NONENVELOPED DNA VIRUSES

PAPOVAVIRIDAE

Human Papovaviridae and Their Disease

Unique Properties of Papovaviruses

There is a small icosahedral capsid virion.

Double-stranded circular DNA genome is replicated and

assembled in the nucleus.

These are two major genera:

o Papilloma: HPV types 1 to 58+ (as determined

by genotype; types defined by DNA homology,

tissue tropism, and association with oncogenesis)

o Polyoma: SV-40, JC virus, and BK virus

Viruses have defined tissue tropisms determined by

receptor interactions and the transcriptional machinery of the cell

Viruses encode proteins that promote cell growth by

binding to the cellular growth-suppressor proteins p53

and p105RB. Polyoma T antigen binds to p105RB and p53. E6 binds to p53, and E7 binds to p105RB.

Viruses can cause lytic infections in permissive cells but

cause abortive, persistent, or latent infections or

immortalize (transform) nonpermissive cells.

Disease Mechanisms of Papovaviruses

Epidemiology of Papovaviruses

Clinical Syndromes Associated with Papillomaviruses

HPV TYPES

SYNDROME COMMON UNCOMMON

SKIN WARTS

Plantar wart 1 2,4

Common wart 2,4 1,7,26,29

Flat wart 3,10 27,28,41

Epidermodysplasia verruciformis

5,8,17,20,36 9,12,14,15,19,21-25,38,46

BENIGN HEAD AND NECK TUMORS

Laryngeal papilloma 6,11 -

Oral papilloma 6,11 2,16

Conjunctival

papilloma

11 -

ANOGENITAL WART

Condyloma acuminatum

6,11 1,2,10,16,30,44,45

Cervical

intraepithelial

neoplasia, cancer

16,18. 11,31,33,35,42-44

Verruca vulgaris. Common warts are typically single or multiple, flesh colored, dome-shaped papules with a rough, verrucous surface. They can occur anywhere on the skin but are most common on exposed surfaces such as the fingers, hands, feet and face.

Common warts with thrombosed vessels (black dot) on the surface.

Verruca plantaris. Plantar warts occur on weight bearing areas of the feet and commonly exhibit overlying hyperkeratosis. Note the punctuate dark brown dots which represent vessel thrombosed in the superficial dermis.

Verruca lanta. Flat warts occur primarily on the face and extremities. They are generally

small, flesh or brown-colored, broad based papules varying in number. Autoinoculation from trauma, such as shaving, is a common

means of viral spread.

Condyloma acuminate. It is characterized by soft, flesh-colored polypoid or acuminate warts that occur in the anogenital region. It can be extensive and cause pain, itching and bleeding.

Laboratory Diagnosis of Papilloma Infections

DNA probe analysis of an HPV-6-induced anogenital condyloma Dark staining is seen over nuclei of koilocytic cells.

Mechanism of spread of polyomaviruses within the body.

Laboratory Diagnosis of Polyomavirus (JC and BK Infections)

TEST DETECTS

Pap smear of urinary epithelial

cells

Viral inclusions

Electron microscopy Virions

Immunofluorescence and immunoperoxidase staining

Viral antigens

DNA probe analysis Viral nucleic acids

Nucleic acid hybridization in

clinical specimens

BK and JC viruses

Nucleic acids

Cell culture

Human diploid lung fibroblasts

Primary human fetal glial cells

Virus isolation-BK

Virus isolation-JC

ADENOVIRIDAE

Unique Features of Adenoviruses

Disease Mechanisms of Adenoviruses

Time Course of Adenovirus Respiratory Infection

Epidemiology of Adenovirus

Illness Associated with Adenoviruses ILLNESS CATEGORY MOST COMMON SEROTYPES

Endemic respiratory disease 1,2,5

Acute respiratory disease of military recruits

3,4,7,14,21

Adenoviral pneumonia 3,4,7b,14,21

Epidemic keratoconjunctivitis 8,19

Pharyngoconjunctival fever 3,7

Less common syndromes

Pertussis syndrome 1,2,3,5

Acute hemorrhagic cystitis 1,4,7,11,21

Hepatic disorders 3,7

Gastroenteritis 9,12,13,18,25-29, 40-42

Intussusception 1,2,5

Musculoskeletal disorders 7

Genital infections 19

Skin infections 2,4,7,21

Infections in immuno-

compromised hosts

32,34-36

Adenovirus conjunctivitis. Adenoviral exanthems are frequently generalized and nonspecific. Other associated findings include fever, rhinitis, pharyngitis, adenopathy and conjunctivitis.

