Family Poxviridae - Viruses And Human Disease

TABLE 7.3 Single-Stranded DNA Viruses

Hosta

Family

Genera

Genome size (kb)

Type species

Inoviridae

4.48.5

Inovirus

Enterobacteriaphage M13

Bacteria

Plectrovirus

Acholeplasma phage MV-L51

Mycoplasma

Microviridae

~4.46.0

Enterobacteria phage ΦΧ174

Microvirus

Bacteria

Spiromicrovirus

Spiroplasma phage 4

Spiroplasma

Bdellomicrovirus

Bdellovibrio phage MAC1

Bacteria

Chlamydiamicrovirus

Chlamydia phage 1

Bacteria

Geminiviridae

2.53.0

Mastrevirus

Maize streak

Plants

Curtovirus

Beet curly top

Plants

Begovirus

Bean golden mosaic-Puerto Rico

Plants

Topocuvirus

Tomato pseudo-curly top virus

Plants

Circoviridae

Circovirus

1.72.3

Porcine circovirus

Vertebrates

Gyrovirus

2.3

Chicken anemia

Vertebrates

[Unassigned genus]

Anellovirus

3.8

Torque teno

Vertebrates

[formerly Circoviridae]

Parvoviridae

4.06.0

Parvovirinae

See Table 7.16

Vertebrates

Densovirinae

Densovirus

Junonia coenia densovirus

Invertebrates

Iteravirus

Bombyx mori densovirus

Silkworms

Brevidensovirus

Aedes aegypti densovirus

Mosquitos

Vertebrates in red indicate humans are among the vertebrates infected. Vertebrates in blue indicate nonhuman hosts only.

a vigorous immune response. For such a strategy of long-

infect invertebrates (Table 7.1). Of the eight genera of the

term persistence to be successful, infection in the majority of

Chordopoxvirinae, seven contain viruses that infect mam-

hosts must be inapparent or cause only moderate symptoms

mals and one, Avipoxvirus, contains viruses that infect birds.

that are not unduly deleterious. Spread may be epidemic and

Only two human poxviruses (viruses for which humans are

accompanied by symptoms during primary infection, but for

the reservoir) are known, variola or smallpox virus, a mem-

some herpesviruses, vertical transmission to infant progeny

ber of the genus Orthopoxvirus, and molluscum contagio-

occurs without producing symptoms and persists for the life

sum virus, the only member of the genus Molluscipoxvirus.

of the animal. For such viruses, transmission needs to occur

The host range of any particular poxvirus is usually nar-

only once per generation for the virus to persist and a mini-

row. The two human poxviruses infect only humans in nature

mal population size is not required to maintain the virus in

and other poxviruses are similarly limited in their natural

nature.

host range. However, a number of mammalian poxviruses

whose primary host is not humans can cause natural, albeit

usually limited, infections of humans, and still other pox-

FAMILY POXVIRIDAE

viruses, including the avian poxviruses, can infect humans

under experimental conditions. Such mammalian and avian

The poxviruses are a very large family of dsDNA-con-

poxviruses have been used as agents for vaccination against

taining viruses that infect mammals, birds, and insects.

virulent human viruses (smallpox, described in detail later)

Eleven genera are recognized, eight of which are classi-

or as vectors to express foreign antigens for the purposes

fied as members of the subfamily Chordopoxvirinae and

of immunization (Chapter 11), because they normally cause

infect vertebrates (Table 7.4), and three of which are clas-

only a limited or an abortive infection of humans and can be

sified as members of the subfamily Entomopoxvirinae and

engineered to express foreign antigens.

TABLE 7.4 Poxviridae (Chordopoxvirinae: Poxviruses infecting vertebrates)

Genus/

Virus name

World

members

abbreviation

Usual host(s)

Transmission

Disease

distribution

Orthopoxvirus

Vaccinia

VACV

Unknown/humans, bovines

Contact

Localized lesions

Worldwide

Variola virus

VARV

Humans/none

Contact

Smallpox (now extinct)

