HERPESVIRUS FAMILY
 Herpes, Pox and Adeno are DNA viruses.
 Herpes has an icosahedral core surrounded by a lipoprotein e...
 The Herpes family contains six important human pathogens: Herpes simplex

virus types 1 and 2, varicella-zoster virus, C...
 Herpes Simplex Type 1 (HSV-1) and Herpes Simplex virus type 2 (HSV-2):
 They differ in their antigenicity and the locat...
HSV-2 cause:
Herpes genitalis, characterized by painful vesicular lesions of

the male/female genitals ant the anal area...
Both HSV-1 and HSV-2 are not known to cause any

significant congenital abnormalities.
Both their infections are associa...
Pathogenesis:
The virus replicates in the skin or mucous membrane at the

initial site of infection and migrates up the ...
HSV binds to heparan sulfate and nectin (receptors on the cell

surface). Viral envelope fuses with the cell membrane and...
Lab diagnosis:
Isolation of virus from the lesion by growth in the cell culture

where CPE is seen in 1-3 days, after wh...
Varicella-Zoster virus (VZV ):
Varicella(chickenpox is the primary disease)
Zoster(shingles) is the recurrent form.
Mo...
Pathogenesis:
Infects the mucosa of the upper respiratory tract then

spreads via blood to the skin where characteristic...
Clinical findings after an incubation period of 14-21

days with brief initial symptoms of fever and malaise
followed by ...
Lab diagnosis:
Usually not necessary. Clinical diagnosis is sufficient.
Tzanck smear and observing multinucleated cells...
Cytomegalovirus (CMV):
Most common cause of congenital abnormalities

(cytomegalic inclusion disease) in neonates.
Impo...
Pathogenesis:
Infection of the fetus can cause cytomegalic inclusion

disease, characterized by multinucleated giant cel...
Clinical findings of Cytomegalic inclusion disease

include microcephaly, seizures, jaundice, deafness
with hepatosplenom...
Lab diagnosis:
Same as isolate virus in cell culture with fluoroscent

antibody staining.
Fluoroscent antibody and hist...
Epstein-Barr virus (EBV):
EBV causes Infectious mononucleosis. Associated with Burkitts

Lymphoma, naso-pharyngeal carci...
Pathogenesis:
Infection occurs in the oropharynx and spreads to the

blood where it infects the B-lymphocytes. Cytotoxic...
 Clinical findings:
 Infectious mononucleosis characterized by fever, sore throat,

lymphadenopathy and splenomegaly wit...
Lab diagnosis:
Hematological approach reveals absolute Lymphocytosis

with about 30% of them abnormal. These are the aty...
Treatment : No antiviral required. High doses of

Acyclovir for life threatening EBV infections.
Human Herpesvirus 8 (HHV-8):
Associated with Kaposi’s sarcoma mespecially in

immunocompromised cases.
Malignant transf...
POX VIRUSES
The poxvirus family includes smallpox virus, vaccinia virus

and molluscum contagiosum virus (MCV).
Poxvirus...
Small pox virus:
Also called Variola virus.
Transmitted by respiratory aerosolor by direct contact

either in the skin ...
Clinical findings:
Incubation of 7-14 days with a sudden onset of fever

and malaise, followed by rashes, worse on the f...
Lab diagnosis:
By growing the virus in cell culture or chick embryo.
Also by detecting viral antigens in vesicular flui...
Molluscum contagiosum virus (MCV) :
Distinct from small poox and vaccinia virus.
The lesion is flesh colored on the ski...
ADENO VIRUS
Adenoviruses are icosahedral, non-enveloped, with DS-

DNA.
It is the only virus with fiber (organ of attach...
Transmitted through aerosol droplet, feco-oral route 9most

common among children) and direct innoculation of
conjunctiva...
Clinical findings include fever, sore throat, runny

nose and conjunctivitis. Lower respiratory tract
involvement is asso...
Lab diagnosis:
Involves isolation of virus in cell culture.
Complement fixation tests and Hemagglutination

inhibition ...
Herpes, pox and adeno viruses 2003
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Herpes, pox and adeno viruses 2003

