HERPES VIRUSES PART II, PARVO VIRUSES, PAPOVO VIRUSESCytomegalovirus Epstain barr virus HHV 6,7,8 Parvoviruses

Papovaviruses

Dr.C.Meenakshisundaram.,MD

CYTOMEGALOVIRUS

MICROBIOLOGY Double-stranded

linear DNA

enveloped virus Member of Herpesviridae family Alpha-herpesvirus subfamily HSV-1 and 2, VZV Beta-herpesvirus subfamily CMV (HHV5), HHV 6, HHV 7 Gamma-herpesvirus subfamily EBV, HHV 8 (KSHV)

www.biosciences.bham.ac.uk

MICROBIOLOGY CMV

150-200 nm in size Icosahedral nucleocapsid containing dsDNA 162 hexagonal protein capsomeres Additional layer of surrounding protein (tegument) Outer membrane envelope with glycoprotein complexes

www.biografix.de

MICROBIOLOGY Largest

member of herpesviridae family 230-240 kilobase pairs Large cytomegalic cells with enlarged nuclei Violaceous intranuclear inclusions surrounded by a clear halo Basophilic stippling may be present in the cytoplasm Replication cycle Immediate early: 4 h Early: 4-24 h Late: 24 h

www.som.tulane.edu

PATHOGENESISLytic virus with cytopathic effect Initial infection Epithelial cells of the salivary gland persistent infection and viral shedding Genitourinary system Proximal tubules near cortical areas Ultimately can be found in several tissues (salivary gland, lung, liver, kidney, intestine, adrenal gland and CNS) Other pathogenic mechanisms Granulomatous reaction, particularly in liver Immune complex formation Vasculitis Establishes a latent host infection May reactivate during a period of immunosuppression secondary to drugs or concurrent infection (eg. HIV)

PATHOGENESIS Incubation

period: 28-60 days Primary infection symptoms: 9-60 days Viremia: 2-3 weeks IgM response: 30-60 days Peak viral titers: 4-7 weeks post infection

EPIDEMIOLOGYCMV prevalence increases Transmission: transplanted with age organ, breast milk, urine, saliva, tears, stool, sexual Risk factors contact, blood, transplacental Work at day care/contact Seldom associated with with children mortality in immunocompetent Blood transfusion hosts (30% of IgG value may suggest active infection

FETAL DIAGNOSISCONGENITAL CMV Ultrasound findings Abdominal and liver calcifications Echogenic bowel Ascites Hepatosplenomegaly CNS involvement poorer prognosis CMV detected in amniotic fluid by culture or PCR Culture sensitivity: 50-69% PCR sensitivity: 77-100% Combined sensitivity: 80-100% Sensitivity of amniotic fluid testing markedly lower if performed before 21 weeks GA

TREATMENT Ganciclovir

Targets UL54 protein Valganciclovir Foscarnet Cidofovir Nucleoside analogue Treatment not usually indicated in immunocompetent patients Indications Treatment of disease in immunocompromised: Retinitis, GI disease, pneumonitis, neurologic disease,

PREVENTION

Behavioral

Modification Avoidance of infectious saliva, urine, bodily fluids and high risk behaviour www.med.nagoya-cu.ac Careful hygiene practices

VACCINES Live

attenuated vaccine developed (Plotkin 1991) Largest trial: Towne 125 strain Partial efficacy Economically beneficial Concerns Reactivation and infection of host Viral shedding from cervix or breast milk Possible oncogenic potential of vaccine virus

Glycoprotein

vaccine (Bourne 2001) Reduced in-utero CMV transmission Improved pregnancy outcome

EPSTEIN BARR VIRUS

DISCOVERY OF EBV 1958-

Burkitt's lymphoma described in the malaria belt of east Africa Epstein and Barr discover EBV through electron microscopy of cells cultured from Burkitt's lymphoma tissue EBV demonstrated as the etiological agent of infectious mononucleosis

1964-

1968-

EBV VIRAL STRUCTUREA

core containing a linear, dsDNA molecule of about 175 kbp. An icosahedral capsid, approximately 100-110 nm in diameter, containing 162 capsomeres with a hole running down the long axis. An amorphous, sometimes asymmetric material that surrounds the capsid, designated as the tegument An envelope containing viral glycoprotein spikes on its surface.