Worldwide

Monkeypox

MPXV

Squirrels/humans, monkeys

Contact

Smallpox-like

West and Central

Africa

Cowpox

CPXV

Rodents/humans, cats,

Contact

Localized lesions

Europe, W. Asia

bovines, zoo animals

Camelpox

CMLV

Camels/none

Contact, aerosols

Localized lesions

Africa, Asia

Ectromelia

ECTV

Unknown/laboratory mouse

Contact, aerosols

Lesions plus

Europe

colonies, foxes, mink

disseminated disease

Volepox

VPXV

Voles/none

Contact

Western United States

Parapoxvirus

Orf

ORFV

Sheep/humans, ruminants

Contact

Localized lesions

Worldwide

Bovine papular stomatitis BPSV

Cattle/humans

Contact

Localized lesions

Worldwide

Pseudocowpox

PCPV

Cattle/humans

Contact

Localized lesions

Worldwide

Parapox of red deer

PVNZ

Red deer/none

Contact

New Zealand

Yatapoxvirus

MTBAb

Yaba monkey tumor

YMTV

Primates/human laboratory

Localized lesions

East and Central

infections

Many nodular

Africa

MTBAb

Tanapox

TANV

?Rodents/primates, humans

Molluscipoxvirus

Molluscum contagiosum MOCV

Humans/none

Contact, including

Worldwide

sexual transmission

lesions

Capripoxvirus

Sheeppox

SPPV

Sheep/none

Contact, fomites,

Asia, Africa

MTBA

Lumpy skin disease

LSDV

Cattle/none

Suipoxvirus

Swinepox

SWPV

Swine/none

MTBA, primarily

Generalized skin

Worldwide

by lice

disease

Leporipoxvirus

Myxoma

MYXV

Sylvilagus rabbits

MTBA, primarily

Benign tumors in

South America,

mosquitos

natural hosts, severe

Western United

disease in European

States, introduced

rabbits

into Australia

Rabbit fibroma

SFV

Sylvilagus rabbits

Eastern United

States

Benign tumors

MTBA

Hare fibroma

FIBV

European hare

Europe

in natural hosts

Squirrel fibroma

SQFV

Sciurus squirrels

Eastern and Western

United States

Avipoxvirus

Many species

Birds

Contact, MTBA

Lesions of skin and

Worldwide

including fowlpox

digestive tract

Hosts are listed as "reservoir host /other naturally infected hosts."

MTBA, mechanical transmission by arthropods.

The poxviruses are exceptional among eukaryotic DNA

Replication of Poxviruses

viruses because they replicate in the cytoplasm. The struc-

An overview of the poxvirus replication cycle is shown

ture of the virion is also unusual, being shaped like a brick

in Fig. 7.1. Following infection, an RNA polymerase within

rather than round or filamentous like most viruses. It has been

the core is activated by the release of the core into the cyto-

argued that the Poxviridae, Iridoviridae, Asfarviridae, and

plasm. This polymerase, together with accessory enzymes

Phycodnaviridae evolved from a common ancestor because

such as the capping enzyme and poly(A) polymerase,

they share a number of genes that distinguish them from other

synthesizes mRNAs that are capped and polyadenylated.

DNA viruses. The first three of these families contain viruses

These are extruded from the core and translated by the

of vertebrates that replicate in the cytoplasm, which as noted

host-cell machinery. Translation of early mRNAs leads to

is an unusual trait for DNA viruses, whereas the last family

further uncoating of the virus and the development of a

contains algal viruses that replicate in the nucleus.

regulatory pathway by which mid-cycle genes and finally

late genes are expressed. Early and mid-cycle functions

Structure of the Virion

include interference with host defense mechanisms and

the replication of the viral genome, whereas late genes are

Poxvirions are large and enveloped. They have a central

primarily involved with formation of progeny virions.

core containing the DNA complexed with multiple proteins.

Poxviruses have large genomes, from 130 to 380 kb, and

The core is biconcave in mammalian viruses (Figs. 2.1 and

encode hundreds of proteins. Because virus replication,

2.24). One or two lateral bodies (normally two in vertebrate

including DNA replication, occurs in the cytoplasm, pox-

viruses and one in invertebrate viruses) flank the core. These

viruses must encode all enzymes required for DNA replica-

contain proteins required for the initiation of viral replication.

tion and production of mRNAs. Thus, the encoded proteins

One or two viral envelopes, which contain a number of virus-

include DNA and RNA polymerases, a poly(A) polymer-

encoded glycoproteins, surround the core and lateral bodies.

ase to polyadenylate mRNAs, a capping enzyme, several

Altogether, virions contain 30 or more structural proteins.

enzymes with functions in nucleotide metabolism, protein

Vaccinia virus, which serves as a model for the family, is

kinases, DNA topoisomerases, as well as the proteins that

shaped like a brick with rounded edges and has dimensions

form components of the virion and the proteins that inter-

of approximately 360 × 270 × 250 nm. Two forms of infec-

fere with host defense mechanisms. Table 7.5 lists many

tious vaccinia virions are known, an intracellular form and

enzymatic proteins encoded by vaccinia virus and Table

an extracellular form. The intracellular form, referred to as

7.6 lists structural proteins and proteins without enzymatic

the intracellular mature virus or IMV, has a lipid-containing

activity. Poxvirus-encoded molecules that interfere with host

surface membrane and can be released by disruption of the

defenses are discussed in Chapter 10.

infected cell. The extracellular form, called the extracellu-

A schematic of the vaccinia virus genome is shown

lar enveloped virus or EEV, has a second, lipid-containing

in Fig. 7.2. It is double stranded and linear but the ends

envelope around it, which contains glycoproteins that are not

of the genome are covalently closed so that the genome

present in the intracellular form.