  1. 1. HERPESVIRUS FAMILY  Herpes, Pox and Adeno are DNA viruses.  Herpes has an icosahedral core surrounded by a lipoprotein envelope. They contain linear, DS DNA as their genome. The virion does not possess a polymerase and uses the host cell RNA polymerase to synthesize its viral mRNA.  They replicate in the nucleus, form intracellular inclusions and are the only viruses that obtain their envelope by budding from the nuclear membrane.  The virions of Herpes contain a Tegument ( a structure located between the nucleocapsid and the envelope) which contains regulatory proteins, such as transcription and translation factors that play a role in viral replication.  Herpes are known to cause Latent Infections, which is the asymptomatic period after the Acute phase of illness. Reactivation can occur. The latent period is associated with the synthesis of non-coding regulatory RNA’s (Latency-associated transcripts /LATS) that suppress replication. Fever, stress, sunlight etc.. Can trigger off the reactivation of viral replication.
  2. 2.  The Herpes family contains six important human pathogens: Herpes simplex virus types 1 and 2, varicella-zoster virus, Cytomegalovirus(CMV), Epstein Barr virus (EBV) and Herpesvirus8.  Herpes simplex type 1 and 2 and varicella-zoster cause a vesicular rash, both in primary infection and subsequent reactivation. CMV and EBV do not.  Herpes simplex type 1 and 2 , Varicella-zoster, and CMV induce the formation of multinucleated giant cells, observed microscopically by the Tzanck smear.  The Herpes family can be subdivided into 3 categories, based on the cell type most often infected and the site of latency:  A) The Alpha herpesviruses consisting of Herpes type 1 and 2, varicella-zoster, infect epithelial cells primarily and cause latent infection in the neurons.  B) The Beta Herpesviruses include the CMV and human herpes6 can infect and become latent in many tissues.  C) The Gamma Herpesviruses are the EBV and human herpesvirus8, infect and become latent primarily in lymphoid cells. EBV is also associated with certain cancers like Burkitts lymphoma and nasopharyngeal carcinoma, and Herpesvirus8 is with Kaposi’s sarcoma.
  3. 3.  Herpes Simplex Type 1 (HSV-1) and Herpes Simplex virus type 2 (HSV-2):  They differ in their antigenicity and the location of lesions caused. HSV-1 lesions are usually above the waist and HSV-2 lesions below the waist.  HSV-1 causes:  Acute gingivostomatitis ( in children, fever and vesicular lesions in the mouth. Primary disease more severe than relapse.  Herpes labialis or cold sores (fever blisters) is milder, recurrent form, characterized by crops of vesicles usually at the mucocutaneous junction of lips or nose, recurrences frequently at the same site.  Keratoconjunctivitis or Keratitis, characterized by corneal ulcersand lesions of the conjunctival epithelium, recurrences can lead to blindness.  Encephalitis, primarily in adults, characterized by a necrotic lesion in one temporal lobe, with fever, headache, vomitting, seizures and altered mental status are typical clinical manifestations. HSV-1 encephalitis has a high mortality rate and cause severe neurologic sequelae in those who survive.
  4. 4. HSV-2 cause: Herpes genitalis, characterized by painful vesicular lesions of the male/female genitals ant the anal area as well. Lesions more severe in primary infection than recurrences. Asymptomatic infections (in urethra/prostae in male and in the cervix in the female)can occur and the affected individual act as carriers. Neonatal encephalitis and neonatal herpes. Aseptic meningitis caused is mild and self-limiting. Neonatal herpes is the infection of the child at birth due to vesicles within the birth canal or asymptomatic viral shedding within the birth canal. The disease varies from severe(disseminated lesions or encephalitis) to milder local( skin, eye, mouth ) to asymptomatic infection. The disease likely to be more severe if the mother is experiencing a primary infection rather than a recurrent one (more viral load and protective IgG formed in primary infection cross the placental barrier).
  5. 5. Both HSV-1 and HSV-2 are not known to cause any significant congenital abnormalities. Both their infections are associated with Erythema multiformae ( red-normal skin-red ring ) thought to be immune-related to the HSV antigens. HSV-1 transmitted by saliva and HSV-2 by sexual contact.
