Download VIRUSES, PLAGUES, HISTORY

VIRUSES,
PLAGUES,
AND
HISTORY
MICHAEL
B. A. OLDSTONE
OXFORD
UNIVBRSITY PRESS
CHAPTER 2
INTRODUCTION
TO THE PRINCIPLES
OF VIROLOGY
Peter Medawar, a biologist awarded the Nobel Prize for Medicine and Physiology in 1960, defined viruses as a piece of nucleic acid surrounded by bad
news (1). True, viruses are nothing more than a speck of genetic material--a
single kind of nucleic acid (segmented or nonsegmented, DNA or RNA) and
a coat made of protein moleculesViruses multiply according to the information contained in this nucleic acid. Everything other than the DNA or RNA
is dispensable and serves primarily to ensure that the viral nucleic acid gets
to the right part of the right sort of cell in the organism hosting the virus,
because viruses cannot multiply until they invade a living cellViruses enter all
cellular forms of life from plants and animals to bacteria, fungi, and protozoa.
Viruses, plants, and animals form the three main groups that encompass allliving things. Plants and animals are cellular organisms and include bacteria and
protozoa,Viruses lack cell walls, are obligatory parasites, and depend for replication on the cells they infect.
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INTIIODUCTION TO TNII!: PIlINCIPL.II!:. 0'" VIIIOL.OGY
~
~
0
--
InfI_nza
(10
®
Polio
Vellowfevef
Smallpox
HIV
.....
9
H....
_I.
Figure 2.1 Viruses have differing life styles and have fIJOlved a variety rf
slulpes and sizes in which to place their genetic material. A scaled
oomp<lmrm rf the varitmS viruses discussed in this bo"k is shown. Viruses
vary from the sl1l41lest,poiiovirus, U! the i4rgest, smallpox virus.
Viruses have relatively few genes compared with other organisms. Measles
virus, yellow fever virus, poliomyelitis virus, Lassa fever virus, Ebota virus,
Hantavirus, as well as the human immunodeficiency virus (HIV), have fewer
than ten genes each, whereas a smallpox virus may contain between 200 and
400 genes. These numbers compare with 5,000 to 10,000 genes for the smallest bacteria and approximately 80,000 to 100,000 genes for a human.
It has been argued that the nucleic acid of viruses evolved from normal cell
genes. Through the alterations of mutation, reassortment, and recombination,
viruses could then have evolved their own genetic structure. Perhaps some
viruses stayed within the parental host from which they evolved and displayed
symbiotic or near-symbiotic relationships. But as viruses moved from one
host species to another or mutated to form new genetic mixtures, these formerly symbiotic viruses may have achieved a high level of virulence. Researchers suspect that the canine distemper virus of dogs or rindepest virus of
sheep may have crossed species to enter humans in whom they mutated sufficienrly to become measles virus. This is postulated because the genomic
sequences of canine distemper virus, rindepest virus, and measles virus have
more in conunon than do sequences from other types of viruses. Such interrelationships between these three viruses likely occurred at the time when
large human populations first lived in close proximity to domestic animals.A
similar event may have enabled simian (monkey) viruses to infect humans,
become HIV, and cause AIDS. In fact, whenever a virus encounters an unf;a-
/
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VIRUSES, PL.AGUIIS, AND HISTORY
miliar organism, the virus may undergo multiple mutations and emerge as a
variant that produces a severe and novel disease.
To maintain itself in nature and to replicate, a virus must undergo a series
of steps. First, the virus contacts the cell to he infected and then attaches to its
surface. A major function of the plasma membrane or outer "skin" of nucleated cells is to act as a barrier against infecting viruses. Yet viruses often cross
through this membrane to carry their genetic material and accessory proteins
into the cell's cytosol (inner comparnnent). Next, the virus penetrates to the
cell's interior, leading to the uncoating or removal of the virus's outer husk.
Thereafter, the virus uses its evolved strategies to express its genes, replicate its
genome (genes placed in the correct order and orientation), and assemble its
component parts (nucleic acids and proteins) in multiple copies or progeny
(offspring). Upon completion of this sequence, mature viruses formed during
the replication process exit tWm the infected cell.
Generally, the attachment and entry of viruses into cells are dependent
both on the activities of the host cell and on the properties of selected viral
genes. The cell has on its surface receptors to which viruses attach and bind
with proteins evolved specifically for that purpose. The cell must also provide
the mechanism for viral penetration after binding has occurred, and for the
internal highway that viruses travel to reach sites in the cell's cytoplasm or
nucleus where replication processes can proceed.