consists, in essence, of a very large single-stranded cir-

Vaccinia virus forms in viral factories in the cytoplasm

cular molecule that is self-complementary. The ends of

of the infected cell. A spherical immature virus 280 nm in

the genome possess inverted terminal repeats that are

diameter first forms in the cytoplasm whose surface mem-

involved in the initiation of DNA replication. A model

brane has been acquired from modified membranes called

for vaccinia DNA replication is shown in Fig. 7.3. The

crescents. Maturation of the immature virus to form the IMV

mechanisms by which DNA replication is initiated have

involves proteolytic cleavage by at least two viral proteases

not been completely worked out, but it is thought that a

that lead to the reorganization of the core and the lateral bod-

viral enzyme specifically nicks the DNA in or near the

ies and the formation of the brick-shaped structure. Some

terminal repetitions, and the 3′ end of the nicked DNA

IMV become further enveloped by a double membrane from

forms a primer for DNA synthesis. Continued elongation

the trans-Golgi or early tubular endosomes, the outer of

of the DNA chain leads to production of concatenated

which is lost as the virus exits the cell to become the EEV.

progeny DNA. These concatamers must subsequently be

Both IMV and EEV are infectious but attach to cells differ-

resolved into genome-length segments whose ends are

ently. The extra membrane in EEV helps to protect the virus

then covalently closed.

from immune surveillance.

Replication of DNA and assembly of progeny virions

The cellular receptors used by poxviruses to enter cells

occurs in what have been called viral factories in the cyto-

have not been characterized. The virus enters by fusion of

plasm. These are electron-dense areas that contain viral DNA

the IMV membrane with the cell plasma membrane. In the

and membranes. Progeny DNA is assembled into cores and

case of EEV, the outer membrane is first disrupted upon

assembly of virions occurs by condensation of membranes

binding to cellular receptors, allowing the IMV membrane to

around the viral core as described before.

fuse with the plasma membrane.

Infecting vaccinia virion

Growth factors,

2. Early mRNA

immune

1. Entry

defense

molecules

Transcription

5. Intermediate mRNA

(Steps 2, 5, and 6)

3. Uncoating

6. Late mRNA

4. DNA Replication

7. Translation

Late enzymes

Structural proteins

8. Assembly

9. Concatemer

NUCLEUS

resolution

10. DNA

Packaging

11. Maturation

12. Golgi wrapping

EUKARYOTIC HOST CELL

13. Exit

Virion-associated

enzymes

Progeny

RNA polymerase

vaccinia

Transcription factors

virions

Capping enzyme

Poly(A) polymerase

FIGURE 7.1

The replication cycle of vaccinia virus. Sequential steps are numbered in order. Note that despite the fact

that vaccinia is a DNA virus, the entire replication cycle takes place in the cytoplasm. Adapted from Fields et al. (1996)

p. 2638.

Interactions with the Host

factor), with the cytokine system so as to prevent an inflam-

Poxviruses produce proteins that stimulate cell develop-

matory response to the virus, or with the induction of apop-

ment and proliferation. Many poxviruses produce homo-

tosis (programmed cell death), among others. The discovery

logues of epidermal growth factor, which are excreted from

of proteins that interfere with host defenses is fairly recent,

the infected cell. Binding of this factor to its receptor induces

and intensive studies are ongoing to understand the full

the cell to enter pathways leading to proliferation and differ-

extent of viral inhibition of host defenses. The complexity

entiation. At least one poxvirus, orf virus, produces a homo-

of the interference by the virus with host antiviral defenses is

logue of vascular endothelial growth factor, which again

illustrated by the recent discovery that a viral protein called

induces cell proliferation upon binding to its receptor.

CrmB encoded by variola virus, which was known to be a

Poxviruses also produce a large number of proteins

homologue of the receptor for TNF and to inhibit the activ-

whose function is to interfere with the host immune system.

ity of TNF by binding to it, has a separate domain that binds

Vaccinia virus, variola virus, and other poxviruses encode

a number of chemokines and inhibits their activity as well.

proteins that interfere with the complement system, with the

Thus, this single protein inhibits a number of host defense

interferon system, with the activity of TNF (tumor necrosis

molecules. This discovery led to the further discovery that

TABLE 7.5 Vaccinia-Encoded Enzymes

Functional group

ORFa

name of enzyme

Properties

DNA Replication

DNA polymerase

E9L

110

Protein kinase

B1R

Phosphorylates H5R

Unknown

D5R

Replication fork, ATP/GTP binding motif A

Uracil DNA glycosylase

D4R

Nicking-joining enzyme

Concatemer resolution

DNA toposiomerase

H6R

ssDNA binding protein

I3L

DNA ligase

A50R

Nonessential

DNA helicase

A18R

DNA-dependent ATPase

Early DNA-related metabolism

Thymidine kinase

J2R

Thymidylate kinase

A4w8R

Ribonucleotide reductase

Provide dNTPs

I4L

Large subunit

F4l

Small subunit

dUTP® dUMP, downregulate dUTP

dUTPase

F2L

DNA repair?