PRIMARY INFECTION DISEASESInfectious Mononucleosis (glandular fever) - fever, lymphadenopathy, and pharyngitis

Chronic active EBV infection - severe illness of more than six months, histologic evidence of organ disease, and demonstration of EBV antigens or EBV DNA in tissue (mimics chronic fatigue syndrome)X-Linked Lymphoproliferative Disease inherited disease of males, absence of functional SAP gene impairs the normal interaction of T and B cells resulting in unregulated growth of EBV-infected B cells.

DISEASES RESULTING FROM EBV INREDUCED IMMUNITY PATIENTS PTLD

(Post-transplant lymphoproliferative disease) -a tumor often found in organ transplant patients Oral Hairy Leukoplakia Nonmalignant hyperplastic lesion of epithelial cellsOral Hairy Leukoplakia

CANCERS ASSOCIATED WITH EBV Nasopharyngeal

Carcinoma Southern China, Northern Africa, and Alaskan Eskimos Elevated titers of IgA antibody to EBV structural proteins Burkitt's Lymphoma Found in equitorial Africa and associated with malaria which doesnt allow T-cells to control proliferation of EBV-infected B cells Tumors present in jaw Hodgkin's Disease EBV DNA detected in tumors Lymphoproliferative Disease Impaired T-cell immunity and cannot control proliferation of EBV-infected B cells

SITE OF INFECTION Infection

of Epithelial Cells by EBV in vitro Active replication, production of virus, lysis of cell Infection of B cells by EBV in vitro Latent infection, with immortalization (proliferate indefinitely) of the virus-infected B cells Linear EBV genome becomes circular, forming an episome, and the genome usually remains latent in these B cells Viral replication is spontaneously activated in only a small percentage of latently infected B cells. Signal transduction pathways can reactivate EBV from the latent state

REPLICATION EBV

replicates in the epithelial cells of the mouth, tongue, salivary glands, and oral cavity EBV infects B cells in the lymph nodes of the oral cavity Once inside B cells, EBV expresses proteins Nucleus: EBNA (Epstein-Barr Virus Nuclear Antigens) Plasma Membrane: LMP (Latent Membrane Proteins) Expression of these proteins stimulates B cell replication in lymph nodes producing clones Since many B cells are infected, polyclonal B-cell growth occurs which allows the disease to begin a long time after initial exposure to EBV

INFECTION AND REPLICATION

MODES OF TRANSMISSION

Intimate

Contact kissing, sharing food, coughing

IMMUNE SYSTEM TO THE RESCUE! (OR NOT)Epithelial cells and polyclonal B cells express the viral-encoded LMP glycoprotein in their plasma membranes Killer T cells recognize the LMP glycoprotein and kill the EBV-infected cells While T cells are mounting an attack on B cells, the immune response of a person is abnormal producing atypical T cells and antibodies that can confirm diagnosis of infectious mononucleosis

IMMUNE SYSTEM TO THE RESCUE!The ability of EBV to persist, despite potent immune effector responses against it, indicates that the virus has evolved strategies to elude the immune system.

SYMPTOMSThe classic triad of mononucleosis are Inflammation of the pharynx (or tonsils) usually severe Fever (higher in the evening) Lymphadenopathy (usually in the neck, groin or under the arms)

SYMPTOMSOther symptoms include: Fatigue and malaise Rash (associated with the use of ampicillin) Headache Abdominal pain Occasional jaundice Enlargement of the spleen and liver

DIAGNOSIS OF EBV Clinical

diagnosis- Classic triad of symptoms lasting 1-4 weeks Serologic test- Shows elevate white blood cell count, an increased number of lymphocytes, greater than 10% atypical lymphocytes Someone who appears to have infectious mononucleosis,a Paul-Bunnell test can be done Serology IF ELISA EBNA - Marker

COMPLICATIONS AND SYMPTOM ALLEVIATIONA

ruptured spleen (rare) Splenectomy anemia (steroid usage)

Hemolytic Airway

obstruction due to enlarged tonsils (steroid usage) platelet production, hypersplenism, or severe anemia (transfusions)

Decreased

TREATMENT OF EBV Infectious

Mononucleosis No specific therapy just nonaspirins and rest Hairy Leukoplakia Acyclovir inhibits EBV replication Lymphoproliferative Disease reduce dose of immunosuppressive medication Surgical removal or irradiation of localized lymphoproliferative lesions

Oral

EBV

PREVENTION AND VACCINES EBV

lymphoproliferative disease infusion of B-celldepleted marrow to offset the proliferation of donor B cells Removal of donor B cells along with T cells

