Herpesviruses

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Herpesviruses

  1. 1. Herpesviruses
  2. 2. HerpesviridaeGeneral characteristics•Set up latent or persistent infection following primary infection•Reactivation are more likely to take place during periods ofimmunosuppression•Both primary infection and reactivation are likely to be more seriousin immunocompromised patients.
  3. 3. Herpesviridae3 Sub-families•Alphaherpesvirinae (HSV-1; HSV-2; VZV) – Grow rapidly – Latency in sensory neurons•Betaherpesvirinae (CMV; HHV-6; HHV-7) – Grow slowly – Latency in salivary glands, kidneys, lymphocytes•Gammaherpesvirinae (EBV; HHV-8/KSHV) – Lymphoproliferative diseases – Latency in lymphoid cells
  4. 4. Herpesviridae
  5. 5. HerpesviridaeHHV-1 Herpes simplex virus type 1 (HSV-1) α 70-90% Oral, ocular lesions; encephalitisHHV-2 Herpes simplex virus type 2 (HSV-2) α 30% Genital lesions; neonatal infectionsHHV-3 Varicella zoster virus (VZV) α 95% Chickenpox; shinglesHHV-4 Epstein-Barr virus (EBV) γ 95% IM; tumors (B cell, epithelial)HHV-5 Cytomegalovirus (CMV) β 80% IM; congenital infections; pneumonia (Tr.)HHV-6A Human herpesvirus-6A β ~100% Roseola; MS?; CFIDS?; immunocomp.HHV-6B Human herpesvirus-6B β ~100% Disease in immunocomp. hostsHHV-7 Human herpesvirus-7 β ~100% some roseolaHHV-8 Kaposi’s sarcoma-associated herpesvirus γ 15% Tumors (B cell, Kaposi’s sarcoma)
  6. 6. HerpesviridaeStructure•Enveloped•Double-stranded, linear DNA•70 to >200 genes•Encode enzymes involvedin nucleic acid metabolism (e.g.,thymidine kinase, ribonucleotidereductase,DNA polymerase) From: Principles of Virology: Molecular Biology, Pathogenesis, and Control. S.J. Flint et al.
  7. 7. HerpesviridaeStructure•Enveloped•Double-stranded, linear DNA•70 to >200 genes•Encode enzymes involvedin nucleic acid metabolism (e.g.,thymidine kinase, ribonucleotidereductase,DNA polymerase) http://www.stdgen.lanl.gov/stdgen/bacteria/hhv1/herpes.html
  8. 8. HerpesviridaeStructure•Enveloped•Double-stranded, linear DNA•70 to >200 genes•Encode enzymes involvedin nucleic acid metabolism (e.g.,thymidine kinase, ribonucleotidereductase,DNA polymerase) Linda Stannard, University of Cape Town, S.A
  9. 9. HerpesviridaeHHV-1 Herpes simplex virus type 1 (HSV-1) α 152 kb Oral, ocular lesions; encephalitisHHV-2 Herpes simplex virus type 2 (HSV-2) α 155 kb Genital lesions; neonatal infectionsHHV-3 Varicella zoster virus (VZV) α 125 kb Chickenpox; shinglesHHV-4 Epstein-Barr virus (EBV) γ 172 kb IM; tumors (B cell, epithelial)HHV-5 Cytomegalovirus (CMV) β 230/236 kb IM; congenital infections; pneumonia (Tr.)HHV-6A Human herpesvirus-6A β 159 kb Roseola; MS?; CFIDS?; immunocomp.HHV-6B Human herpesvirus-6B β 162 kb Disease in immunocomp. hostsHHV-7 Human herpesvirus-7 β 153 kb some roseolaHHV-8 Kaposi’s sarcoma-associated herpesvirus γ 138 kb* Tumors (B cell, Kaposi’s sarcoma)
  10. 10. Human HerpesvirusHerpes Simplex Viruses
  11. 11. Herpes Simplex VirusProperties•Belong to the alphaherpesvirus subfamily•Double stranded DNA enveloped virus•Genome of around 150 kb – HSV-1 and HSV-2 share 50 - 70% homology•Man is the only natural host for HSV.•HSV-1 and HSV-2 – Several cross-reactive epitopes within each other – Antigenic cross-reaction with VZV.