D9R

hydrolyze 8-oxo-GTP

D10R

NPH Ib

DNA dependent NTPase

D11L

RNA Transcription

RNA polymerase

Multisubunit enzyme

RPO147

J6R

147

RPO132

A24R

133

RPO35

A29L

RPO30

E4L

Transcription factor

RPO22

J4R

RPO19

A5R

RPO18

D7R

RNA polymerase-associated protein

H4L

RAP94, early promoter-specificity factor

Early transcription factor

DNA-dependent ATPase

A7L

ETR subunit 1

D6R

ETR subunit II

Poly(A) polymerase

E1L

Catalytic subunit

J3R

Stimulatory subunit, methyltransferase

Capping enzyme

RNA triphosphatase, guanyltransferase

D1R

Large subunit, catalytic activities

D12L

Small subunit, stimulates transferase

NPH IIb

RNA/DNA dependent NTPase

I8R

Protein kinase 2

F10L

Phosphorylates serines and threonines

Glutaredoxin

O2L

Thioltransferase, dehydroascorbate reductase

ORFs are named and color coded according to the restriction map shown in Fig. 7.2.

NPH, nucleoside triphosphate phosphohydrolase.

Source: Adapted from Fields et al. (1996) Table 3 on p. 2645 and data from Goebel et al. (1990).

TABLE 7.6 Vaccinia-Encoded

Inverted repeat

Unique sequences

Nonenzymatic Components

160,000 bp

10,000 bp

Location in

ORFa

Properties

virion

N K

Membrane of

I5L

8.7

Hydrophobic

intracellular

L1R

27.3

Myristylated, hydrophobic

I G

mature virus

H3L

37.5

Hydrophobic

Tandem repeats

H5R

22.3

Phosphorylated by B1R to

give 3436 kD

900 bp

1300 bp

900 bp

D8L

35.3

Cell-surface binding, virulence

FIGURE 7.2 Schematic representation of the DNA of vaccinia virus.

D13L

61.9

Rifampicin resistance

Upper part: linear double-stranded DNA with terminal hairpins and inverted

A13L

7.7

Oligomeric

repeats (not to scale). Center line is the HindIII restriction map (* indicates

the TK gene). Color coding of the HindIII fragments is the same as that

A14L

10.0

Oligomeric

used in Tables 7.5 and 7.6. Lower line diagrams the internal structure of the

A17L

23.0

Dimer, neutralizing epitope

terminal repeats. Adapted from Fenner et al. (1988).

A27L

12.6

Fusion protein, neutralizing

epitope, required for EEV,

nonessential

Core of intracellular

F17R

11.3

Phosphoprotein, DNA

mature virus

binding

Genus Orthopoxvirus

I7L

49.0

Homology to toposiomerase II

The best known poxviruses are the orthopoxviruses.

G7L

41.9

Processed

Vaccinia virus has been widely studied in the laboratory as a

L4R

28.5

Structural protein VP8

model for the replication of poxviruses and has been used to

D2L

16.9

immunize hundreds of millions of people against smallpox

D3R

28.0

virus, also known as variola (from the Latin word for "spot-

A3L

72.6

Major core protein P4b

ted"). The extensive knowledge of vaccinia virus gained

A4L

30.8

from laboratory and clinical studies has also led to its use

A10L

102.3

Major core protein P4a

as a vector to express foreign antigens in cultured cells or in

animals (Chapter 11). Other members of the genus infect a

A12L

20.5

Processed

variety of domestic and wild animals (Table 7.4). Two simi-

Specific to enveloped

F13L

41.8

Envelope antigen

extracellular virus

larity trees are shown in Fig. 7.4. One illustrates the rela-

A34R

19.5

N-glycosylated, homologous

(EEV)

tionships among the genera of the Chordopoxvirinae, and

to lectin, EEV release

the second illustrates the relationships among the orthopox-

A36R

25.1

viruses. All orthopoxviruses are sufficiently closely related

A56R

34.8

N- and O-glycosylated,

that they are cross protective.

hemagglutinin, nonessential

B5R

35.1

Complement control protein,

required for EEV,

Smallpox Disease

homologue to C3L

Smallpox once caused vast epidemics in human popula-

ORFs are named and color coded according to the restriction map shown

tions. It was already endemic in India 2000 years ago and had

in Fig. 7.2.

spread to China, Japan, Europe, and northern Africa by 700

Source: Adapted from Fields et al. (1996) Table 2 on p. 2643 with

A.D. It was introduced into the New World by the Europeans

additional information from Goebel et al. (1990).

during their explorations and settlement. Infection resulted in

a fatality rate of 2030% in most populations and at one time

the virus infected virtually the entire population of Europe.

Thus, the virus was responsible for a significant fraction of

all human deaths on the Continent. Data from London in

the 1700s show that, depending on the year, between 4 and

variola and other poxviruses produce a family of chemo-

18% of all deaths in the city were due to smallpox. When

kine inhibitors. It is clear that these various viral functions

introduced into virgin populations in the New World, the

are required for successful viral infection of their hosts in

mortality rate was much higher, probably due in part to a

nature, and the existence of these viral activities has been

lack of previous selection for resistance to smallpox and

very useful for our understanding of host defenses against

in part due to the breakdown of the social system caused

viral infection. We will return to this topic in Chapter 10.

