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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
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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