  12. 12. Herpes Simplex VirusProperties•HSV is spread by contact – saliva, tears, genital and other secretions•There are 2 peaks of incidence – at 0 - 5 years – late teens (when sexual activity commences)•HSV-1 causes infection “above the belt” – Only 40% of clinical isolates from genital sores are HSV-1;•HSV-2 causes infection “below the belt” – Only 5% of strains isolated from the facial area are HSV-2;
  13. 13. Herpes Simplex VirusProperties•Primary infection – is usually subclinical in most individuals; – It is a disease mainly of very young children ie. those below 5 years; – the most common form of infection results from a kiss; – 10% of the population acquires HSV through the genital route.•The virus then establishes latency in the craniospinal ganglia.•The exact mechanism of latency is not known, it may be true latency wherethere is no viral replication or viral persistence where there is a low level ofviral replication.
  14. 14. Herpes Simplex Virus From: Principles of Virology: Molecular Biology, Pathogenesis, and Control. S.J. Flint et al.
  15. 15. Herpes Simplex VirusProperties•Recurrence – Associated with physical or psychological stress, infections (especially pneumococcal and meningococcal) fever, irradiation (including sunlight), and menstruation. – 45% of orally infected individuals; – 60% of patients with genital herpes; – The mean number of episodes per year is about 1.6…(!?!?!?)
  16. 16. Herpes Simplex Virus From: Principles of Virology: Molecular Biology, Pathogenesis, and Control. S.J. Flint et al.
  17. 17. Herpes Simplex VirusClinical Manifestations•Acute gingivostomatitis•Herpes Labialis (cold sore)•Ocular Herpes•Herpes Genitalis•Other forms of cutaneous herpes•Meningitis•Encephalitis•Neonatal herpes
  18. 18. Herpes Simplex VirusDiagnostic•Direct Detection – Electron microscopy (rapid result but cannot distinguish between HSV and VZV) – Immunofluorescence (distinguish HSV and VZV) – PCR (routine for the diagnosis of herpetic encephalitis)•Virus Isolation – 1 - 5 days•Serology – 1-2 weeks before antibodies appear n: – Used to document to recent infection.
  19. 19. Herpes Simplex VirusTreatmentAcyclovir – this the drug of choice for most situations at present.– Intravenous for HSV infection in normal and immunocompromised patients;– Oral treatment and long term suppression of mucocutaneous herpes and prophylaxis of HSV in immunocompromised patients;– Topically for HSV infection of the skin and mucous membranes;Famciclovir and valacyclovir– oral only, more expensive than acyclovir.Other older agents (idoxuridine, trifluorothymidine, Vidarabine (ara-A)
  20. 20. Herpes Simplex Virus De Clercq, E. Nat. Rev. Microbiol. 2:704, 2004.
  21. 21. Human HerpesvirusVaricella Zoster Virus
  22. 22. Varicella Zoster VirusProperties•Belong to the alphaherpesvirus subfamily•Double stranded DNA enveloped virus•Genome of around 123 kb – Genome size 125 kbp, long and short fragments with a total of 4 isometric forms.
  23. 23. Varicella Zoster VirusProperties• Varicella (chickenpox) is an endemic disease.– Highly communicable (attack rate of 90% in close contacts);•Most people become infected before adulthood– Classic diseases of childhood;– Highest prevalence occurring in the 4 - 10 years old age group;– 10% of young adults remain susceptible;•Primary Infection– Entry via the respiratory tract– Incubation period of 14-21 days– fever, lymphadadenopathy. and widespread vesicular rashs
  24. 24. Varicella Zoster VirusProperties•Herpes zoster – occurs sporadically – at any age (more frequently >50 years)•The virus reactivates in the ganglion andtracks down the sensory nerve to the area ofthe skin innervated by the nerve, producinga varicella form rash in the distribution of adermatome.•There is a characteristic eruption ofvesicles in the dermatome which is oftenaccompanied by intensive pain which maylast for months (postherpetic neuralgia);
  25. 25. Varicella Zoster VirusComplications•Varicella – rare but occurs more frequently in adults and immunocompromised patients; – Most common complication is secondary bacterial infection of the vesicles; – Severe complications which may be life threatening include viral pneumonia, encephalititis, and haemorrhagic chickenpox.•Herpes Zoster – rare but occurs more frequently in immunocompromised patient; – Herpes zoster affecting the eye and face may pose great problems; – Major concerns are: encephalitis and disseminated herpes zoster.
  26. 26. Varicella Zoster VirusDiagnostic•Direct Detection – Electron microscopy (rapid but cannot distinguish between HSV and VZV) – Immunofluorescence (distinguish HSV and VZV) – PCR (routine for the diagnosis of herpetic encephalitis)•Virus Isolation – 2 - 3 weeks•Serology – VZV IgG  past infection; – VZV IgM  recent primary infection; Cytopathic Effect of VZV in cell culture: Note the ballooning of cells. (Coutesy of Linda Stannard, University of Cape Town, S.A.)