ZC B A

ABCD

zc b a

bc d

Nick of 3 strand

Primer extension

ZC B A

c b a ABCD

zc b a

CBAabc d

Loopback as primer

Z BA

c b a ABCD

ABC

cz a

abc d

Elongation through hairpin

BCD

CBA

abc

Nick at arrowhead to

Complex

start second round

Z cba

Concatemers

Simple concatemer forma-

tion

dcba

ABCD

abc d

DAB C

Resolve concatemers

ZC B A

abc z

dcba

ABCD

abcd

zc b a

ABCZ

DCBA

FIGURE 7.3 Model for the replication of orthopox DNA. Replication is initiated by nicking one strand at the red arrow

near the left end of the DNA. This is followed by primer extension and loopback to form an internal primer. Extension

then occurs through the hairpin at the right end of the molecule to form a concatemer. Concatemer resolution occurs by

nicking at the blue arrows. Parental DNA is shown in blue, new strands in red. Redrawn from data in Moyer and Graves

(1981) and Traktman (1990).

by the simultaneous infection of most of the population.

of the Americas by the Europeans was discussed in

As one example, smallpox coming up from Mexico swept

Chapter 4. A detailed description of the effect of smallpox

across the high plains of the western United States in the

virus on human civilization through the ages can be found

late 1700s, reducing the population of the Mandan, Ojibwa,

in the book Princes and Peasants: Smallpox in History by

Pawnee, Arikara, and other tribes by as much as two-thirds.

D.R. Hopkins. The history of nations has often been changed

Then in 1837 an epidemic of smallpox in Native American

by the early death of rulers from smallpox or from the appear-

populations along the upper Missouri River began with its

ance of smallpox in armies. As one example of interest to

introduction by passengers on a steamboat that came upriver

Americans, an invasion of Canada by American troops dur-

from St. Louis. In this epidemic it is estimated that 99% of

ing the Revolutionary War, with the idea of adding Canada

the Mandan died and half of the Hidatsa and Arikara. Other

to the American colonies, failed in part because an epidemic

tribes also suffered enormous losses leading to the depopu-

of smallpox swept through the American troops.

lation of the region. The importance of smallpox, measles,

Smallpox virus was exclusively a human virus, maintained

and other Old World plagues in the conquest and settlement

by person-to-person contact, and recovery from the disease

Chordopoxvirinae

Orthopoxviruses

Crocodilepox

CRV

Avipox

Camelpox

CNPV

FWPV

Variola major

Molluscipox

Monkeypox

Variola minor

MOCV

Parapox

ORFV

BPSV

Vaccinia

Suipox

SWPV

Capripox

Orthopox

Cowpox

SPPV

LSDV

VACV

ECTV

YLDV

Yatapox

Ectromelia

YMTV

0.02

0.2

SFV MYXV

changes per residue

Leporipox

FIGURE 7.4 Phylogenetic trees of the Chordopoxvirinae. (A) Unrooted tree illustrating the relationships between the

various genera. Eighty-three proteins from crocodilepox were aligned with similar data sets from other Chordopoxvirinae

using the program MUSCLE. Adapted from Afonso et al. (2006) Figure 5. (B) Unrooted tree of the Orthopox genus from

aligned coding sequences of the DNA polymerase gene. Adapted from Chen et al. (2003) Figure 3. Virus abbreviations:

CRV, crocodilepox; CNPV, canarypox; FWPV, fowlpox; ORFV, Orf; BPSV, bovine papular stomatitis; VACV, vaccinia;

ECTV, ectromelia; YLDV, Yaba-like disease; YMTV, Yaba monkey tumor; MYXV, myxoma; SFV, Shope fibroma;

LSDV, lumpy skin disease; SPPV, sheeppox; SWPV, swinepox; MOCV, molluscum contagiosum. Domains in (A) and

virus names in (B) are color coded by host, blue for vertebrates; pink and red for primates including humans; and purple

for birds. Scales indicate approximate number of changes per amino acid residue.

resulted in lifelong immunity to the virus. Thus, it was a dis-

7.5B is a photograph of a man who was blinded by smallpox

ease of civilization. As was described for measles virus, it

infection and illustrates the extent of facial scarring that can

must have originated from a nonhuman poxvirus, possibly a

occur as a result of smallpox.

poxvirus of a domesticated animal, at the time that the devel-

opment of human civilization led to the presence of large pop-

Immunization against Smallpox

ulation centers and the domestication of animals.

