M. Tvorko

The Herpesviruses

• All members show latency and cause recurrent infection– more severe with advancing age, cancer chemotherapy, or

other conditions that compromise the immune defenses• Large enveloped icosahedral dsDNA• Replicates within nucleus

Herpesviridae

• large Family; 8 infect humans– HSV-1– HSV-2– VZV – CMV– EBV– HHV-6– HHV-7– HHV-8

Epidemiology of Herpes Simplex

Viruses • Transmission

– direct exposure to secretions containing the virus

– active lesions most significant source

– genital herpes can be transmitted in the absence of lesions

• HSV multiplies in sensory neurons, moves to ganglia– HSV-1 enters 5th cranial

nerve– HSV-2 enters lumbosacral

spinal nerve trunk ganglia

Epidemiology of Herpes Simplex Viruses

• Recurrent infection triggered by various stimuli – fever, UV radiation,

stress, mechanical injury

• Newly formed viruses migrate to body surface– produce a local skin or

membrane lesion

Type 1 Herpes Simplex (HSV – 1)

• Herpes labialis – fever blisters, cold sores– most common recurrent HSV-1

infection– vesicles occur on mucocutaneous

junction of lips or adjacent skin– itching and tingling prior to

vesicle formation– lesion crusts over in 2-3 days and

heals• Herpetic gingivostomatitis

– infection of oropharynx in young children

– fever, sore throat, swollen lymph nodes

• Herpetic keratitis – ocular herpes

Type 2 Herpes Simplex (HSV – 2)

• Genital herpes – herpes genitalia – starts with malaise, anorexia,

fever, and bilateral swelling and tenderness in the groin

– clusters of sensitive vesicles on the genitalia, perineum, and buttocks

– urethritis, painful urination

• Recurrent bouts usually less severe– triggered by menstruation,

stress, and concurrent bacterial infection

Herpes of the Newborn

• HSV-1 and HSV-2• Potentially fatal in the

neonate and fetus• Infant contaminated by

mother before or during birth

• hand transmission by mother to infant

• Infection of mouth, skin, eyes, CNS

• Preventative screening of pregnant women– delivery by C-section if

outbreak at the time of birth

Diagnosis, Treatment, and Control

• Vesicles and exudate are typical diagnostic symptoms

• scrapings from base of lesions showing giant cells– culture and specific tests for diagnosing severe or

disseminated HSV

• direct fluorescent antibody tests• Treatment

– acyclovir, famciclovir, valacyclovir; topical medications

Varicella-Zoster Virus (VZV)

• virus enters neurons & remains latent• later reactivation of the virus results in

shingles with vesicles localized to distinctive areas– dermatomes

• treatment – acyclovir, famciclovir, interferon

• live attenuated vaccine

Epstein-Barr Virus (EBV)

• HSV-4• infects lymphoid tissue & salivary glands• transmission

– direct oral contact & contamination with saliva

• by mid-life 90-95% of all people are infected • causes mononucleosis

– sore throat, high fever, cervical lymphadenopathy

• Complications include:– heart defects– facial paralysis– rupture of the spleen– jaundice (hepatitis)

Epstein-Barr Virus (EBV)

• 30-50 day incubation• most cases

asymptomatic• Burkitt’s lymphoma

– associated with chronic co-infections with malaria

• nasopharyngeal carcinoma in Chinese & African men

Human Herpes Virus 6

• HHV-6• T-lymphotropic virus• transmitted by close

contact• very common • causes roseola

– an acute febrile disease in babies 2-12 months

• can cause encephalitis, cancer

Human Herpes Virus 6

• begins with fever, followed by a faint maculopapular rash

• usually self-limited• adults may get mono-like symptoms,

lymphadenopathy, hepatitis• over 70% of MS patients show signs

of infection

Diseases of the Skin Caused by Herpesviruses

HEPATITIS B VIRUS:

HEPATITIS B VIRUS:

