Poxviridae

Properties of Poxviridae 348

Pathogenesis and Immunity 352

La bora tory Diagn osis 352

Human Infections with Orthopoxviruses 353

Human Infections with Parapoxviruses 356

Molluscum Contagiosum 356

Yabapox and Tana pox 357

The family Poxviridae is divided into two subfamilies, Clmrdopoxviriniie (poxviruses of vertebrates) and Eiitoniopoxvirinae (poxviruses of insects); only the former are of importance in medicine. The subfamily Chordopoxvirinae contains eight genera, distinguished on the basis of genetic, antigenic, and morphologic differences. Several poxviruses causes diseases in humans: smallpox (now extinct), vaccinia (including a strain called buffalopox virus), monkeypox, molluscum contagiosum, cowpox, milker's nodes, orf, and tanapox (Table 21-1). Smallpox and molluscum contagiosum are specifically human diseases; the others are zoonoses.

All diseases caused by poxviruses are associated with skin lesions, which may be localized or may be part of a generalized rash, as in smallpox and human monkeypox. Smallpox, once one of the great plagues of mankind, which has played an important role in human history and a central role in the development of virology, was eradicated from the world in J 977 (see Chapter 15) and is not further discussed.

Properties of Poxviridae

The poxviruses are the largest and most complex of all viruses. Figure 21-1 A,C,D illustrates the structure of the brick-shaped virion of vaccinia virus, which is characteristic of that of all the poxviruses affecting humans except those belonging to the genus Parnpoxvirus, shown in Fig. 21-1B. There is no nucleocapsid conforming to either of the two types of symmetry found in

Table 21-1

Diseases Produced in Humans bv Poxviruses

Genus

Disease

Clinical features

Oilhopiixviru^

Ptirapowmrf

Mol/uscifxni'irus Yrrlaptm'irus

Smallpox (now extinct) Variola major

Variola minor

Vaccination (vaccinia) Complications (rare)

Monkeypox Cow pox Milker's nodes Orf

Molluscum contagiosum Yabapox

Tana pox

Generalized infection with pustular rash; case-

fatalily rale 10-25% GeneTati/ed infection with pustular rash, case-

fatality rate •= 1% Local pustule, slight malaise

Postvaccinia! encephalitis, high mortality Progressive vaccinia; high mortality Eczema vaccinatum; low mortality Auloinoculation and generalized vamma, nonlelhal

Generalized with pustular rash, case-fatality rate 15%

Localised ulcerating inlection of skin, usually acquired from cows or cats Trivial localized nodular infection of hands acquired from cows Localized papulovesicular lesion of skin acquired from sheep Multiple benign nodules in skin Localized skin tumors acquired from monkeys (rare)

Localized skin lesions probably from arthio-pod bites; common in parts of Africa most other viruses; hence, the virion is sometimes called a "complex" virion. An outer membrane of tubular-shaped lipoprotein subunits, arranged rather irregularly, encloses a dumbbell-shaped core and two "lateral bodies" of unknown nature. The core contains the vtral DNA and associated proteins. Especially in particles released naturally from cells, rather than by cellular disruption, there is an envelope (Fig. 21-1D) which contains cellular lipids and several virus-specified polypeptides.

The nucleic acid is dsDNA (Table 21-2), varying m size from 130 kbp for parapoxviruses io 220 kbp for cowpox virus; the DNA of vaccinia virus (191,636 bp) and variola virus (186, 102bp) have been completely sequenced. Restriction endonuclease maps of the genome provide the definitive criterion for the allocation of strains to a particular species of the genus Orthopoxvirus (e.g., cowpox virus, which may infect many different species of animals); species of Parapoxvtrus cannot be so readily grouped in this way.