Hematoxylin and eosin-stained sample of adenovirus. Pneumonia, showing inflammation, necrosis and exudates.

PARVOVIRIDAE

Unique Properties of Parvoviruses

Disease Mechanisms of B19 Parvovirus

Mechanism of Spread of parvovirus within the body

Time course of parvovirus (B19) infection. B19 causes biphasic

disease: first, an initial, lytic infection phase characterized by

febrile, influenza-like symptoms and then a noninfectious immunological phase characterized by a rash and arthralgia.

(Insert time course picture)

Epidemiology of B19 Parvovirus Infections

A slapped-cheek appearance is typical of the rash for erythema infectiosum.

Erythema infectiousum. The third stage of Fifth’s disease begins as the rash starts to

fade with areas of central clearing. This leaves a reticulated or lacy pattern of

erythema which can last several weeks. The most common complication is join

involvement ranging from mild arthralgias to overt arthritis.

NONENVELOPED DNA VIRUSES

HUMAN HERPESVIRUSES

Properties Distinguishing the Herpesviruses

Unique Features of Herpesviruses

HERPES SIMPLEX VIRUS 1 AND 2

Disease Mechanisms for Herpes Simplex Virus

Clinical course of genital herpes infection. The time course and

symptoms of primary and recurrent genital infection w/ HSV-2 are compared.

Epidemiology of HSV Infection

Disease syndromes of HSV. HSV-1 and HSV-2 can infect the same tissue and cause similar diseases but have a predilection for the sites and diseases indicated.

Primary herpes gingivostomatitis is the most common herpes simplex virus-1 infection in children. Vesicles, erythema and swelling occur in the oral cavity and on the lips. Erosion of vesicles leave small shallow ulcers on an erythematous base.

Cold sore of recurrent herpes labialis.

Herpatic whitlow is characterized by inoculation of the HSV virus into the skin of one or more fingers causing painful superficial or deep vesicles or bullae with a whitish blue-hue.

Herpetic coneal ulcer. Corneal infection due to HSV is characterized by dendritic ulcers which are branching morphologic appearance of the lesions. Recurrent infections can lead to scarring and impairment of vision.

Eczema herpticum (Kaposi’s varicelliform eruption). Note the vesicles, superficial ulcers and crusts in the antecubital fossa of this toddler with atopic dermatitia.

Genital Herpes. It begins as vesicles or pustules which progress to erosions and ulcers, generally lasting 1-3 weeks. Associated local symptoms for both primary and recurrent genital HSV infections include severe pain, itching, dysuria, inguinal adenopathy and urethral or vaginal discharge.

Neonatl herpes. Newborns may acquire primary herpes simplex virus (HSV) infection in utero, during delivery or postnatally. Cutaneous involvement may be minimal or extensive and is not necessarily indicative of the severity of concurrent systemic disease.

Laboratory Diagnosis of HSV infections

Tzanck stain of herpetic vesicle. Note the large multinucleated giant cell. The preparation is obtained by scraping the base of a new, freshly opened vesicle and staining with Giemsa stain or toluidine blue.