HBV SPREAD MAINLY BY PARENTERAL

ROUTE• DIRECT PERCUTANEOUS INOCULATION

OF INFECTED SERUM OR PLASMA• INDIRECTLY THROUGH CUTS OR

ABRASIONS• ABSORPTION THROUGH MUCOSAL

SURFACES• ABSORPTION OF OTHER INFECTIOUS

SECRETIONS (SALIVA OR SEMEN DURING SEX)

HBV SPREAD MAINLY BY PARENTERAL ROUTE• POSSIBLE TRANSFER VIA INANIMATE

ENVIRONMENTAL SURFACES• VERTICAL TRANSMISSION SOON

AFTER CHILDBIRTH (TRANSPLACENTAL TRANSFER RARE)

• CLOSE, INTIMATE CONTACT WITH AN INFECTED PERSON

WHO IS AT GREATEST RISK FOR HBV INFECTION?

• LAB PERSONNEL WORKING WITH BLOOD PRODUCTS

• SEXUALLY ACTIVE HOMOSEXUALS

• PERSONS WITH MULTIPLE AND FREQUENT SEX CONTACTS

• MEDICAL/DENTAL PERSONNEL

HBV - Diagnosis HBV - Diagnosis

Acute InfectionAcute Infection

0 2 4 6 0 2 4 6

HBsAg

Anti-HBsAnti-HBsAnti-HBcAnti-HBc

Anti-HBc IgMAnti-HBc IgM

Months YearsMonths Years

HBeAg

HBV DNA

Anti-HBeAnti-HBe

HBV - VaccineHBV - Vaccine

Vaccine Age Group Dose Volume # Doses (ug) (ml)

Engerix-B 0-19 yr 10 0.5 3 (mo 0,1,6) 20 yr 20 1.0 3 (mo 0,1,6)

Adults onhemodialysis 40 2.0 4 (mo 0,1,2,6)

Recombivax HB 0-19 yr 5 0.5 3 (mo 0,1,6) 20 yr 10 1.0 3 (mo 0,1,6)

(Optional 2-dose) 11-15 yr 10 1.0 2 (mo 0, 4-6)Adults on

hemodialysis 40 1.0* 3 (mo 0,1,6)

Vaccine Age Group Dose Volume # Doses (ug) (ml)

Engerix-B 0-19 yr 10 0.5 3 (mo 0,1,6) 20 yr 20 1.0 3 (mo 0,1,6)

Adults onhemodialysis 40 2.0 4 (mo 0,1,2,6)

Recombivax HB 0-19 yr 5 0.5 3 (mo 0,1,6) 20 yr 10 1.0 3 (mo 0,1,6)

(Optional 2-dose) 11-15 yr 10 1.0 2 (mo 0, 4-6)Adults on

hemodialysis 40 1.0* 3 (mo 0,1,6)

1949. Enders et al.: first cell cultures for cultivation of polioviruses1953. Rowe et al.: removed tonsills for tissue culture

„blind” passages

cytopathic effect (roundish cells)

adenovirusvirions

AD (Adenoid Degeneration)APC (Adenoidal-Pharygeal-Conjuctival)ARD (Acute Respiratory Disease)RI (Respiratory Illness)

ADENOVIRUS (1956)

normal (healthy) cell culture

AdenovirusesAdenoviruses

• nonenveloped, ds DNA• 30 types associated with human

disease• infect lymphoid tissue, respiratory

& intestinal epithelia & conjunctiva• oncogenic in animals, not in

humans• spread by respiratory & ocular

secretions• causes colds, pharyngitis,

conjunctivitis, keratoconjunctivitis, acute hemorrhagic cystitis

• inactivated polyvalent vaccine• Inclusion bodies

VIRION: icosahedral, 80-90 nm252 capsomers: 12 fibers at thevertices, 240 hexons,12 structural proteins (polypeptides)

NUCLEIC ACID: ds DNAREPLICATION in cytoplasm, virion assembly in the nucleus

CLASSIFICATION OF ADENOVIIRUSESCLASSIFICATION OF ADENOVIIRUSES

Genera:Aviadenovirus (birds),Ataadenovirus (reptiles, ruminants, birds, brush-tail possum)Siadenovirus (frog, birds)Ichtadenovirus (new, fish)

