HERPESVIRUSES-VIROLOGY {S1}

1. HERPESVIRUSES-VIROLOGY {S1} BY RANJEET RAMAN

2. Common features of herpes viruses large (105-235 kb) dsDNA with sequential gene expression ​viral DNA synth defines early from late genes ​Viral structure: envelope, tegument, capsid, DNA ​Lifelong infection with reactivation from latency ​CPE: cytocidal, intranuclear inclusions, giant cells

3. Life cycle ​Virus replicates in skin/mucosa, infects nerves, enters ganglion by retrograde transport where it remains latent, upon reactivation infection spreads down the nerve (explains distribution of primary infection) ​​Latency in ganglia: protected from immune system, doesn’t divide

4. Reactivation, e.g. by UV light, immunosupp., trauma, hormones, fever ​Infection requires specific glycoproteins, capsid and some teguments enter cell, VHS turns off host prot synth, VP16 activates immediately early genes (followed by early, intermediate, and late genes)

5. Viral DNA cleaved from concatemers, virus assembly in nucleus ​Mechanism to establish latency is unknown, but involves LAT mRNA

6. ALPHA HERPESVIRUSES ​HSV ​HSV1 usually oral-labial infection but HSV2 usually genital infection ​infection may occur in other places, e.g. cornea, esophagus, lung ​Dx by Tzanck smear, culture, or PCR of CSF ​neonatal transmission risk, avoid by C-section ​HSV encephalitis: usually confined to temporal lobes

7. VZV ​Varicella = chickenpox, zoster = shingles ​Chickenpox Respiratory transmission, high attack rate ​Latency in sensory ganglia ​Shingles: reactivation of VZV, unilateral vesicular eruption that follows dermatomes, painful ​VZV vaccine protects 85%; also can block VZV replication with acyclovir and famciclovir

8. BETA HERPESVIRUSES ​CMV ​Congenital infection associated with microcephaly and other defects ​Postnatal infection usually asymptomatic ​CMV retinitis common in AIDS patients ​HHV-6 ​Associated with roseola (rash and fever in infants) ​HHV-7 ​Not dz associated

9. GAMMA HERPESVIRUSES ​Latency established in cells that can divide (provides another method of viral replication) ​EBV ​Immortalizes B cells ​Normally T cells suppress proliferation of EBV-infected B cells; it is thought imbalance in number of EBV B and T cells leads to cancer ​CD21 is the EBV receptor ​Nearly everyone is infected, saliva transmission

10. Can cause infectious mononucleosis, cleared out by T cells Sx: sore throat, fever, generalized lymphadenopathy, splenomegaly, atypical lympocytes ​Dx by monospot test for first month (interestingly, tests for Ab’s against a sheep antigen), IgG or EBNA presence for older infections

11. Latent viral replication not dependent on viral DNA polymerase (acyclovir-insensitive), only dependent on EBNA-1 ​Tumor association ​Post-transplant lymphoproliferative disorder: probably related to immunosuppression of EBV T cells, treat with EBV specific CTLs

12. Burkitt’s lymphoma: t(8;14), more common malarial-associated form always EBV-associated but sporadic Burkitt’s is not ​Nasopharyngeal carcinoma: always EBV-associated, common in Chinese ​Hodgkin’s dz: ~30% EBV-associated

13. HHV-8 (KSHV) ​Kaposi’s sarcoma associated with 4 groups ​Children in Africa ​Old men in the Mediterranean ​Organ transplant recipients ​Homosexual AIDS patients/male-male sexual intercourse ​Infects B cells but insufficient for immortalization

14. Herpes Viruses Structurally, these are large, enveloped viruses with dsDNA and tegument proteins ​between the capsid and envelope. Biologically, they all have both lytic and latent lifecycles.

15. Herpes Simplex This is an alpha-herpesvirus. Spread by direct contact of mucosal or abraded surfaces. Herpes simplex first establishes latency, then periodically becomes a lytic infection. 70% of adults have Herpes simplex, and primary lesions just cause inflammation and ​sores, although may cause temporal lobe encephalitis. In neonates, it can ​disseminate after passage through infected vagina, and can be fatal. HSV1 usually oral lesions, HSV2 usually genital lesions.