There are over 100 different polypeptides in the virion. The core proteins include a transcriptase and several other enzymes, and numerous antigens are recognizable by immunodiffusion. The lipoprotein outer membrane of the virion is synthesized dc novo, not derived by budding from cellular membranes; the envelope, when present, is derived from membranes of the Golgi apparatus but contains several virus-specific polypeptides. Most of the pro-

Poxviridae

Fig. 21-1 Poxviridae (A) Negatively stained vaccinia virion, showing surface structure of rodlets or tubules characteristic of the outer membrane of the genera Orthopoxvirus, Mollusitpoxvirus, and ><iffl/»<m'jnf,v (B) Negatively stained orf virion, showing characteristic surface structure of the outer membrane of the genus Parapoxvmis (C) Thin section of vaccinia virion in its narrow aspect, showing Ibe biconcave core (r) and the two lateral bodies (lb) (I.)) Thin section of mature extracellular vaccinia virion lying between two cells The virion is enclosed by an envelope originating from altered Golgi membranes, bar Kit) nm [A, D, From S Dales, / Cell Biol 18, 51 (1963); B, from J Nagmgton, A A. Newton, and R W J lorne. Virology 23,461 (1964); C, from B G T Pogo and S Dales, Pm Nat) Acad Sri USA 63, 820 (1969) /

Fig. 21-1 Poxviridae (A) Negatively stained vaccinia virion, showing surface structure of rodlets or tubules characteristic of the outer membrane of the genera Orthopoxvirus, Mollusitpoxvirus, and ><iffl/»<m'jnf,v (B) Negatively stained orf virion, showing characteristic surface structure of the outer membrane of the genus Parapoxvmis (C) Thin section of vaccinia virion in its narrow aspect, showing Ibe biconcave core (r) and the two lateral bodies (lb) (I.)) Thin section of mature extracellular vaccinia virion lying between two cells The virion is enclosed by an envelope originating from altered Golgi membranes, bar Kit) nm [A, D, From S Dales, / Cell Biol 18, 51 (1963); B, from J Nagmgton, A A. Newton, and R W J lorne. Virology 23,461 (1964); C, from B G T Pogo and S Dales, Pm Nat) Acad Sri USA 63, 820 (1969) /

teins are common to all members of any one genus, although each species is characterized by certain specific polypeptides, whereas a few others appear to be shared by all poxviruses of vertebrates. There is extensive cross-neutralization and cross-protection between viruses belonging to the same genus, but none between viruses of different genera. Genetic recombination

Table 21-2

Properties of Poxviruses of Vertebrates

1 ight genera, members of genera Oi/frdpiuein/s, /'rmipoH'uiis, Ynln/nOTiMe;, and Mollii^cipoxvirus infect humans

Most genera virion brick-shaped with rounded corneis, 250 x 200 x 200 nm, irregular arrange-menl of tubules on outer membrane, />?frr/wnr'/r/rs virion ovoid, 260 x nm, with regular spiral arrangement of tubule on outer membrane Complex structure with core, lateral bodies, outei membrane, and sometimes envelope Linear dsDNA, 130 kbp (Pnmpoxvirns), 170-250 kbp (Orf/m/winis)

Iranscriplase, transcription factor, poly(A) polyineiase, capping enzyme, methylating en/ymes in virion

Cytoplasmic replication, enveloped particles released by exocytosis, nonenveloped particles released by cell lysis occurs readily between viruses of the same genus, but rarely between those of different genera.

Poxviruses are resistant to ambient temperatures and may survive many years in dried scabs. Orthopoxviruses are ether-resistant, but parapoxviruses are ether-sensitive.

Viral Replication

Replication of poxviruses occurs in the cytoplasm and can be demonstrated in enucleate cells. To achieve this total independence from the cell nucleus, poxviruses, unlike other DNA viruses, have evolved to encode dozens of enzymes required for transcription and replication of the viral genome, several of which must be carried in the virion itself. After fusion of the virion with the plasma membrane or via endocytosis, the viral core is released into the cytoplasm (Fig. 21-2).

Transcription is initiated by the viral transcriptase, and a transcription factor, capping and methylating enzymes, and a poly(A) polymerase also carried in the core of the virion enable functional capped and polyadenylated mRNAs to be produced, without splicing, within minutes after infection. The polypeptides produced by translation of these mRNAs complete the uncoat-ing of the core, and transcription of about 100 "early" genes, distributed throughout the genome, occurs before viral DNA synthesis begins. Early proteins include DNA polymerase, thymidine kinase, and several other enzymes required for replication of the genome. Poxvirus DNA replication involves the production of concatemeric forms as intermediates, but details of the mechanism are still unknown.