MASTADENOVIRUS (vertebrates animals: more than 100 serotypes, 52 human serotypes)

MASTADENOVIRUS GENUS

Groups (previosly: Subgenera, grouping based on lenght offiber, G/C content of DNA, agglutination of red blood cells (HA),oncogenicity)A highly oncogenic (types 12, 18, A highly oncogenic (types 12, 18,

31)31)B weekly oncogenic (types 3,7, 11, 14,16, 21, 34, 35, 51)C cell transformation in tissue culture (types 1, 2, 5, 6)D cell transformation in tissue culture (types 8-10, 13, 15, 17, 19, 20,22-30, 32, 33, 36-39, 42-50)E none (type 4)F ? (types 40, 41)G (new group) ? (type 52)

DISEASES CAUSED BY ADENOVIRUSES

DIFFERENT SEROTYPES - SAME DISEASESAME SEROTYPE - DIFFERENT DISEASES

RESPIRATORY TRACT INFECTIONS:pharyngitis: types 1,2,3,5,7,acute respiratory disease of recruits: types 4, 7,14, 21pharyngoconjunctival fever: types 3,7pneumonia: 1,2,3,7pertussis-like syndrome: type 5

EYE INFECTIONS :

pharyngoconjunctival fever (conjunctivitis),epidemic keratoconjunctivitis: types 8,19,37 (swimming pool, nosocomial: eye droplets, tonometer) in all age groupfollicular conjunctivitis: 3,4,11

ENTERIC INFECTIONS: second incausative agents causinggastroenteritis in infants (AV types 40, 41,the first one is rotavirus) and AV type 53 in adults

diagnozis: EM, ELISA or latex agglutination

Urinary tract infections: acute haemorrhagic cystitis: types 11, 21 (children, young adults)

INFECTIONS IN IMMUNO-COMPROMISED PATIENTS: encephalitis,pneumonia, gastroenteritis, generalized disease (type 5 and new serotypes: 34, 35)(PREVENTION: „live” adenovirus serotypes 4 and 7 in enterosolvent capsule)

RECOMBINANT ADENOVIRUSES (GENE THERAPY)

Introduction of foreign genes(malignant diseases, diseasesbased on gene defects)immune therapy (cytokin genes),moleculare therapy (tumorsuppressor genes), virus therapy

DNA

NUCLEIC ACID: (-) DNA

REPLICATION: in the nucleus, withthe help of cellular enzymes

CLASSIFICATION:Family: PARVOVIRIDAE

Subfamily: PARVOVIRINAE

Genera:

ERYTRHOVIRUS (B19)Bocavirus (human bocavirus)Parvovirus (RA-1)Dependovirus (requires helper virus : AAV, Adenovirus Associated Virus)Densovirus (animal pathogens)

VIRION: icosahedral, 20-25 nm

adenovirus AAV

PARVOVIRUSESParvus: very small

ERYTHEMA IINFECTIIOSUM„FIIFTH DIISEASE”

(morbiillllii,, chiickenpox,, rubelllla,, scarllet fever )

• Human parvovirus B19 (respiratory droplets, seasonality: autumn, winter, high % of seropositivity)

• special affinity to red blood cells (haematological changes)• severe situation in chronic anaemia• in pregnancy: spontaneous abortion, malformations

Papillomavirus• papilloma

– benign, squamous epithelial growth, wart or verruca

• caused by 100 different strains of HPV

• common seed warts – Fingers

• plantar warts – soles of feet

• genital warts – prevalent STD

• transmissible through direct contact or contaminated fomites

• Incubation– 2 weeks – more than a year

Genital Warts

• most common STD in US• over 6 M new cases each year• 30 M carriers of one of the 5 types of

HPV associated with genital warts• strong association with cervical & penile

cancer– type 16 & 18

• Treatment– podophyllin chemical treatment, cauterization,

freezing, laser surgery, immunotherapy