are the persistent infection of cells by ret-
cell is infected.
roviruses and the latent infection of cells by viruses such
In latent infections, no virus replication occurs. The
as herpesviruses, in which the cell survives with its proper-
best understood case of latent infection is that of temperate
ties little altered except for the new ability to produce virus.
bacteriophage, which express genes that repress the repli-
However, another possible outcome is the transformation of
cation of the virus. Once the lysogenic state is established,
the cell, which involves not only the survival of the cell but
in which viral replication is repressed, it can persist indefi-
an alteration in its growth properties caused by deregulation
nitely. Among vertebrate viruses, many of the herpesviruses
of the cell cycle. Transformed cells may be able to induce
are capable of latently infecting specialized cells that are
the formation of a tumor if they are produced within an ani-
nonpermissive or semipermissive for virus replication. As
mal or are injected into an animal after formation ex vivo.
one example, herpes simplex virus type 1 establishes a life-
Transformation of a cell needs to be distinguished from
long, latent infection of neurons of the trigeminal ganglia.
tumorigenicity, the ability of the transformed cell to cause a
In this case it is thought that latent state arises because the
tumor. Transformed cells may fail to cause a tumor because
neuron lacks cellular factors required for the transcription
they are rejected by the host's immune system or because
and replication of the viral DNA, rather than because of the
the transformed cells lack some properties required for the
production of a herpes protein that suppresses replication.
growth of a tumor in an animal, in which case additional
Reactivation of the virus at times leads to active replica-
mutations may eventually allow tumors to form.
tion of the virus in epithelial cells innervated by the infected
The avian and mammalian sarcoma viruses, specialized
neuron, resulting in fever blisters, usually at the lip margin.
retroviruses that arise when a cellular oncogene is incorpo-
rated into the retroviral genome, can transform cells in cul-
ture and cause tumors in animals. It was this feature that led
Persistent Versus Chronic Infection
to their discovery in the first place and resulted in intensive
Persistent infection and chronic infection are often used
study of the retroviruses. Cellular oncogenes encode pro-
interchangeably, but these two terms will be distinguished
teins that regulate the cell cycle. They induce the cell to enter
here in order to describe two types of infections that persist
S phase, in which DNA replication occurs, on receipt of
Search WWH :