With the onset of DNA replication there is a dramatic shift in gene expression. Transcription of "intermediate" and "late" genes is controlled by binding of specific viral proteins to characteristic promoter sequences. Virion assembly occurs in circumscribed areas of the cytoplasm ("viral factories").

DNA Con

JrjjermwJIatB mRNfc\ ^UteUansac! valors

Fig. 21-2 Diagram illustrating Ihe replication ryele ot vaccinia virus See text fur details |J;rom B Moss, Sacmc 252, 16« f199!) J

JrjjermwJIatB mRNfc\ ^UteUansac! valors

?Utfl enzymes ~ Early Iranscriptbn fadoi jf/S Structural proteins s.

Morphogenesis 4-20 hours

Fig. 21-2 Diagram illustrating Ihe replication ryele ot vaccinia virus See text fur details |J;rom B Moss, Sacmc 252, 16« f199!) J

Spherical immature particles can be visualized by electron microscopy; the outer bilayer becomes the outer membrane of the virion, and the core and lateral bodies differentiate within it. This outer membrane is not derived by budding from cellular membrane but is synthesized de novo. Some of the mature particles move to the vicinity of the Golgi complex, acquire an envelope, and are released from the cell by exocytosis. However, most particles are not enveloped and are released later by cell disruption. Both enveloped and nonenveloped particles are infectious, but enveloped particles are more rapidly taken up by cells and appear to be important in the spread of virions through the body.

Several poxvirus genes code for proteins that are secreted from infected cells and affect the response of the host to infection. Among these virokines is a homolog of epidermal growth factor, a complement regulatory protein, proteins conferring resistance to interferon, and yet others suppressing the immune response by inhibiting certain cytokines (see Table 7-1). Now that the complete sequence of vaccinia virus is known, we can anticipate the discovery of many additional genes affecting the host response to infection.

Pathogenesis and Immunity

All poxvirus infections are associated with lesions of the skin, which may be localized or generalized. The lesions associated with many diseases are pustular, but lesions due to molluscum contagiosum virus, parapoxvirus, and yata pox virus are proliferative. Generalized poxvirus infections have a stage of leukocyte-associated viremia, which leads to localization in the skin and to a lesser extent in internal organs. Immunity to such infections is prolonged. However, in some localized poxvirus infections, notably those produced by parapoxviruses, immunity is short-lived and reinfection is common.

Laboratory Diagnosis

The morphology of the virions is so characteristic that electron microscopy is used to identify them in negatively stained vesicle fluid or biopsy material taken directly from skin lesions. All orthopoxvirus virions have the same appearance, which is shared by the virions of molluscum contagiosum and tan a pox; milker's nodes and orf viruses can be distinguished by the distinctive appearance of the parapoxvirus virion.

The usual method of isolation of orthopoxviruses is by inoculation of vesicle fluid or biopsy material on the chorioallantoic membrane (CAM) of chick embryos, where discrete lesions known as pocks become visible within a few days. Cowpox virus produces much more hemorrhagic lesions on the CAM than does vaccinia virus. The parapoxviruses, molluscum contagiosum virus, and tanapox virus do not grow on the CAM. Orthopoxviruses grow well in cell culture, parapoxviruses and tanapox virus less readily, and molluscum contagiosum virus has not yet been satisfactorily cultivated.

Identification of the particular species of orthopoxvirus, for example, differentiation between variola and monkeypox viruses or between vaccinia and cowpox viruses, can be made by animal inoculation methods, of which the CAM and rabbit skin systems are the most useful. Each species of orthopoxvirus has a distinctive DNA map demonstrable by digestion with restriction endonucleases.

Human Infections with Orthopoxviruses Vaccinia

The origin of vaccinia virus is obscure, but it probably evolved from cowpox or smallpox virus. For smallpox vaccination, the virus was inoculated into the superficial layers of the skin of the upper arm by a "multiple puncture" technique. Severe complications occasionally occurred in children with eczema who were mistakenly vaccinated or were infected by contact. Eczema vaccinatum was rarely fatal, especially if treated with vaccinia-immune human gammaglobulin. Other very rare but more serious complications were progressive vaccinia, which occurred only in persons with defective cell-mediated immunity, and postvaccinia! encephalitis.