  27. 27. Varicella Zoster VirusTreatment•Uncomplicated varicella is a self limited disease and requires no specifictreatment. However, acyclovir had been shown to accelerate the resolution ofthe disease and is prescribed by some doctors.•The International Herpes Management Forum recommends that antiviraltherapy should be offered routinely to all patients over 50 years of agepresenting with herpes zoster: – acyclovir, valicyclovir, and famciclovir; – little difference in efficacy between them;
  28. 28. Varicella Zoster VirusPrevention•Preventive measures should be considered for individuals at risk – leukaemic children, neonates, and pregnant women; – passive immunization with Zoster immunoglobulin (ZIG) is the preparation of choice but it is very expensive.•A live attenuated vaccine is available. – Great reluctance to use it in the past, especially in immunocompromised individuals since the vaccine virus can become latent and reactivate later on; – Recent data suggests that the vaccine is safe.
  29. 29. Human HerpesvirusCytomegalovirus
  30. 30. CytomegalovirusProperties•Belong to the betaherpesvirus subfamily• Nucleocapsid 105nm in diameter, 162 capsomers• Double stranded DNA enveloped virus – long and short segments orientated in either direction
  31. 31. CytomegalovirusProperties•Transmitted vertically or horizontally usually with little effect on the host; – Transmission may occur in utero, perinatally or postnatally; – Sexual transmission may occur as well as through blood and blood products and transplanted organ.•In developed countries with a high standard of hygiene, 40% of adolescentsare infected and ultimately 70% of the population is infected. In developingcountries, over 90% of people are ultimately infected.•Once infected, the person carries the virus for life which may be activatedfrom time to time, during which infectious virions appear in the urine and thesaliva.
  32. 32. CytomegalovirusProperties•Congenital infection - may result in cytomegalic inclusion disease – isolation of CMV from the saliva or urine within 3 weeks of birth. – affects 0.3 - 1% of all live births – second most common cause of mental handicap after Downs syndrome and is responsible for more cases of congenital damage than rubella.•Transmission occur s following primary or recurrent CMV infection. – May be transmitted to the fetus during all stages of pregnancy; – 40% chance of transmission to the fetus following a primary infection.;
  33. 33. CytomegalovirusProperties•Perinatal infection – acquired mainly through infected genital secretions, or breast milk; – 10 times more common – 2 - 10% of infants are infected by the age of 6 months worldwide – usually asymptomatic•Postnatal infection – mainly occurs through saliv – usually asymptomatic – syndrome of infectious mononucleosis may develop
  34. 34. CytomegalovirusCytomegalic Inclusion Disease•CNS abnormalities - microcephaly, mental retardation, spasticity, epilepsy,periventricular calcification.•Eye - choroidoretinitis and optic atrophy•Ear - sensorineural deafness•Liver - hepatosplenomegaly and jaundice which is due to hepatitis.•Lung - pneumonitis•Heart - myocarditis•Thrombocytopenic purpura, Haemolytic anaemia•Late sequelae in individuals asymptomatic at birth - hearing defects andreduced intelligence.
  35. 35. CytomegalovirusDiagnostic•Direct Detection – biopsy specimens may be examined histologically for CMV inclusion antibodies or for the presence of CMV antigens; – The pp65 CMV antigenaemia test is routinely used for rapid diagnosis; – PCR for CMV-DNA...•Virus Isolation – requires up to 4 weeks for result. – rapid culture methods (DEAFF) can provide a result in 24-48 hours.•Serology – CMV IgG  past infection; – CMV IgM  recent primary infection;
  36. 36. CytomegalovirusTreatmentAnti-CMV agents in current use are ganciclovir, forscarnet, and cidofovir.•Congenital infections - it is not usually possible to detect congenital infectionunless the mother has symptoms of primary infection. If so, then the mothershould be told of the chances of her baby having cytomegalic inclusiondisease and perhaps offered the choice of an abortion.•Perinatal/postnatal infection - it is usually not necessary to treat•Immunocompromised patients - it is necessary to make a diagnosis of CMVinfection early and give prompt antiviral therapy;
  37. 37. Human HerpesvirusEpstein-Barr Virus
  38. 38. Epstein-Barr VirusProperties•Belong to the gammaherpesvirus subfamily• Nucleocapsid 100nm in diameter, 162 capsomers• Double stranded DNA enveloped virus – Genome is a linear double stranded DNA molecule with 172 kbp – The viral genome does not normally integrate into the cellular DNA but forms circular episomes which reside in the nucleus. – The genome is large enough to code for 100 - 200 proteins
  39. 39. Epstein-Barr VirusPropertiesTwo epidemiological patterns are seen with EBV.•In developed countries (2 peaks of infection) – 80-90% of adults are infected; – the first in very young preschool children aged 1-6 years old; – the second in adolescents and young adults aged 14 – 20•In developing countries – 90% of children are seropositive – infection occurs at a earlier age (<2 years old)
  40. 40. Epstein-Barr VirusProperties•Transmitted by contact with saliva, in particularly through kissing.•Once infected, a lifelong carrier state develops whereby a low grade infectionis kept in check by the immune defenses. – Low grade virus replication and shedding can be demonstrated in the epithelial cells of the pharynx of all seropositive individuals.•EBV is able to immortalize B-lymphocytes in vitro and in vivo•Furthermore a few EBV-immortalized B-cells can be demonstrated in thecirculation which are continually cleared by immune surveillance mechanisms.
