DNA -VIRUSES 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) 28

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 29

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 31

Acute Infection HBsAg Anti-HBs Anti-HBc Anti-HBc IgM HBeAg HBV DNA 0 2 4 6 HBsAg Anti-HBs Anti-HBc Anti-HBc IgM Months Years HBeAg HBV DNA Anti-HBe HBV - Diagnosis Slide 80 Serological Markers of Acute HBV Infection Incubation period of HBV infection ranges from 60 to 180 days. HBsAg is the first serological marker of acute HBV infection. Early in the course of acute HBV infection, markers of active viral replication (HBeAg and HBV DNA), are also detectable. As the patients recover, serum HBV DNA level markedly decrease but may remain detectable by PCR assay for up to several decades, HBeAg to anti-HBe seroconversion occurs and finally HBsAg becomes undetectable. Persistence of HBsAg for more than 6 months indicates progression to chronic HBV infection. Anti-HBc IgM is the first antibody to be detected and usually persists for several months. It may be the only marker of acute HBV infection during the ‘window’ period after HBsAg is cleared and before anti-HBs is detected. Recovery from acute HBV infection is indicated by the presence of anti-HBc IgG and anti-HBs.

HBV - 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 on hemodialysis 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) hemodialysis 40 1.0* 3 (mo 0,1,6) Slide 95 Dose schedule of HBV vaccine Two recombinant HBV vaccines are currently available in the United States: Engerix-B (GlaxoSmithKline Biologicals) and Recombivax HB (Merck & Co., Inc.). The two vaccines can be used inter-changeably. Conventional 3-dose schedules include injections at 0, 1, and 6 months for immunocompetent people. The dose recommended for children and adolescents is lower while that for immunocompromised adults such as dialysis patients is higher. In adolescents aged 11 to 15 years, Recombivax HB has been approved for use in a 2-dose, 10ug regimen, with the second dose given 4 to 6 months after the first. This 2-dose regimen should increase compliance and reduce costs. CDC. Hepatitis B virus: a comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination: recommendations of the immunization practices advisory committee (ACIP). MMWR 1991;40 (RR-13):1-19. Koff RS. Hepatitis A, hepatitis B, and combination hepatitis vaccines for immunoprophylaxis. An update. Dig Dis Sci 2002;47:1183-94.

Adenoviruses ADENOVIRUS (1956) 1949. Enders et al.: first cell cultures for cultivation of polioviruses 1953. Rowe et al.: removed tonsills for tissue culture „blind” passages cytopathic effect (roundish cells) normal (healthy) cell culture AD (Adenoid Degeneration) APC (Adenoidal-Pharygeal-Conjuctival) ARD (Acute Respiratory Disease) RI (Respiratory Illness) ADENOVIRUS (1956) adenovirus virions

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 nm 252 capsomers: 12 fibers at the vertices, 240 hexons, 12 structural proteins (polypeptides) NUCLEIC ACID: ds DNA REPLICATION in cytoplasm, virion assembly in the nucleus

CLASSIFICATION 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 of fiber, G/C content of DNA, agglutination of red blood cells (HA), oncogenicity) A highly oncogenic (types 12, 18, 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)

DIFFERENT SEROTYPES - SAME DISEASE SAME SEROTYPE - DIFFERENT DISEASES DISEASES CAUSED BY ADENOVIRUSES DIFFERENT SEROTYPES - SAME DISEASE SAME SEROTYPE - DIFFERENT DISEASES

RESPIRATORY TRACT INFECTIONS: pharyngitis: types 1,2,3,5,7, acute respiratory disease of recruits: types 4, 7,14, 21 pharyngoconjunctival fever: types 3,7 pneumonia: 1,2,3,7 pertussis-like syndrome: type 5 EYE INFECTIONS : pharyngoconjunctival fever (conjunctivitis), epidemic keratoconjunctivitis: types 8,19,37 (swimming pool, nosocomial: eye droplets, tonometer) in all age group follicular conjunctivitis: 3,4,11

ENTERIC INFECTIONS: second in causative agents causing gastroenteritis 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) DNA Introduction of foreign genes (malignant diseases, diseases based on gene defects) immune therapy (cytokin genes), moleculare therapy (tumor suppressor genes), virus therapy

PARVOVIRUSES Parvus: very small VIRION: icosahedral, 20-25 nm NUCLEIC ACID: (-) DNA REPLICATION: in the nucleus, with the 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) adenovirus AAV

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 caused by 100 different strains of HPV 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