With the eradication of smallpox, routine vaccination of the general public with vaccinia virus ceased to be necessaiy, and the requirement that international travelers should have a valid vaccination certificate was abolished. Vaccination of military personnel has also ceased in most countries. However, strains of recombinant vaccinia virus as vectors incorporating genes for protective antigens for several different pathogens are being developed for the production of vaccines against several diseases (see Chapter 13), although none is yet in use. Much less virulent strains of vaccinia virus than those used for smallpox vaccination are being developed for use as vectors, and the strains used will be much less likely to produce serious complications than those previously used for smallpox vaccination.

Buffalopox

Buffalopox has occurred in water buffaloes (Buhalis bubnhs) in Egypt, the Indian subcontinent, and Indonesia and still occurs in India. By restriction mapping, the causative virus has been shown to be vaccinia virus, although most strains differ from laboratory strains of vaccinia virus (and those used for smallpox vaccination in India) in some biological properties. The disease is characterized by pustular lesions on the teats and udders of milking buffaloes; occasionally, especially in calves, a generalized disease is seen. Human infections produce lesions on the hands and face of milkers, who are no longer protected by vaccination against smallpox. The epidemiology is illustrated in Fig. 21-4B.

Human Monkeypox

Human infections with monkeypox virus, a species of Orthojioxvtrus, were discovered in West and Central Africa in the early 1970s, after smallpox had been eradicated from the region The signs and symptoms are very like those of smallpox, with a generalized pustular rash, fever, and toxemia (Fig. 21-3).

Child Moiiuscum Contagiosum Diseases

Fig. 21-3 Human monkeypox. Front and rear views of a 7-year-old Zairean girl with monkeypox, on the eighth day after the appearance of the rash, which is indistinguishable in its evolution, appearance, and distribution from the rash of smallpox. The gross enlargement of the superficial lymph nodes seen in human monkeypox was not seen in smallpox [From J G-Broman, Kalisa Rut), M V. Steniowski, E Zanotto, A. I. Gromyko, and I Anta, Human monkeypox, 1970 79 Hull Wl/O 58, 165 (1980).]

Fig. 21-3 Human monkeypox. Front and rear views of a 7-year-old Zairean girl with monkeypox, on the eighth day after the appearance of the rash, which is indistinguishable in its evolution, appearance, and distribution from the rash of smallpox. The gross enlargement of the superficial lymph nodes seen in human monkeypox was not seen in smallpox [From J G-Broman, Kalisa Rut), M V. Steniowski, E Zanotto, A. I. Gromyko, and I Anta, Human monkeypox, 1970 79 Hull Wl/O 58, 165 (1980).]

Human monkeypox occurs as a rare zoonosis in villages in tropical rain forests in West and Central Africa, especially in Zaire. It is probably acquired by direct contact with wild animals killed for food, especially squirrels and monkeys A few cases of person-to-person transmission occur, but the secondary attack rate is too low for the disease to become established as an endemic human infection. Up to December 1986, when intensive surveillance ceased, only 400 cases had been diagnosed. Vaccination with smallpox vaccine (vaccinia virus) immunizes against monkeypox but is not justified, since the disease is so rare.

Cowpox

I lumans can acquire three different poxvirus infections from cows, usually as lesions on the hands after milking, vaccinia (in the days of smallpox vaccination), cowpox (caused by an Orthopoxvirus), and milker's nodes (caused by a Pnrapoxvinis). Despite the name, the reservoir hosts of cowpox virus are rodents, from which it occasionally spreads to cats, cows, humans, and zoo animals, including large cats and elephants (Fig. 21-4A).