&; described above, the attachment Or binding of a viral protein (specifically, an amino acid sequence within that protein) to a cell receptor is the first
step that initiates infection of a cell. The unique distribution of certain receptors and either their limitation to a few cell types or, instead, their broad range
on many different cell types dictate how many portals of entry exist for a
virus. Further, the type of cells with such receptors and/or with the ability to
replicate a given virus often determines the severity of illness that a virus can
cause and the distribution of areas (organs, tissues, cells) in the body affected,
and the host's potential for recovery. For example, infections of neuronal cells
in the central nervous system that are not replaceable or of cells of the heart
whose function is essential to life are more ominous than infection of skin
cells which are less critical to survival and are replaceable.
An example of a cellular receptor is a molecule called CD4, which is abundant on the surfaces of some lymphocytes (white blood cells) derived from
the ~ymus (CD4+ T cells). The CD4 molecule is also present, but less plentiful, on monocyte macrophages (macrophages are infection fighting cells, an
activated form of monocytes) in the blood and in certain tissues of the body.
The CD4 molecule along with certain chemokine (cell-attracting) molecules
is the receptor for HIV. Because the CD4 receptor appears on relatively few
INTRODUCTION TO THE PRINCIPLES 0" VIROLOGY
11
cell types that HIV can infeCt, these viruses attack only limited sites in the
body (2,3). By contrast, a molecule called CD46, the cell receptor for measles
virus, appears on many types of cells (4-7). CD46 is found on epithelial cells,
which line most cavities including the nose, pharynx, respiratory tree, and gut;
on endothelial cells lining blood vessels; on lymphocytes/macrophages; and
on neuronal cells in the brain. The common presence of the CD46 receptors
correlates with the widespread replication of measles virus during infection.
In addition to access through specific cell receptors, viruses can enter cells
by other means. When a foreign agent composed of foreign proteins (antigens) such as a virus enters the body, a defensive response by the host produces antibodies that bind to the antigen in an attempt to remove it. Because
antibodies are shaped roughly like the letter "Y," they can bind to cells in two
ways. First, via their arms (the two upper parts of the "Y"), antibodies use a
combining site (the so-called FAb'2 site) to interact specifically with antigens
on cells. Second, with a part of their stalk (the bottom part of the "Y") called
the Fe region, antibody molecules can bind to receptors (Fe receptors) on
certain cells. Mter antibodies made by the host's immune system against
viral antigens bind to those antigens an infectious virus-antibody complex
forms (8). By binding to the cell via the Fe receptor, the virus as part of the
virus-antibody complex can enter that cell even though its surface may not
contain a specific receptor for the virus.
Not all cells that bind and take in a virus have the appropriate machinery
to replicate that virus. Therefore, binding to a receptor and entry of a virus
into a cell may not result in production of progeny.To summarize, the susceptibility of a specific cell for a virus is dependent on at least three factors. First,
a functional receptor must be present on the cell. Second, a specific viral protein, or sequence within the protein, must be available to bind to the cell
receptor. Third, the cell must possess the correct machinery to assist in replication of the virus.
The post-binding step in which viruses can penetrate a cell is an active
process and depends on energy. Occurring within seconds of binding/attachment, penetration follows either by movement of the entire virus across the
cell's plasma membrane, a process called phagocytosis (more specifically, endocytosis), so that the virus particle is pinched off inside a vacuole or compartment of the cell, or by fusion of the cell's membrane with the virus's outer
envelope. Mter penetration, the virus sheds its protective protein coat and
then releases its viral nucleic acids. This procedure is followed by replication of
the viral genome, during which the host cell's protein manufacturing equipment actually synthesizes new viruses-their progeny. To produce abundant
amounts of their own proteins, viruses must evolve strategies that provide
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VIRUSES, PL. ... C.UI!!i$. AND HISTORY
advantages for synthesizing viral materials instead of host cells' materials.
Viruses accomplish this feat either by abolishing the cell's ability to make its
own products or by conferring a selective advantage for the making of viral
products.
Whatever the route, once the viral genome and proteins form, they assemble as multiple progeny viruses, they mature, and they leave the infected cell.
Individual viruses have evolved unique processes and "patented" them for
success in this process. Once formed as a mature particle, viruses wspJay distinctive sizes and shapes.
How do viruses cause disease? Three distinct pathways are available (9, 10).
By the first, the virus or its proteins are directly toxic to a cell. In this instance,
the virus kills its host cell. With some viruses this process serves to release
virus particles from the inside of a cell to the outside environment. Alternatively, a second mechanism enables a virus to avoid killing the cell but instead
to alter its function. By this means, the synthesis of an important product
made by a cell is turned down or rurned up'. For example, a nonlethal virus
infection of cells that make growth hormone can diminish the amount of this
hormone made by the infected host cell.As a result the host fails to grow and
develop normally. The third way in which injury and disease can follow a viral
infection is through the participation of the host's immune response. As stated
in Chapter 3, the immune response to viruses is generated to rid infected cells
of virus progeny and to remove infectious virus from the host's blood and
other body fluids. By destroying virally infected cells, the immune system can
damage tissues that are critical to healthy function of the organism. Additionally, virus-antibody immune complexes can form that subsequently can be
deposited Of become trapped in kidneys and blood vessels, which are then
injured. Thus, another side of the usually protective immune response is its
destructive potential. The study of such processes is called immunopathology.