Although infection by smallpox begins as an upper res-

So great was the fear caused by smallpox that a technique

piratory disease, spread by aerosolization of virus shed from

of immunization was developed by the tenth century, called

skin poxes, infection becomes systemic and many organs are

variolation, in which people were deliberately infected by

infected. The virus replicates extensively in the skin, leading

smallpox using dried skin from pox lesions. The infecting

to pocks that can cover the entire body. These pocks leave

virus was delivered by blowing the inoculum up the nose

scars, particularly in the facial area, which mark a person for

or by inoculation into the skin. Infection via either method

life, and at one time the fear of scarring on recovery from

led to relatively low mortality, about 12% compared with

smallpox appears to have been at least as terrifying as the fear

2030% following natural infection, and the disease was

of death caused by the disease. A photograph of an infected

milder with less scarring.

child in Fig. 7.5A, taken on the eighth day of rash, illustrates

Jenner developed the modern concept of vaccination when

the ubiquitous nature of pox formation that can occur. Figure

he introduced and popularized the use of cowpox virus as a

FIGURE 7.5 Effects of smallpox. (A) Child with smallpox, on the eighth day of the rash. The rash began to develop

one day after the onset of fever. From Fenner et al. (1988) p. 15. (B) Adult after recovery, who is now blind and has deeply

pigmented pocks. From Fenner et al. (1988) p. 57.

vaccine against smallpox. It was known that milkmaids had

Vaccinia virus infection is localized to the area inoculated

beautiful complexions because they never contracted small-

in the vast majority of people, leading to a localized lesion

pox, and there was some evidence that their resistance to

that results in a pock. This vaccination procedure gave

smallpox resulted from infection with cowpox virus, which

solid immunity against smallpox but because of the limited

was occupationally acquired. In milkmaids, cowpox virus

replication of the virus in humans, the immunity was not

caused localized lesions, usually on the hands where they

considered to be lifelong and periodic reimmunization was

came in direct contact with the virus during milking, but the

practiced. Vaccinia virus has been used to immunize hun-

lesions did not spread. The virus is antigenically related to

dreds of millions of people over the years. It is generally

smallpox virus and will protect against infection with small-

safe, but infection of a small fraction of people results in

pox. Jenner's investigation in the 1790s included inoculation

a more serious disease. The most serious reaction in peo-

of a young boy with cowpox virus and then challenging him

ple with apparently normal immune systems is encephalitis,

with virulent smallpox virus, to which the boy was found

which is usually fatal but very rare (1 in a million vaccinees).

to be resistant, an experiment that could not be performed

Skin rash occurs more often but is not life threatening. In

today because of ethical considerations.

people whose immune system is impaired, progressive vac-

Jenner then introduced cowpox virus as a vaccine against

cinia may develop because the individual cannot control the

smallpox in the general population. This concept was contro-

replication of the virus, which results in a fatal illness.

versial at first, but gradually won widespread acceptance. The

virus now used for immunization is referred to as vaccinia,

Eradication of Smallpox

derived from the Latin name for cow. However, the relationship

between modern vaccinia virus and cowpox virus is a mystery.

Following the introduction of vaccination, the incidence

At some time in the last century, the source of the virus was

of smallpox declined and the virus was largely eliminated

changed and no one knows where vaccinia virus came from.

from developed countries. Interestingly, there also appeared

Modern vaccinia virus exhibits a fairly wide experimental host

a variant of smallpox that produced only a 1% mortality rate,

range. It has been suggested that it was derived from a domestic

called variola minor or alastrim (from the Portuguese word

animal other than the cow, perhaps a horse.

meaning something that "burns like tinder, scatters, and

Jenner "vaccinated" people by placing a drop of vaccinia-

spreads from place to place"). Variola minor was endemic in

containing solution on the skin and then scarifying the skin

Africa and the Americas and coexisted with variola major.

in some way, allowing the virus to replicate in this region.

Beginning in the 1960s, the World Health Organization

(WHO) began an intensive campaign to eradicate smallpox

the rationale being that smallpox virus represents a great

virus from human populations. Such a campaign was pos-

threat to the human population, which is now largely non-

sible because smallpox was exclusively a human virus, there

vaccinated and within another generation will be completely

was only a single serotype, vaccination with vaccinia virus

susceptible to infection by smallpox. If the virus were to be

was safe and effective, and inapparent infection was virtually

released, whether accidentally or deliberately, it could again

unknown. Every case of smallpox was tracked down, infected

cause devastating epidemics. However, the original date for

patients were quarantined, and all contacts were immunized

destruction of viral stocks has already passed and the dead-

against smallpox. Over a period of about 10 years, smallpox

line has been extended more than once. This issue has been

epidemics became less frequent and more completely con-

controversial because many scientists believe that further

tained until finally the virus was, in fact, eliminated (Fig.

useful information can be obtained from the study of small-

7.6). The last case of natural smallpox occurred in 1977, and

pox virus. The genes that block human antiviral defenses

vaccination against the virus is no longer practiced because

have only recently been described, for example, and there are

of the possible side effects of the vaccine. Smallpox is the

surely secrets of viral virulence that we do not understand.

first virus to be deliberately exterminated, and the effort and

Furthermore, new forms of smallpox virus might arise. For

dedication required to accomplish this were remarkable.

example, monkeypox virus causes a disease in humans that

is similar to smallpox but with greatly reduced transmissi-

bility. Variants or recombinants able to spread more readily

What Do We Do Now?

could well arise. (Could this have been the origin of small-

The remaining, known stocks of smallpox virus are now

pox in the first place?) Thirdly, there is no guarantee that if

stored in two laboratories, the Centers for Disease Control

the known smallpox stocks in the United States or in Russia

and Prevention in Atlanta and the Vector Laboratories

were destroyed, smallpox virus would cease to exist. There

in Novosibirsk. These viruses are still being worked with

may be other stocks in laboratories around the world (the

and there is an effort being made to sequence many dif-

virus was very widespread at one time and extensively stud-

ferent strains of the virus and to obtain cDNA clones of

ied). It is known that the Russians weaponized smallpox at

them. The WHO has adopted the principle that all remain-

one time, and the virus would make a good agent for bioter-

ing stocks of smallpox should at some time be destroyed,

rorists, an all-too-real concern in today's world.

