HERPESVIRIDAE

• STRUCTURE: ds-DNA, linear, enveloped.

  • Tegument: Amorphous protein structure that surrounds the capsid.

• DIAGNOSIS: Cell culture will show intranuclear inclusion bodies.

• ALPHA-HERPES VIRUSES: Grow very rapidly, have a broad host-range. Latency is usually in neural tissue.

  • REPLICATION: Occurs in the nucleus.

    • HSV-1 and HSV-2 binds to a heparin sulfate receptor, present on every cell in the body.

    • Immediate Early Genes:

      • alpha-Trans inducing Protein, associated with the tegument, induces the production of the immediate early genes.

      • The protein-products from these genes are transported back into the nucleus, where they induce transcription of the delayed early genes.

    • Delayed Early Genes: Encodes about 15 proteins involved in viral DNA replication, including DNA polymerase and Thymidine kinase. Viral DNA replication then occurs.

    • Late Genes: They encode structural proteins, formed after DNA replication is complete. More than 50% of formed virions are released from cell.

  • HERPES SIMPLEX:

    • STRUCTURE: More than 8 glycoproteins on viral envelope. HSV-1 and HSV- show about 50% antigenic relatedness.

    • PATHOGENESIS:

      • Acute infection is usually local, producing vesicles which are infectious and often ulcerate.

      • Latent Infection: Virus travels up neuron to ganglion where it becomes latent.

        • During latent infection, the virus does not replicate. Only a set of genes called latency-associated transcripts (LAT) are transcribed.

        • For oral Herpes (HSV-1), the virus remains latent in the Trigeminal Ganglion.

        • Reactivation can occur as a result of stress, immunosuppression, illness, etc.

    • DIAGNOSIS: Look for Cytopathic Effect (CPE) 24-36 hrs after inoculation of vesicular sample in tissue culture.

      • Can see multinucleated Giant cells.

      • Can use Neutralization Test or immunofluorescence.

    • HERPES SIMPLEX 1 (HHV-1, HSV-1): Infection usually occurs early in childhood, and in some communities more than 90% seroconversion is seen by age 10.

      • MANIFESTATIONS:

        • Encephalitis: Acute febrile disease.

        • Keratoconjunctivitis: May result in permanent corneal damage and visual impairment.

        • Acute Herpetic Gingivostomatitis: Almost always caused by HSV-1. Happens in toddlers.

        • Herpes Labialis: Primarily HSV-1, but both can infect.

    • HERPES SIMPLEX 2 (HHV-2, HSV-2):

      • Due to cross-reactivity, individuals with HSV-1 infection get a milder form of HSV-2 infection.

      • MANIFESTATIONS:

        • Genital Herpes: Primarily HSV-2, but both can infect.

          • May be associated with fever, malaise, and inguinal lymphadenopathy.

          • Virus goes up and remains latent in lumbo-sacral ganglia.

        • Neonatal Herpes: Perinatal transmission of HSV-2, during an active infection, through the birth canal. Outcome can range from subclinical to severe.

        • Proctitis:

        • Meningitis:

        • Whitlow: HSV-1 or HSV-2. Infection of fingers in healthcare personnel or kiddies who suck their thumbs.

    • TREATMENT:

      • Idoxuridine: Topical ointment

      • Ara-A: Older drug inhibits DNA replication, but it's toxic. Used for encephalitis, or topically for keratitis.

      • IUDR: Acts on DNA replication and is too toxic to use systemically.

      • Acyclovir: Converted into triphosphate form by viral Thymidine Kinase. It blocks viral DNA polymerase and is virtually non-toxic. It does not cure latent infection but it's great for symptomatic infections.

  • VARICELLA-ZOSTER VIRUS (HHV-3, VZV):

    • REPLICATION: Daughter virions remain largely cell-associated.

    • TRANSMISSION is probably respiratory. Nasal mucosa.

    • PATHOGENESIS:

      • Latent Infection: VZV virus remains latent in dorsal root ganglion, where it can later reactivate to form Zoster.

    • MANIFESTATIONS:

      • Chicken-Pox (Varicella):

        • Symptoms: Fever and malaise. Rash starts on trunk and spreads outward to extremities.

        • In early infection, eosinophilic inclusion bodies are found in nuclei of infected cells.

        • Complications:

          • Encephalitis is a rare complication, associated with increased mortality (10%) and permanent CNS residual damage (10%).

          • Varicella Pneumonia: Rare in children; 20-30% of adults.

      • Shingles (Zoster): Reactivation infection, occurs (usually) unilaterally over a single dermatome, often over the face.

        • Skin lesions identical to Varicella.