The balance between the protective and destructive processes of the immune
system is in large part responsible fOf the clinical symptOIJl5 (what the patient
states he or she has) and signs (what the doctor finds) that accompany a virus
infection.
How were viruses recognized as dangers to health? Although the diseases
caused by viruses were known in antiquity, viruses were not acknowledged as
separate infectious agents until about a hundred years ago, in the late 1890s.
The mid-1800s were the time of the discovery of bacteria and the pioneering work of Louis Pasteur, Robert Koch, and their associates. During that
period, the laboratory culturing process was developed so that bacteria could
be grown at will, then fixed on glass slides, stained, and observed under the
microscope. Bacteria were retained on filters with specific pore sizes, which
Figull' 2.2 Th~ PasICl,T·ChllmlH-,/mld I)'~ fillrT ronntcttd 11111
hllnd pump Ilnd uJed III (h~ Auttur Ins/illlle l/lWllrd III~ end ".f Ihe
tlitlclUlll1I ct"wl)'.
Figu~ 2.3 Lmis H1SICIlr, """11, 1I1I'lh Rf1hcr1 K«hJollndtd lilt disdplillC
".I miaubilll"K)'. PaslMU IIls11 lIf/mlllllcd (redl,etd vim/met in) sntl'ml
inJtclillllS agtnts, jndllding mbits vim.!, 1/1 mllke ~nts.
allowed calculation of ~ bacterium's size. Aftcr their identification, specific
bacteria could be linked with particular disease states. This was the framework
in which the first virusc:s were uncove~d. Just before the current cennlry
beg:ln, Dmiui losifovich Iv:movski (11 ) in Russia and Martinu5 Beijerinck
(12) in tbe Netherlands demomtrnted that the material responsible for a dis-
"
Figure 2.4 Fn'~drirlJ ~JfI" (riglrt) and his reacher om/ mrnlor Rohert
Koch (lift), who wilh Lollis PasU!4r crt:al~d Ihe fi eld of microbiology.
LoejJJn aud Hml Frosch isolated thtjirsllluimJl/ virus,fool~alld·maIUJr
virus, in 1898. Tht lIiniS was Jep~rrJltdfrom bacuri~ by lIS ability /0 plW
lilro/4gI/ Q Pasltljr- Chombrrlmrdjilter.
ease of tobacco plants instead of being retained passed through the pores of a
Pasteur-Chamherland filter without losing infectivity.The investigators found
that this soluble residue of filtr:ltioll could somehow grow on healthy tobacco
leaves. Their result was the first report of a plane virus, the tobacco mosaic
virus. Similarly, Friedrich Loeffler and Paul Frosch (13) in Germany concluded that the agent causing foot-and-mouth disease of cows also passed
through porcelain filte rs and induced symptoms of disease when inoculated
into previously healthy cattle. These observ:ltions, highly controversial at the
time. provided the basis for defining viruses as subcellular entities that could
cause distinct forms of tissue destruction, which became marks of specific
diseases.
Most viral infections are recognized as an acute illness. That is, the causative
virus enters the body, multiplies in one or more tissues, and spreads locally
through the blood or along nerves.The incubation period of two days to two
or three weeks is followed by signs and symptoms of disease and local or
widespread tissue damage. Viruses can be isolated from the patient's blood
(serum or blood cells) or secretions for a short time j ust before and after the
appearance of symptoms. Afterward, the infected host either recovers from
the infection and is often blessed with life-long immunity to that virus, or
dies during the acute phase of illness.
Distinct from acute infections are persistent infections in which the:
immune response fails to completely remove viruses from the body, lnd those
INTRODUCTION TO THE PRINCIPL.E. OF VIROL.OGY
15
Acute 1n1ectlon
(MUIIpoI, muaIn,. yellow mw, polio. . . .
,...", hMIff1)
TIm. (daya) --+
ChronlclPersiatent Infection
{HfVJ
Tim. (yeara)--+
Figure 2.5 Infectiom caused by villlSes differ. Some are acute and the
outcome is decided within a week or two. Others, /ike HIV, routinely rnn a
years-long infectious rourse in the human host. The darkened area indicates
the presence of virus.
remaining persist for months or years. As in the case of HIV infection, viruses
can be recovered for years throughout the long course of infection. Although
all components (antibodies and T cells) of the immune response are generated
during HIV infection, and for a considerable period of time the amount of
virus load is markedly reduced, the response is not capable of terminating the
infection. Then, during the terminal stage of the illness, T-cell immunity
declines or vanishes and a high viral load recurs. Figure 2.5 shows the differences between acute and persistent infection. How the immune response is
constituted and how it attacks viruses are described in the next chapter.