A Humans

A Humans

B Humans

7 Wild rodont reservoir

Fig. 21-4 Diagram illustrating the epidemiology of cowpox (A) and buffalopox (B) Solid lines denote known paths of transmission, broken lines presumed or possible paths of transmission (A) There are probably several different wild rodent hosts of cowpox virus in Europe and adjacent parts of Asia, from which cowpox virus enters the other animals indicated •''Natural hosts include gerbils and susliks in Turkmenia, Raliiis iinrnr^inis in Russia, and probably voles and field mice in Britain. hOutbreak in the Moscow Zoo (B) In the days of smallpox vaccination, vaccinated humans sometimes infected cows and water buffaloes with vaccinia virus Buffalopox, caused by vaccinia vitus, appears to have remained enzootic in several states in India, and it constitutes a continuing source of infection of humans, who in turn may reinfect buffaloes By analogy with cowpox, it is possible that the true reservoir host of buffalopox (vaccinia) virus is some species ot wild rodent, but if so this has not been identified

7 Wild rodont reservoir

Fig. 21-4 Diagram illustrating the epidemiology of cowpox (A) and buffalopox (B) Solid lines denote known paths of transmission, broken lines presumed or possible paths of transmission (A) There are probably several different wild rodent hosts of cowpox virus in Europe and adjacent parts of Asia, from which cowpox virus enters the other animals indicated •''Natural hosts include gerbils and susliks in Turkmenia, Raliiis iinrnr^inis in Russia, and probably voles and field mice in Britain. hOutbreak in the Moscow Zoo (B) In the days of smallpox vaccination, vaccinated humans sometimes infected cows and water buffaloes with vaccinia virus Buffalopox, caused by vaccinia vitus, appears to have remained enzootic in several states in India, and it constitutes a continuing source of infection of humans, who in turn may reinfect buffaloes By analogy with cowpox, it is possible that the true reservoir host of buffalopox (vaccinia) virus is some species ot wild rodent, but if so this has not been identified

Fig. 21-5 Localized zoonotic infections with poxviruses Lesions on hands acquired by milking infected cows: (A) cowpox, caused by an orthopoxvirus, and (B) milker's nodes, caused by a parapoxvirus. (C) Orf, a parapoxvirus lesion acquired by handling sheep or goats suffering from contagious pustular dermatitis (D) fanapox, lesion on arm of a child in Zaire, probably transmitted mechanically by mosquitoes from an animal reservoir host (A, B, Courtesy Dr D Baxby; C, courtesy Dr. J Nagington, D, courtesy Dr Z. Jtvek.)

Fig. 21-5 Localized zoonotic infections with poxviruses Lesions on hands acquired by milking infected cows: (A) cowpox, caused by an orthopoxvirus, and (B) milker's nodes, caused by a parapoxvirus. (C) Orf, a parapoxvirus lesion acquired by handling sheep or goats suffering from contagious pustular dermatitis (D) fanapox, lesion on arm of a child in Zaire, probably transmitted mechanically by mosquitoes from an animal reservoir host (A, B, Courtesy Dr D Baxby; C, courtesy Dr. J Nagington, D, courtesy Dr Z. Jtvek.)

Cowpox virus has been found only in Europe and adjacent parts of the former Soviet Union it produces ulcers on the teats and the contiguous parts of the udder of cows, and it is spread through herds by the process of milking. Currently, infection with cowpox virus is more commonly seen among domestic cats, from which it is occasionally transmitted to humans. The lesions in humans usually appear on the hands and develop just like primary vaccinia (Fig. 21-5A), although fevei and constitutional symptoms can be more severe.

Human Infections with Parapoxviruses Milker's Nodes

Milker's nodes (Fig. 21-5B) also occur on the hands of humans, derived from lesions on cows' teats. Unlike cowpox, it is primarily a disease of cattle and occurs worldwide. In humans the lesions are small nonulcerating nodules. Immunity following infection of humans does not last long, and second attacks may occur at intervals of a few years. The disease is trivial, and no measures for prevention or treatment are warranted.

Orf is an old Saxon term applied to the infection of humans with the virus of contagious pustular dermatitis ("scabby mouth") of sheep and goats. The disease of sheep, which occurs all over the world, is found particularly in Iambs during spring and summer and consists of a papulovesicular eruption that is usually confined to the Hps and surrounding skin. Infection of humans occurs as a single lesion on the hand or forearm (Fig. 21-5C) or occasionally on the face; a slowly developing papule becomes a flat vesicle and eventually heals without scarring. Orf is an occupational disease associated with handling of sheep or goats.

