How herpesviruses are tested on Step 1
Expect a lesion, a latency site, a congenital infection, or a malignancy, and a question asking for the virus, its latency site, or the drug and its mechanism.
After primary infection, the viral genome persists as an episome without making virions. Stress, immunosuppression, UV light, or aging can trigger reactivation.
The eight human herpesviruses
Group by subfamily and latency site.
| Virus | Spread | Classic disease | Diagnostic clue |
|---|---|---|---|
| HSV-1 | Saliva | Gingivostomatitis, herpes labialis, keratitis, temporal-lobe encephalitis | Tzanck; PCR of CSF; temporal lobe on MRI |
| HSV-2 | Sexual; perinatal | Genital herpes, neonatal herpes, aseptic meningitis | Painful vesicles on an erythematous base |
| VZV | Respiratory | Varicella (lesions in different stages), zoster in one dermatome | Tzanck; clinical |
| EBV | Saliva | Infectious mononucleosis; Burkitt, Hodgkin, nasopharyngeal carcinoma | Monospot (heterophile); atypical CD8⁺ T cells |
| CMV | Body fluids, transplant, congenital | Congenital deafness, retinitis (CD4 < 50), transplant pneumonitis | "Owl's eye" intranuclear inclusions |
| HHV-6/7 | Saliva | Roseola: high fever, then rash; febrile seizures | Rash appears as fever breaks |
| HHV-8 | Sexual | Kaposi sarcoma, primary effusion lymphoma | Purple plaques; spindle cells |
Infectious mononucleosis: avoid contact sports (splenic rupture) and amoxicillin (rash).
Latency and reactivation
Shingles illustrates the latency cycle most clearly.
Antiviral therapy
Nucleoside analogues need to be phosphorylated before they can inhibit viral DNA polymerase. The first phosphorylation step is what differs between viruses.
| Drug | Activation | Use | Key toxicity |
|---|---|---|---|
| Acyclovir, valacyclovir | Viral thymidine kinase | HSV, VZV | Crystalline nephropathy — hydrate |
| Ganciclovir, valganciclovir | CMV UL97 kinase | CMV | Bone marrow suppression (leukopenia) |
| Foscarnet | None (pyrophosphate analogue) | Resistant CMV or HSV | Nephrotoxicity, hypocalcemia, hypomagnesemia, seizures |
| Cidofovir | None (nucleotide analogue) | Resistant CMV | Nephrotoxicity — give with probenecid |
Resistance to acyclovir usually reflects a mutated thymidine kinase; foscarnet and cidofovir still work because they bypass it.
A man with AIDS and a CD4 count of 30/mm³ reports floaters and blurred vision. Funduscopy shows yellow-white retinal infiltrates with hemorrhage. Why would acyclovir be a poor choice?
- Retinitis with hemorrhage at a CD4 count under 50 is classic for CMV.
- Acyclovir requires phosphorylation by viral thymidine kinase.
- CMV does not encode thymidine kinase; it uses the UL97 phosphotransferase instead.
- Ganciclovir is a substrate for UL97 and is activated in CMV-infected cells.
Answer. CMV lacks thymidine kinase, so acyclovir is not activated. Use ganciclovir or valganciclovir, along with antiretroviral therapy.
Congenital and neonatal herpesvirus infections
Herpesviruses are part of the TORCH group and cause some of the most serious congenital and neonatal infections.
| Virus | Timing | Findings |
|---|---|---|
| CMV | Transplacental, any trimester | Sensorineural hearing loss, periventricular calcifications, microcephaly, chorioretinitis, blueberry muffin rash |
| HSV-2 (or HSV-1) | Usually during delivery | Skin-eye-mouth vesicles, encephalitis, or disseminated disease in the first weeks |
| VZV | First 20 weeks of pregnancy | Congenital varicella: limb hypoplasia, cicatricial skin scars, eye defects |
| VZV | Maternal rash 5 days before to 2 days after delivery | Severe neonatal varicella — give VZIG |
Cesarean delivery is recommended when genital lesions are present at the onset of labor.