  6. 6. Pathogenesis: The virus replicates in the skin or mucous membrane at the initial site of infection and migrates up the neuron by retrogade axonal flow and becomes latent in the sensory ganglion cells of the trigeminal ganglia (HSV-1) or lumbar and sacral ganglia. During latency, most viral DNA is located in the cytoplasm. On reactivation by stress, fever hormonal changes, trauma etc.. the virus migrates down the neuron and replicates in the skin causing lesions. The typical skin lesion is a vesicle that contains serous fluid filled with virus particles and cell debris. Multinucleated cells are typically found at the base of the lesion. Immunity is incomplete and cell mediated immunity important to suppress reactivation ,severity and spread of the infection.
  7. 7. HSV binds to heparan sulfate and nectin (receptors on the cell surface). Viral envelope fuses with the cell membrane and the nucleocapsid and tegument proteins are released into the cytoplasm. Viral nucleocapsid docks on to a nuclear pore and the genome DNA along with tegument protein VP16, enters the nucleus. VP16 interacts with cellular transcription factors transcribing Immediate early (IE) genes by the host cell RNA polymerase. Translated IE proteins regulate the synthesis of early proteins such as DNA polymerase that in turn replicates the genome and late protein synthesis begins . These late, structural proteins are transported to the nucleus, where virion assembly occurs. The virus obtains its envelope by budding through the nuclear membrane.
  8. 8. Lab diagnosis: Isolation of virus from the lesion by growth in the cell culture where CPE is seen in 1-3 days, after which virus is identified by fluoroscent antibody staining of the infected cells or by detecting virus-specific glycoproteins in ELISA. Rapid diagnosis using the Tzanck smear, where cells from the base of the vesicles are stained with Giemsa stain, indentifying presence of multi-nucleates giant cells. Treatment: Acyclovir (acycloguanosine) is the treatment of choice. Prevention: Avoid contact with the vesicular lesion or ulcer.
  9. 9. Varicella-Zoster virus (VZV ): Varicella(chickenpox is the primary disease) Zoster(shingles) is the recurrent form. Morphologically same but antigenically different from HSV. Virus transmitted by respiratory droplets and by direct contact with varicella or zoster lesions. Varicella highly contagious. In hospital surroundings, can cause life-threatening disseminated infections in immunocompromised patients.
  10. 10. Pathogenesis: Infects the mucosa of the upper respiratory tract then spreads via blood to the skin where characteristic vesicular rash occurs. Multinucleated giant cells with intranuclear inclusions seen in the base of the lesions. Infects sensory neurons and carried by retrograde axonal flow into the cells of the Dorsal root ganglia where it becomes latent. Reactivation causes vesicular skin lesions and the characteristic nerve pain of the Zoster. Immunity, life long for varicella, but zoster can occur usually once.
  11. 11. Clinical findings after an incubation period of 14-21 days with brief initial symptoms of fever and malaise followed by vesicular rash on the trunk and spreads to the head and extremities. The rash evolves from papules to vesicles, pustules and crusts. Itching is a prominent symptom. Reye’s syndrome (encephalopathy and liver degeneration) is associated with VSV infection. Zoster infection involves painful vesicles along the sensory nerve of the head or trunk lasting for weeks followed by post-zoster neuralgia.
  12. 12. Lab diagnosis: Usually not necessary. Clinical diagnosis is sufficient. Tzanck smear and observing multinucleated cells and for definitive diagnosis by isolating virus in cell culture and specific antiserum. No treatment required. Acyclovir for immunocompromised individuals or disseminated disease. Prevention includes vaccine for varicella (children from 1-12 years) and vaccine for Zoster (adults above 60 who have had varicella) . Both contain live, attenuated VZV. Zoster vaccine contains many (14) times more VZV than varicella vaccine. Not to be given to immunocompromised individuals. Varicella-zoster immune globulin also available for prophylaxis.