MoIIuscum Contagiosum

The specifically human disease molluscum contagiosum, caused by the only virus in the genus MoUuscipoxvinis, consists of multiple discrete modules 2-5 mm in diameter, limited to the epidermis, and occurring anywhere on the body except on the soles and palms. The nodules are pearly white or pink in color and are painless. At the top of each lesion there is an opening through which a small white core can be seen. The disease may last for several months before recovery occurs. Cells in the nodule are greatly hypertrophied and contain large hyaline acidophilic cytoplasmic masses called molluscum bodies. These consist of a spongy matrix divided into cavities in each of which are clustered masses of viral particles that have the same general structure as those of vaccinia virus.

The incubation period in human volunteers varies between 14 and 50 days. Attempts to transmit the infection to experimental animals have failed, and reported growth in cultured human cells has been hard to reproduce. The disease is most commonly seen in children and occurs worldwide, but it is much more common in some localities, for example, parts of Zaire and Papua New Guinea. The virus is transmitted by direct contact, perhaps through minor abrasions and sexually in adults. In developed countries communal swimming pools and gymnasiums may be a source of infection.

Yabapox and Tanapox

Two members of the genus Yatapoxvirus occur naturally only in tropical Africa. Yabapoxvirus was discovered because it produced large benign tumors in Asian monkeys kept in a laboratory in West Africa. Subsequently, cases occurred in primate colonies in the United States. Similar lesions have occurred after accidental inoculation of a laboratory attendant handling affected monkeys and in human volunteers.

Tanapox is a relatively common skin infection of humans in parts of Africa extending from eastern Kenya to Zaire. It appears to be spread mechanically by insect bites from a reservoir in wild animals of some unknown species. The skin lesion starts as a papule and progresses to an umbilicated vesicle (Fig. 21-5D), but pustulation never occurs. Occasionally multiple lesions occur. There is usually a febrile illness lasting 3-4 days, sometimes with severe headache, backache, and prostration.

Further Reading

Butter, R M. L., and Palumbo, G. J. (1991). Poxvirus pathogenesis Microbiol. Rev 55, 80 Dumbell, K., and Richardson, M (1993) Virological investigations of specimens from buffaloes affected by buffalopox in Maharashtra State, India, between 1985 and 1987 Arch Virol 128, 257.

Fenner, F. (1990) Poxviruses. In "Fields Virology" (B. N Fields, D. M Knipe, R M. Chanock, M S Hirsch, J. L Melnick, T. P. Monath, and B Roizman, eds ), 2nd Ed , p 2113 Raven, New York

Fenner, F. (1994) Poxviral zoonoses In "Handbook of Zoonoses, 2nd Ed , Section B, Viral" (G W

Beran, ed ), p. 503. CRC Press, Boca Raton, Florida Fenner, F, and Nakano, J. H. (1988) Poxi'irtditc The Poxviruses In "Laboratory Diagnosis of Infectious Diseases, Volume II- Viral, Rickettsial and Chlamydial Diseases" (E. H Lennette, P Halonen, and F. A Murphy, eds ), p. 177. Spiinger-Verlag, New York Fenner, F., Henderson, D A , Arita, I., Jezek, Z-, and Lndnyi, I D (1988). "Smallpox and Its

Eradication." World Health Organization, Geneva Fenner, F., Wittek, R., and Dumbell, K R. (1989) "The Orthopoxviruses " Academic Press, San Diego.

Jezek, Z., and Fenner, F. (1988). Human monkeypox Mono%r Virol 17

Moss, B. (1992). Molecular biology of poxviruses. In "Recombinant Poxviruses" (M M Binns and

G L. Smith, eds.), p. 45 CRC Press, Boca Raton, Florida. Robinson, A. and Lyttle, D ) (1992). Para poxviruses Their biology and potential as recombinant vaccines In "Recombinant Poxviruses" (M M. Binns and G L Smith, eds.), p. 285 CRC Press, Boca Raton, Florida. Turner, P. C,, and Moyer, R W, eds (1990) Poxviruses Curr Top. Microbiol Immunol. 163, 125.

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