(1)

(2)

(3)

Africa

Asia

Europe

Americas

Oceania

1923

Year

FIGURE 7.6 Number of countries reporting the occurrence of endemic smallpox between 1923 and 1978, grouped by

continents. (1) marks the WHO resolution on global smallpox eradication in 1959; (2) shows the start of the intensified

eradication program in 1967; (3) marks the last case of smallpox on October 22, 1977 in Somalia. From Fenner (1983).

Because of concerns that smallpox might reappear, there

It infects humans under natural conditions but was thought

is a need to develop new vaccines against it. Although small-

to be only a rare zoonosis. The disease in humans caused

pox was eradicated using vaccinia virus as a vaccine, the

by monkeypox virus is clinically very similar to smallpox,

virus is more reactogenic than is tolerated in modern vac-

and it was not recognized as a distinct human pathogen until

cines, and the production of the vaccine uses outmoded tech-

the eradication of smallpox in Africa. There are two strains

nology. Further, people with an impaired immune system, an

of monkeypox virus, a West African strain found in Sierra

increasing fraction of the population, cannot be given vac-

Leone, Nigeria, Liberia, Ivory Coast, and Gambia and a

cinia virus. To develop a new vaccine that is safe and effec-

central African strain found in Zaire (now the Democratic

tive, an animal model is important. A model of smallpox

Republic of Congo) and the Central African Republic. The

disease in cynomolgus macaques has been developed, using

West African virus causes many fewer cases and the cases

infection by variola virus itself, another reason to keep stocks

are less severe with no deaths reported to date. The cen-

of the virus. Approaches to producing an effective vaccine

tral African strain has caused almost a thousand cases of

that is safer than vaccinia include using highly attenuated

severe disease since 1970 with a fatality rate of about 10%

virus. One approach is to use replication incompetent virus

in individuals who had not been vaccinated for smallpox.

as a possible vaccine. Replication incompetent viruses can

Epidemics of monkeypox in the Democratic Republic of

be derived from vaccinia virus by deleting essential genes,

Congo in 19961998 resulted in about 400 cases of disease.

and viruses such as canarypox virus are inherently replica-

The first wave of these epidemics lasted from February to

tion incompetent in mammals. Such vaccine candidates can

August 1996 and involved 89 cases of clinical disease with

now be tested in a monkey model for their effectiveness in

six deaths. A follow-up investigation of monkeypox in the

preventing disease following smallpox infection.

area in February 1997, which included a hut-by-hut search for

active cases in 12 villages, gave evidence that up to 73% of

monkeypox cases resulted from secondary human-to-human

Monkeypox Virus

transmission (Fig. 7.7). Furthermore, three of the deaths

Monkeypox virus was thought to be a virus of monkeys

were in children less than 3 years old and a large propor-

but is now known to be associated with squirrels and rodents.

tion of cases were in persons <15 years old. Thus, it appears

Secondary Cases

Primary Cases

Feb Mar Apr May June July Aug Sept Oct Nov Dec

Jan Feb

1996

1997

Month of rash

FIGURE 7.7 Number of monkeypox cases by date of rash onset in 12 villages in the Katako-Kombe health zone, Kasai-

Oriental, Zaire, February 1996February 1997. Note that most of the cases are secondary cases resulting from human-to-

human transmission. From MMWR (1997).

that the outbreak is the result of the cessation of vaccination

pox in this epidemic, 30 persons were immunized with the

against smallpox in the late 1970s, since smallpox vaccina-

smallpox vaccine. These vaccines included veterinarians,

tion is also protective against monkeypox. Monkeypox virus

health care workers, laboratory workers, and household con-

is therefore a human pathogen that can cause fatal illness,

tacts of patients. One vaccinee, who reported a rash, was

spread from person to person, and cause outbreaks of disease

confirmed as having monkeypox.

in susceptible populations. To date, spread has been limited,

but the potential for wider spread exits if the virus mutates so

Molluscum Contagiosum

that it is more readily transmissible from person to person.