  13. 13. Cytomegalovirus (CMV): Most common cause of congenital abnormalities (cytomegalic inclusion disease) in neonates. Important cause of viral pneumonia in the immunocompromised. Antigenically different from other members of the Herpes family. As giant cells are formed, known as cytomegalo. Mode of transmission is varied from across the placenta, within the birth canal, and breast milk. In young children spreads through saliva and sexually in adults (present in semen and cervical secretions), during blood transfusion and organ transplant..
  14. 14. Pathogenesis: Infection of the fetus can cause cytomegalic inclusion disease, characterized by multinucleated giant cells with prominent intranuclear inclusions. Congenital abnormalities more common when fetus infected during the first trimester. CMV enters latency in the monocytes reactivated ( in cervical cells resulting in infection of newborn) when cellmediated immunity is reduced and can persist in kidneys for years. As the assembly of the MHC-I complex is unstable in CMV infected cells, viral antigens are not displayed properly and can evade action by the cytotoxic T-cells. Thus, CMV can cause an immunosuppressive effect by inhibiting T-cells.
  15. 15. Clinical findings of Cytomegalic inclusion disease include microcephaly, seizures, jaundice, deafness with hepatosplenomegaly and mental retardation in severe cases. Systemic CMV infections like pneumonitis and hepatitis in immunocompromised cases.
  16. 16. Lab diagnosis: Same as isolate virus in cell culture with fluoroscent antibody staining. Fluoroscent antibody and histologic staining of inclusion bodies in giant cells appear as oval owl’s eye shaped. Pp65 is a nucleocapsid protein of CMV, identified within infected leukocytes using fluoroscein labelled monoclonal antibody. Treatment : Ganciclovir (cytovene) effective. Prevention: No vaccine. Blood and all pre disposing factors to be screened for CMV.
  17. 17. Epstein-Barr virus (EBV): EBV causes Infectious mononucleosis. Associated with Burkitts Lymphoma, naso-pharyngeal carcinoma, other B-cell lymphomas and Hairy leukoplakia. It can also infect the epithelial cells of the pharynx and cause a severe sore throat. EBV antigenically different. Most important diagnostic antigen is the Viral Capsid antigen(VCA). EBV mainly infects the lymphoid cells, primarily Blymphocytes. In latent stage, its genome is in the nucleus, not integrated into the cellular DNA. Mode of transmission through saliva (kissing) . Blood transmission is rare.
  18. 18. Pathogenesis: Infection occurs in the oropharynx and spreads to the blood where it infects the B-lymphocytes. Cytotoxic Tcells react against the infected B-cells and these Atypical lymphs are seen in the blood smear. IgM antibodies as the first line of immune response is diagnostic of acute infection. Non-specific heterophil antibodies are found. Heterophil, because they are detected by different antigens from the ones that induced them. These heterophil antibodies can agglutinate sheep and horse RBC’s in the lab.
  19. 19.  Clinical findings:  Infectious mononucleosis characterized by fever, sore throat, lymphadenopathy and splenomegaly with hepatitis and encephalitis in some patients.  Can cause a severe fatal progressive form of Infectious mononucleosis in children with X-linked lymphoproliferative syndrome, a inherited immunodeficiency of the mutated gene coding for a signal transcduction protein required for both T-cell and NK-cell function.  Hairy leukoplakia manifests as a whitish, lesion with hairy surface on the lateral side of the tongue, especially in immunocompromised HIV cases.  EBV associated with Burkitt’s lymphoma and other malignancies.  EBV associated post-transplant lymphoproliferative disorder(PTLD) manifesting as a B-cell lymphoma, following bone-marrow and solid organ transplants due to their immunosuppressed condition.
  20. 20. Lab diagnosis: Hematological approach reveals absolute Lymphocytosis with about 30% of them abnormal. These are the atypical lymph which appear as large with an expanded nucleus, and an abundantly vacuolated cytoplasm. These are the cytotoxic T-cells that react with the infected B-cells. The heterophil antibody titer useful for prior detection (as antibody titers decline on recovery). EBV specific antibody tests to diagnose difficult cases. IgM VCA antibody response for early diagnosis. No isolation of the virus done as it is very difficult.