16. Herpes simplex replicates in the epidermis, then infects sensory nerve terminals. It ​travels retrograde to sensory ganglia and spreads to other neural tissues. This ​often does not kill the cell, but inserts viral genome into neurons. It can then reactivate, traveling back down the axon and causing large primary lesions. ​Reactivation is triggered by UV light, hormonal changes, and fever.

17. At the cellular level, viral DNA is injected into the host nucleus, but it is not infectious ​without tegument proteins. One protein, host shut-off protein, turns off host ​protein synthesis. Transcription initiation factor then activates transcription of ​early genes. Tegument proteins enter nucleus along with viral DNA.

18. Lytic cycle: Transcription initiation factor starts the transcription of early genes such as ​thymidine kinase (the same thymidine kinase that activates Acyclovir!). Viral ​DNA replication begins (this is when Acyclovir exerts its effect) and late genes, ​such as structural proteins, are synthesized. Note that both early and late genes ​are active in the lytic phase.

19. Latent cycle: If tegument proteins fail to enter the nucleus with the viral DNA, normal ​cell synthesis continues and viral DNA remains latent.

20. Herpes Varicella-Zoster (α-herpesvirus) Varicella is chickenpox, a highly contagious rash. Respiratory spread. Zoster is shingles, which is a unilateral rash with dermatomal distribution. Shingles is a ​reactivation of the same childhood virus, which in adulthood tracks back down ​sensory neurons to trace out a unilateral dermatomal rash.

21. The rash can spread ​virus by direct contact (not respiratory spread), often spreading chickenpox to ​children. Shingles causes very severe pain and neuralgia. As with Herpes simplex, only the lytic phase is associated with disease and viral spread.

22. Cytomegalovirus (CMV) CMV is a β-herpesvirus transmitted in saliva and sex fluids. Like Herpes simplex and ​varicella/zoster, its lytic phase is associated with disease, while its latent phase is ​relatively unremarkable.

23. CMV primary infection causes mononucleosis. Congenital infection causes microcephaly and growth retardation. The latent phase occurs in hematopoietic cells, which become giant and swollen.

24. Epstein-Barr virus (EBV) EBV is a γ-herpesvirus. In contrast to alpha and beta herpes viruses, EBV causes ​infection during its latent phase. All adults are permanently colonized with EBV! EBV primary infection is via saliva, and is a classic cause of mononucleosis.

25. EBV immortalizes B cells. These cells produce very little virus, but the latency genes ​drive perpetual proliferation. This is tumorigenic, causing Burkitt’s lymphoma. ​Upon B cell infection, T cells proliferate and try to kill as many B cells as possible. ​But EBV persists as closed DNA circles, and its LMP1 gene helps cause malignancy.

26. Because Acyclovir inhibits viral DNA polymerase (a lytic gene), it has no effect on EBV! ​EBV uses host proteins in its latent phase. It is totally resistant to Acyclovir.

27. The lytic phase is only important insofar as it causes mono (kissing disease), which is ​sore throat, fever, high mononuclear cell count. T cells proliferate after B cells ​get infected, and these T cells are the “atypical lymphocytes” of mono.

28. Mono is associated with polyclonal IgG which also bind sheep erythrocytes, which is the ​basis of the mono spot test.

29. EBV-associated tumors 1. Post-transplant lympho proliferative disease (PTLD) is an outgrowth of immortal B cells. ​Often “treated” with Acyclovir and Gancyclovir although these target lytic ​infections so this is not rational therapy.

30. 2. Burkitt’s lymphoma is a childhood tumor of the face and mandible. Always ​associated with EBV infection. Associated with malaria. 3. Nasopharyngeal cancers occur mostly in Chinese men, and are always from EBV. 4. Hodgkin’s disease has some association with EBV.

31. Kaposi’s Sarcoma Used to only occur in Mediterranean men, but now occurs with HIV and in gay men. EBV is present in all cases of Kaposi’s sarcoma. For some weird reason, Kaposi’s sarcoma is associated with gay sex in a way that it is not ​really associated with blood transfusion or IV drug use. Very unusual.