Review questions: CMV, EBV, and KSHV

1. Describe the cascade regulation of a herpesvirus infection.

2. Why is acyclovir more active in infected cells vs. uninfected cells? What is its
mechanism of action?
3. How is CMV spread? What illnesses can it cause?
4. How are CMV infections treated?
5. What are the symptoms of infectious mononucleosis?
6. What lab tests would you perform to distinguish a CMV from an EBV
mononucleosis?
7. Describe the use of EBV markers in staging the infection.
8. Compare and contrast PTLD, Burkitts lymphoma, NPC, and hairy leukoplakia.
9. Why is KSHV considered necessary but not sufficient to cause KS?
10. Compare and contrast AIDS-related and classical KS.
11. Name 2 other clinical presentations caused by KSHV.
1. The cascade regulation of herpesviruses comprises three phases: immediate early,
early, and late gene expression. Immediate early genes encode transcription factors
that redirect host RNA polymerase II to viral promoters. This results in expression of
the early gene products, which are enzymes and other proteins, such as a virally-
encoded DNA polymerase, necessary for genome replication. Once the genome is
replicated, the immediate early proteins direct synthesis of the late proteins, which are
the structural proteins. Accordingly, herpesviruses are an example of sequential,
headful packaging.

2. Acyclovir is more active in infected cells because it is dependent on the herpes

thymidine kinase to obtain the first of three phosphate groups necessary to become an
active nucleoside analog. Once acyclovir achieves its triphosphate form, it becomes a
preferred substrate of the herpes DNA polymerase and is incorporated into replicating
virus genome DNA strands where it prevents further elongation.

3. Contact with fluids such as saliva or excrement.

Sexual transmission, particularly in gay male populations.
In utero.
Organ transplantation
Childhood infections are often asymptomatic while adolescent and adult infections
can cause mononucleosis. AIDS patients suffer from pneumonitis, retinitis, and
colitis. Most in utero infections are asymptomatic but can lead to deafness or mental
retardation in 10% of infections. The most significant outcome of transplant cases is
a severe pneumonitis.

4. Severe infections are treated with ganciclovir and CMV Ig. AIDS patients may
develop resistance to ganciclovir, so foscarnet and cidofovir are second line therapies.

5. EBV mono is characterized by sore throat, fever, malaise, lymphadenopathy,

sometimes a rash or jaundice. An inflamed spleen can occur, so athletes should be
held out of contact sports.

6. A Monospot test can be run to look for heterophile antibodies; however, these are
only produced about one-half the time in EBV patients. Blood smear should show at
least 50% swollen lymphocytes with lobulated nuclei in EBV; CMV causes a high
percentage of swollen lymphocytes. A shell vial assay can be run to demonstrate
CMV infection. More modern techniques include PCR analysis.

7. The first IgG expression is directed to VCA (viral capsid antigen), likely due to the
high level expression of this antigen. Later, IgG to EBNA (Epstein-Barr nuclear
antigens) proteins is raised, even though these antigens are expressed before VCA. A
patient that is VCA+ EBNA- is likely undergoing an acute, primary infection whereas
a patient that is VCA+ EBNA+ likely had a past infection.

8. PTLD: Posttransplant lymphoproliferative disease is caused by EBV immortalization

of B cells through latency, and hence is a lymphoma. Generally occurs during the
 first year posttransplant, most often in previously EBV seronegative patients.
Treatment is to reduce immunosuppression.

Burkitts lymphoma is another lymphoma caused by EBV latency. B cells attach to

the jaw bone to form a tumor. In the African form, early infection leads to
chromosomal rearrangements that place c-myc under a powerful Ig promoter.
Malaria also plays a role by providing immunosuppression. Only 20% of non-
African cases involve EBV.

Nasopharyngeal carcinoma is a neoplasm of epithelial cells that harbor latent EBV.

The association with EBV is worldwide and it is prominent in south China where
nitrosamines derived from salted fish are believed to contribute. Long-term prognosis
is not good.

Hairy leukoplakia is a productive infection of the epithelial cells of the tongue.

Because lytic replication is involved, the infection is responsive to ACV. Rarely seen,
but sometimes seen in AIDS patients.

9. KSHV (HHV-8) has been found in more than 90% of KS tumors, both AIDS-related
and classical KS, but is almost never found in the general population of the US. It is
not sufficient to cause KS alone because it must rely on a drop in the immune
response to lead to KS.

10. AIDS-related KS: Sexually transmitted, but apparently absent from semen. Almost
exclusively seen in gay men, virtually never seen in lesbians or patients who
contracted AIDS via blood transfusion. HIV infection provides the necessary
immunosuppression. Once, half of all AIDS patients developed KS within 10 years
of AIDS diagnosis, now significantly reduced and well controlled. Treatment targets
HIV, not KSHV.

Classical KS: Endemic in Mediterranean and sub-Saharan Africa. Not sexually

transmitted. Old age provides immunosuppression.

11. Primary effusion lymphoma and Castlemans disease.