  21. 21. Treatment : No antiviral required. High doses of Acyclovir for life threatening EBV infections.
  22. 22. Human Herpesvirus 8 (HHV-8): Associated with Kaposi’s sarcoma mespecially in immunocompromised cases. Malignant transformation is by inactivation of the RB(retinoblastoma) tumor suppressor gene. KS is a malignancy of vascular endothelial cells that contains many spindle shaped cells and erythrocytes. The lesions are dark purple, flat to nodular and appear at multiple sites such as skin, oral cavity and soles. Internally lesions occur in the GI tract. No specific antiviral therapy and no vaccine against HHV8.
  23. 23. POX VIRUSES The poxvirus family includes smallpox virus, vaccinia virus and molluscum contagiosum virus (MCV). Poxviruses are the largest and most complex viruses. They are brick shaped , DS-DNA, a disc shaped core with a double membrane and a lipoprotein envelope. The virion contains a DNA-dependent RNA polymerase, as it replicates in the cytoplasm with no access to cellular RNA polymerase. Single serotype and infects only humans. Replication cycle entirely in the cytoplasm, unusual for a DNA virus.
  24. 24. Small pox virus: Also called Variola virus. Transmitted by respiratory aerosolor by direct contact either in the skin lesions or on fomites such as bedding. Pathogenesis: Virus infects the upper respiratory tract and local lymph nodes and enters the blood stream (primary viremia). Internal organs infected and the virus reenters the blood (secondary viremia)and spreads to the skin. The rash is the result of the virus replication in the skin followed by cytotoxic T-cells attacking virus-infected cells.
  25. 25. Clinical findings: Incubation of 7-14 days with a sudden onset of fever and malaise, followed by rashes, worse on the face and extremities than on the trunk. The rash evolves from macules to papules, vesicles, pustules and finally crusts in 2-3 weeks.
  26. 26. Lab diagnosis: By growing the virus in cell culture or chick embryo. Also by detecting viral antigens in vesicular fluid by immunofluorescense. Prevention: By vaccine containing live attenuated vaccinia virus is innoculated intradermally.
  27. 27. Molluscum contagiosum virus (MCV) : Distinct from small poox and vaccinia virus. The lesion is flesh colored on the skin, painless nonpuritic and not inflammed with a charcteristic cup-shaped crater with a white core.The lesion consists of hyperplastic epithelial cells with a cytoplasmic inclusion body containing MCV progeny. MCV transmitted by close contact, and common in children and immunocompromised individuals. Treatment is to boost cell-mediated immunity.
  28. 28. ADENO VIRUS Adenoviruses are icosahedral, non-enveloped, with DS- DNA. It is the only virus with fiber (organ of attachment and is a hemagglutinin) protruding from each of the 12 vertices of the capsid. The fiber, purified free from the virions is toxic to human cells. They cause a variety of upper and lower respiratory disease like pharyngitis, conjunctivitis (pink eye), common cold and pneumonia. Keratoconjunctivitis, hemorrhagic cystitis and gastroenteritis can also occur. Virus assembly occurs in the nucleus and released by cell lysis and not by budding.
  29. 29. Transmitted through aerosol droplet, feco-oral route 9most common among children) and direct innoculation of conjunctiva with fingers. 41 antigenic types known based on their type specific fiber protein. Pathogenesis: These infect the mucosal epithelium of several organs like the respiratory tract, the GI tract and the conjunctivas. Immunity based on type specific neutralizing antibody and is life long. Acute infection leads to cell death with the latent infection particularly in the adenoidal and tonsillar tissues of the throat.
  30. 30. Clinical findings include fever, sore throat, runny nose and conjunctivitis. Lower respiratory tract involvement is associated with bronchitis and atypical pneumonia. Hematuria and dysuria prominent in hemorrhagic cystitis. Gastroenteritis with non-bloody diarrhea in children below 2 years.
  31. 31. Lab diagnosis: Involves isolation of virus in cell culture. Complement fixation tests and Hemagglutination inhibition tests are diagnostic. No antiviral therapy. Prevention by hygiene. No vaccine for civilian use.

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