  41. 41. Epstein-Barr VirusClinical Manifestations1.Infectious Mononucleosis2.Burkitts lymphoma3.Nasopharyngeal carcinoma4.Lymphoproliferative disease and lymphoma in the immunosuppressed.5.X-linked lymphoproliferative syndrome6.Chronic infectious mononucleosis7.Oral leukoplakia in AIDS patients8.Chronic interstitial pneumonitis in AIDS patients.
  42. 42. Epstein-Barr VirusDiagnostic•Direct Detection – PCR for CMV-DNA... – Immunohistochemestry for viral proteins in tissue samples•Serology – EBV IgG VCA  past infection; – EBV IgM VCA  recent primary infection;
  43. 43. Epstein-Barr VirusPrevention•A vaccine should be able to control both BL and NPC. – Such a vaccine must be given early in life. – Would also be useful in seronegative organ transplant recipients and those developing severe IM, such as the male offspring of X-linked proliferative syndrome carriers.•The antigen chosen for vaccine development is the MA antigen gp 340/220 asantibodies against this antigen are virus neutralizing. – This vaccine is being tried in Africa.
  44. 44. Human HerpesvirusOther Human Herpesvirus
  45. 45. HHV-6 and HHV-7Properties•Belong to the betaherpesvirus subfamily•Double stranded DNA genome of 170 kbp•Despite related HHV-6 and HHV-7 share limited nucleotide homology andantigenic cross-reactivity.•Infect: – T-lymphocytes (most frequently) – B-lymphocytes
  46. 46. HHV-6 and HHV-7Properties•HHV-6 and HHV-7 are ubiquitous and are found worldwide. – transmitted mainly through contact with saliva and through breast feeding.•HHV-6 and HHV-7 infection are acquired rapidly after the age of 4 monthswhen the effect of maternal antibody wears off. – By the time of adulthood, 90-99% of the population had been infected by both viruses.•Like other herpesviruses, HHV-6 and HHV-7 remains latent in the body afterprimary infection and reactivates from time to time.
  47. 47. HHV-6 and HHV-7Clinical Manifestations•HHV-6 is associated with Roseala Infantum, – which is a classical disease of childhood. – Most cases occur in infants between the ages of 4 months and two years. – A spiking fever develops over a period of 2 days followed by a mild rash. – There are reports that the disease may be complicated by encephalitis.•HHV-7 has no firm disease association•Although both viruses may be reactivated inimmunocompromised patients, it is yet uncertainwhether they cause significant disease sinceCMV is almost invariably present.
  48. 48. HHV-6 and HHV-7Diagnosis and Treatment•Only few virology laboratories offer a diagnostic for HHV-6 or HHV-7 – The technique for virus isolation is complicated – Therefore serology is the mainstay of diagnosis where specific IgM and IgG are detected. – Molecular diagnosis has been the best approach•There is no specific antiviral treatment for HHV-6 and HHV-7 infection.
  49. 49. HHV-8 / KSHVProperties•Belong to the gammaherpesviruses subfamily•Originally isolated from cells of Kaposi’s sarcoma (KS) – firmly associated with Kaposi’s sarcoma as well as some lesser known malignancies such as Castleman’s disease and primary effusion lymphomas•The seroprevalence of HHV-8 is low among the general population but ishigh in groups of individuals susceptible to KS, such as homosexuals.•Unlike other herpesviruses, HHV-8 does not have a ubiquitous distribution.
  50. 50. HHV-8 / KSHVProperties•Belong to the gammaherpesviruses subfamily•Originally isolated from cells of Kaposi’s sarcoma(KS) – firmly associated with Kaposi’s sarcoma as well as some lesser known malignancies such as Castleman’s disease and primary effusion lymphomas•The seroprevalence of HHV-8 is low among thegeneral population but is high in groups ofindividuals susceptible to KS, such ashomosexuals.•Unlike other herpesviruses, HHV-8 does not havea ubiquitous distribution.

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