Molluscum contagiosum virus is the sole representative

of the genus Molluscipoxvirus. It is a widely distributed

Monkeypox in the United States

human virus that is spread by contact, including sexual con-

tact. The virus causes a skin disease characterized by raised

An outbreak of monkeypox virus occurred in the

lesions. The disease is chronic but usually resolves within

Midwestern United States in 2003. The virus was imported

a few months, and the illness is considered to be trivial in

with a shipment from Ghana of more than 700 squirrels and

immunocompetent individuals. In HIV-infected patients,

rodents that included Gambian giant rats, rope squirrels,

however, the disease can be more troublesome. It has not

brushtail porcupines, tree squirrels, striped mice, and dor-

been possible to grow the virus in cultured cells, and all

mice. These animals, at least some of which were infected

virus for laboratory study has been derived from lesions of

with monkeypox, were intended as pets and were distributed

infected individuals, which usually contain large amounts of

to many states. One such transfer of some Gambian giant

virus. Despite this limitation, the genome of the virus has

rats and dormice went to a facility in Illinois where they

been completely sequenced and molecular biological studies

were housed in the vicinity of U.S. prairie dogs that were

are under way.

also intended as pets. The prairie dogs became infected by

the virus and were subsequently distributed in seven states

including Illinois. A total of 71 people in six states became

Rabbit Myxoma Virus

ill with monkeypox contracted from the prairie dogs, 18 of

Rabbit myxoma virus, a member of the genus

whom were hospitalized. Half of the cases were confirmed

Leporipoxvirus, has been widely used in Australia to control

by laboratory testing (Fig. 7.8). There were no deaths from

populations of the European rabbit, which was introduced

this West African strain of monkeypox, which as described

with disastrous results into Australia by European settlers.

causes a milder illness in humans than does the Central

The history of the virus in Australia represents a facinating

African strain. To prevent the continuing spread of monkey-

Suspect

Probable

Confirmed

23 25

May

June

FIGURE 7.8

Number of monkeypox cases by date of illness onset during May and June of 2003 in Illinois, Indiana,

Kansas, Missouri, Ohio, and Wisconsin, reported as of July 8, 2003. Date of onset was unknown for two additional cases.

From MMWR (2003) Vol. 52, p. 642.

story of viral evolution in the field and is one of the best

in which people went out in large groups and killed as many

studied examples of coevolution of both a virus and its host.

rabbits as possible were undertaken in order to reduce the

The story has important implications for our understanding

rabbit population, but it was a losing game. To make matters

of virushost interactions.

worse, the introduced foxes preferred the Australian fauna

Rabbit myxoma virus is native to the Americas, where

to the introduced rabbits anyway, and constituted a second

it causes a localized skin fibroma in American rabbits. The

plague on the native fauna, which have not evolved to deal

virus is mechanically transmitted by mosquitoes. It does not

with mammalian predators.

replicate in the mosquito (it is not an arbovirus), but the mos-

In an effort to eliminate or control the rabbit population,

quito can transmit the virus when mouthparts become con-

rabbit myxoma virus was introduced. At first this strategy

taminated by feeding on an infected rabbit with skin lesions.

was very successful and the rabbit population was reduced

It was discovered early that, although the virus causes a triv-

by an estimated 95%. It was believed that the virus would

ial illness in American rabbits, it causes a systemic infection

have to be broadcast every year in order to continue the cam-

in European rabbits that is fatal more than 99% of the time,

paign against the rabbits, but there was hope that the rab-

a disease called myxomatosis.

bit plague would end. However, soon after its release, new

In Australia, a land of marsupials, the European rabbit

strains of virus arose that were less virulent, as illustrated in

was introduced for hunting or as potential food for foxes,

Fig. 7.9. These strains prevailed because they persisted more

which in turn had been introduced for the pleasures of fox

successfully in the rabbit population--less virulent viruses

hunting. The rabbits multiplied as rabbits proverbially do

remained within a host longer and were transmitted to new

and became a plague. The enormous populations of these

rabbits more successfully than virus that rapidly killed its

introduced rabbits depleted agricultural crops and also

host. Furthermore, rabbits that survived infection with the

threatened to overwhelm a number of Australian marsupials

less virulent strains were now immune to the virulent virus,

by competing with them for the food supply. A significant

making it more difficult to control the rabbits by reintroduc-

percentage of Australian native mammals have gone extinct

tion of a virulent strain (although rabbits have a short life

and rabbits have played an important role in the extinction of

span and herd immunity is not very important in resistance

a number of them. Rabbits have also caused problems from

to disease). With time the virus became progressively less

erosion by depleting large areas of ground cover. Campaigns

virulent but, interestingly, strains of very low virulence never

100

% Fatality MDOD

<13

>99%

Grade 1

95-99% 14-16

Grade 2

70-95% 17-28

Grade 3

50-70% 29-50

Grade 4

<50%

Grade 5

1950

1954

1957

1960

1965

1968

1972

1978

Year

FIGURE 7.9 Virulence of field isolates of myxomatosis virus over a number of years in Australia after the introduction

of a grade 1 virus for biological control in 1950. Field isolates were classed as belonging to one of the five grades of

virulence on the basis of average survival times (MDOD = mean day of death) of six laboratory rabbits inoculated with

each isolate. This measure closely correlates with case fatality rates (which defined the original grades of virulence).

Isolates were collected over intervals of 3 to 5 years, and the collective data for each interval are plotted at a year in the

midpoint of the interval. Data from Fenner (1983).

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