FDA-Approved Antiviral Treatments for Herpesvirus Infections HERPES SIMPLEX VIRUS 1 AND 2

Acyclovir

Adenosine Arabinoside Iododeoxyuridine

Trifluridine VZV

Acyclovir

Varicella-zoster immune globulin (VZIG)

Zoster immune plasma EBV

None CMV

Ganciclovir Foscarnet* *ALSO INHIBITIS HSV AND VZV

VARICELLA-ZOSTER VIRUS

Disease Mechanisms of VZV

Mechanism of spread of VZV within the body

Time course of varicella (chickenpox)

Epidemiology of VZV Infection

Varicella. After an incubation period of approximately 14-16 days the disease begins with low grade fever, malaise and the appearance of a characteristic generalized pruritic vesicular Eruption (“dewdrop on a rose petal”).

Characteristic skin rash of varicella demonstrating all of the stages of evolution of the rash.

Varicella in a child. The eruption generally begins on the trunk or head and spreads centrifugally. New lesions generally begin to crust within 1-2 days. It is common to find various-sized papules, vesicles, pustules and crusts all present on the skin at the same time. Varicella in an adult. Over 90% of primary

varicella infections occur in children. In adolescents, adults and immunocompromised patients, the disease can be more severe. Secondary bacterial skin infections, otitis media, pneumonia, encephalitis, hepatitis and Reye’s syndrome are well known complications of varicella infection.

Differences between Chickenpox and Smallpox Chickenpox Smallpox

Distribution Relative density is centripetal. Predominance on flexor surfaces and flexures

Relative density is centrifugal Predominance on extensor surfaces and prominences

Mode of Evolution

Lesions appear in crops Lesions progress from stage to stage synchronously

Time of evolution

Rapid Relatively slow

Lesions Superficial Ova or totally irregular Unilocular Scarring slight and superficial

Deep set Tend to be circular and regular Vesicles multilocular Scarring severe and deep

Acute herpes zoster. After primary varicella-zoster virus infection, the virus persists in a latent form and can be reactivated, resulting in herpes zoster or “shingles”. Herpes zoster is characterized by papules, vesicles and pustules on an inflammatory base in a dermatomal distribution, frequently associated with burning pain and tenderness.

Tzanck stain of the contents of a varicella vesicle. Note the multinucleated giant cells. These represent swollen epidermal cells

containing intercytoplasmic viral inclusion.

EPSTEIN-BARR VIRUS

Disease Mechanisms of Epstein-Barr Virus

Pathogenesis of EBV. EBV is acquired by close contact between persons

through saliva and infects the B cells. The resolution of the EBV infection and many of the symptoms of infectious mononucleosis result from the activation of T cells in response to the infection.

Cellular Antigens Associated with EBV-Infected Cells NAME ABB. CHAR. BIO. ASSOC. CLIN. ASSOC.

EBV nuclear antigen

EBNA Nuclear EBNA is a nonstructural antigen and is the first antigent to appear; EBNA is seen in all infected transformed cells, and it binds to cell DNA.

Anti-EBNA develops late in infection.

Early antigen

EA-R EA-D

Only cytoplasmic Diffuse in cytoplasm and nucleus

EA-R appears before EA-D; its appearace is the first sign that an infected cell has entered lytic cycle. -

Anti-EA-R is seen in Burkitt’s lymphoma. Anti-EA-D is seen in infectious mononucleosis.

Viral capsid antigen

VCA Cytoplasmic VCA is a late antigen; it is found in virus producer cells.

Anti-VCA IgM is transient; anti-VCA IgG is persistent.

Lymphocyte- defined membrane antigen

LYDMA - LYDMA is not found on Burkitt’s lymphoma cells; iti s found on cells infected in vitro, and is found on nonproducer cells

LYDMA is not detectable by antibody.

Membrane antigen

MA Cell surface MAs are the envelope glycoproteins

Same as VCA.

Heterophile antibody

Recognition of Pul-Bunnell antigen on sheep, horse, or bovine erythrocytes

EBV-induced B-cell proliferation promotes production of heterophile antibody.

Early symptoms occur in more than 50% of patients.

Epidemiology of Epstein-Barr Virus Infection

Serological Profile for EBV Infections

Clinical course of infectious mononucleosis and laboratory findings of those with infection. EBV infection may be asymptomatic or produce the symptoms of mononucleosis. The incubation period can last as long as 2 months.