No

vaccine found so far, though vaccine studies are underway

SUMMARY As

many as 95% of adults between 35 and 40 years old have been infected. children become infected with EBV but do not usually show symptoms. EBV occurs during adulthood it causes infectious mononucleosis 35-50% of the time. lifelong, persistent infections - majority are benign

Many

When

Causes

HHV 6Ubiquitous,spreads through saliva in early infancy Variants A and B Variant B is the cause of common childhood illness Exanthum subitum In old age group it is associated with infectious mononucleosis syndrome, focal encephalitis In immunodeficient it is associated with pneumonia and disseminated disease

HHV 7 Transmitted

through saliva

Shares CD4 receptor on T cells and thus contributes to furthur depletion of CD4 T cells in HIV infected patients

HHV 8 At

first Isolated from Kaposi sarcoma lesions in patients, of known HIV statuswas later found in Kaposi sarcoma lesions in patients that were HIV negative

It

PARVO VIRUS

Parvovirus structure

From Medical Microbiology, 4th ed., Murray, Rosenthal, Kobayashi & Pfaller, Mosby Inc., 2002, Fig. 53-1.

Autonomous parvovirus replication

From Medical Microbiology, 5th ed., Murray, Rosenthal, Kobayashi & Pfaller, Mosby Inc., 2002, Fig. 56-2.

Helper dependent parvovirus (AAV) replication

Infection with adenovirus Infection without adenovirusLytic replication

AAV DNA integrates into chromosome 19

Superinfect with adenovirus

Parvovirus pathogenesis

From Medical Microbiology, 5th ed., Murray, Rosenthal & Pfaller, Mosby Inc., 2005, Fig. 56-5.

PARVOVIRUS B19 Structure

Small (5 kb) linear ssDNA genome, naked capsid,B19

Pathogenesis

respiratory transmission replication in nucleus, host dependent, needs helper virus Presents as respiratory infection with an erythematous maculopapular rash and arthralgia Erythema infectiosum starts with prominent erythema of cheeks spreading to trunk and limbs followed by lymphadenopathy and arthralgia

PARVOVIRUS B19It occurs in young children and is called fifth disease Transient aplastic crisis in children with chronic hemolytic anaemias Infection during second or third trimester may result in hydrops fetalis Diagnosis

serology, viral nucleic acid

Treatment/prevention

None

Parvovirus pathogenesis

From Medical Microbiology, 5th ed., Murray, Rosenthal & Pfaller, Mosby Inc., 2005, Fig. 56-3.

PAPOVA VIRUSPa papilloma virus of human beings Po - polyoma virus of mice Va vaculating virus of monkey Small , non enveloped ,DNA viruses

SIMIAN VACULATING VIRUS 40 (SV 40)Isolated from uninoculated rhesus and cyenomologus monkey kidney tissue cultures Produces prominent cytoplastic vaculation when inoculated into kidney cell cultures Oncogenic for newborn hamsters Medical importance in preparation of live viral vaccines Live viral vaccines should be manufactured in monkey kidney tissue cultures tested and found free from SV 40 infection

PAPILLOMA VIRUS- SPECIES SPECIFIC Human

papilloma virus infections only humans Grow only in organ cultures of human skin >70 types have been recognized based on genetic homology Serotypes 1,2,3,4 verrucus vulgaris (common warts ) children and adolescents on hands and feet

PAPILLOMA VIRUS Serotypes

6, 11-Condylomata acuminata or genital warts moist soft, pedunculated found on external genitalia,Transmitted venereally,may occasionally turn malignant Serotypes 6,11-intraepithelial neoplasia Serotypes16,18-more severe invasive malignancies ca cervix and ca uterus

HUMAN PAPOVA VIRUSES Poduce

malignancies in patients with impaired immunity JC virus- isolated in 1971 from a patient with hodgkins disease and progressive multifocal leucoencephalopathy(PML) Reported from USA ,UK , and FRANCE Grows only in human fetal glial cell cultures Highly oncogenic Malignant gliomas on inoculation into newborn hamsters .

BK VIRUS Isolated

in 1971 from urine of a patient who underwent a kidney transplant Differs from JC virus Grows in a wide range of primary and continuous cell cultures Less oncogenic

BK AND JC VIRUSES Primary

infection in child hood

Multiplies in brain and renal tract

Reactivation

from latent infection during immunodeficiency states