• BETA-HERPES VIRUSES: Grow slowly, have a narrow host range, latency in various tissues.

  • CYTOMEGALOVIRUS (HHV-5, CMV):

    • REPLICATION: About 25% of infected virions leave the cell.

    • PATHOGENESIS:

      • Primary infection is usually asymptomatic.

      • Found in cervix of up to 10% of healthy women.

    • EPIDEMIOLOGY:

      • 50-70% of women of child-bearing age are seropositive.

      • Pregnant women usually have subclinical infection. 10-15%

      • CMV is the most common agent of congenital infection, about 1% of all live births.

    • MANIFESTATIONS:

      • In children, may see hepatitis, interstitial pneumonitis, or acquired hemolytic anemia.

      • Cytomegalic Inclusion Disease: Congenital CMV infection. Either intrauterine or early post-natal infection with CMV.

        • May be asymptomatic, or result in mental retardation or death.

        • Large intranuclear inclusions can be seen on histo, in salivary glands, liver, pancreas, kidneys, endocrine glands, brain.

      • Infectious Mononucleosis: CMV is responsible for 10% of cases. It differs from EBV Mono in that you won't see heterophil antibodies.

      • IMMUNOCOMPROMISED:

        • CMV Pneumonitis or hepatitis is common, or occasionally generalized disease.

        • CMV infection is frequently seen in transplant patients.

    • TREATMENT: Ganciclovir

      • Acyclic analog of guanosine inhibits CMV DNA Polymerase.

        • In Immunocompromised, the drug is good for CMV retinitis, esophagitis, and colitis, and less effective for CMV pneumonitis.

    • VACCINE: Live vaccine under clinical trials.

  • HUMAN HERPES VIRUS 6 (HHV-6): Infects T-Cells and monocytes, producing a latent infection.

    • MANIFESTATIONS:

      • Roseola (Exanthem Subitum): HHV-6 has etiological role in this childhood disease. Child presents with drastically high fever for 3-4 days, followed by rash all over body.

      • Fever, encephalitis, hepatosplenomegaly are all possible.

      • Persistent lymphadenopathy, fatigue and malaise may happen in adults.

      • Fatal Fulminant Hepatitis: HHV-6 was isolated from one infant with this disease.

  • HUMAN HERPES VIRUS 7 (HHV-7): Not much known. T-Cells are primary target, and it may cause some cases of childhood roseola.

• GAMMA-HERPES VIRUSES: Intermediate growth speed, lymphotropic viruses that infect B and T cells.

  • EPSTEIN-BARR VIRUS (HHV-4, EBV):

    • REPLICATION:

      • EBV binds complement receptor CR2 on B-Cells to gain access to cell.

      • About 25% of infected virions leave the cell.

    • PATHOGENESIS:

      • EBV infects and immortalizes human B-Cells. This can result in B-Cell transformation, as in Burkitt's Lymphoma.

      • Infected cells contain multiple virions and express viral antigens. Expressions of these antigens may occur alone, or in conjunction with a productive infection of viral particles.

        • Lymphocyte-detected Membrane Antigen (LYDMA)

        • EBV-Specific Nuclear Antigen (ESNA)

    • DIAGNOSIS: Monospot Test. Look for antibodies against sheep RBC's. If you see hemagglutination, then the antibodies are present and the test is positive.

    • MANIFESTATIONS: Generally ubiquitous virus usually infects in early childhood.

      • Infectious Mononucleosis: Results when initial infection occurs at a later time. EBV causes polyclonal activation of B-Cells.

        • Heterophil Antibodies: Infected B-Cells make these antibodies, which are directed against whatever antigen to which the B-Cell has been sensitized.

        • Atypical Lymphocytes: Activated T-Cells. In response to the B-Cells, the T-Cells proliferate, leading to fever and lymphadenopathy. The T-Cells get activated and form atypical lymphocytes.

        • In the end, the B-Cell is put under control and infection stops. Virus becomes latent in B-Cells.

      • IMMUNOCOMPROMISED: Particularly susceptible to reactivation disease. May see invasive lymphomas, or EBV lesions of mouth called hairy leukoplakia.

      • Burkitt's Lymphoma: Malignant tumor of jaw and face, usually found in kids in Africa.

        • Results from translocation of c-Myc oncogene next to an IgG gene in B-Cells, as a result of EBV infection.

      • Nasopharyngeal Carcinoma: In adults, endemic to China.

    • VACCINE: Vaccine against C3B complement receptor is under development.

  • HUMAN HERPES VIRUS 8 (HHV-8):

    • MANIFESTATIONS: Kaposi Sarcoma.

    • TRANSMISSION: HHV-8 is probably sexually transmitted.

Category: Microbiology Notes