Papular acrodermatitis of childhood Gianolti-Crosti disease) – a distinctive erythematous, discrete popular eruption that is acrally located with relative sparing of the trunk. Associated findings may include lymphadenopathy, hepatomegaly and

evidence of hepatitis.

Ampicillin rash in a patient with infectious mononucleosis when antibiotics (usually ampicillin) are administered during primary EBV infection, a red or copper colored morbilliform eruption may appear. The rash begins on the trunk and gradually spreads over the entire body.

Hairy leukoplakia caused by EBV. Atypical T-lymphocyte (Downey cells) characteristic of infectious mononucleosis.

CYTOMEGALOVIRUS

Disease Mechanisms of CMV

Epidemiology of Cytomegalovirus Infection

CMV Syndromes TISSUE CHILDREN/ADULTS IMMUNOSUPPRESSED

PATIENTS

Predominant nature of disease

Inapparent infection (prominent presentation of disease

Disseminated disease, severe disease

Eyes - Chorioretinitis

Lungs - Pneumonia

Gastrointestinal tract

- Esophagitis, colitis

Nervous system Polyneuritis, myelitis Meningitis and encephalitis, myelitis

Lymphoid system Mononucleosis syndrome, posttransfusion syndrome

Leukopenia, lymphocytosis

Major Organs Carditis, hepatitis Hepatitis

Neonates Deafness, mental retardation

-

Congenital cytomegalovirus (CMV) infection. Cutaneous rash is unusual in acquired CMV infections but is common in congenital CMV infections. Congenital CMV may range from asymptomatic to profound with systemic manifestations including intrauterine growth retardation, hepatosplenomegaly, pneumonia, neonatial jaundice, thrombocytopenia, central nervous system involvement and chrioretinits. Skin findings include purpuric paules and nodules.

Clinical course of CMV infection

Laboratory Tests for Diagnosis of CMV infection

CMV-inefcted cell with basophilic nuclear inclusion body.

HERPESVIRUS 6

Roseola infantum or exanthum subitum is a common exanthema of childhood caused by infection with human herpesvirus 6. It is characterized by a febrile illness with mild constitutional symptoms lasting 3-5 days. After rapid defervescence, a pink macular or maclopapular rash appears primarily on the trunk and lasting hours to days.

POXVIRIDAE

Unique Properties of Poxviruses

Disease Mechanisms of Poxvirus

Spread of Smallpox within the body.

The virus enters and replicates in the respiratory tract without causing symptoms or contagion. The virus infects macrophages, which enter the lymphatic system and carry the virus to regional lymph nodes. The virus then replicates and initiates a viremia, causing the infection to spread to the skin (rash). A secondary viremia causes the development of additional lesions throughout the host, followed by death or recovery with or without sequelae. Recovery was associated with prolonged immunity and lifelong protection.

Time Course of Smallpox Infection

Properties of Smallpox that Led to Its eradication

Diseases Associated with Poxviruses

Discrete vesiculopustular

stage of smallpox. Smallpox (variola) is a highly contagious

disease cuased by Poxvirus

variolae, which apparently has been eradicated from the

world.

Molluscum contagiosum is a common, benign viral infection of the skin and mucous membranes characterized by distinct single or multiple dome-shaped papule which are flesh or pink colored. Central umbilication can occur.

Skin lesion of molluscum contagiosum.

Vaccinia. Three to 5 days after primary inoculation with vaccinia virus. A vesicle forms, followed by a pustule, which increases in size for 9-10 days and then heals

leaving a scar. Severe localized erythema may occur at the injection site.

Orf Lesion on finger of taxidermist.

Microscopic view of molluscum contagiosum. Epidermis filled with molluscum bodies.

Wright’s stain of the extruded contents of a molluscum papule. Note the blue stained viral inclusions (molluscum bodies) within the cytoplasm of epidermal cells.