Herpesviruses are the USMLE’s favorite “long-game” pathogens: they infect you once, then quietly persist for life, reactivating when conditions are right. If you can master their shared structure (enveloped dsDNA), their signature trick (latency in specific cell types), and the classic clinical syndromes they cause, you’ll pick up a ton of easy points on both Step 1 (mechanisms, latency sites) and Step 2 (presentations, complications, treatment).
The Herpesviridae Family: The Big Picture (Step 1 Core)
All the “classic” human herpesviruses you’re responsible for here:
- HSV-1 / HSV-2 (Herpes simplex viruses)
- VZV (Varicella-zoster virus; HHV-3)
- EBV (Epstein–Barr virus; HHV-4)
- CMV (Cytomegalovirus; HHV-5)
Shared high-yield features
- Enveloped, linear dsDNA viruses
- Icosahedral capsid
- Replicate in the nucleus
- Establish lifelong latency with reactivation
- Sensitive to ether/detergents (enveloped → less stable in environment)
First Aid cross-reference: Microbiology → Viruses → DNA viruses → Herpesviruses (latency sites, classic disease associations)
High-Yield Table: Latency Sites + Reactivation Clues
| Virus | Primary infection (classic) | Latency site (HY!) | Reactivation trigger/clinical clue |
|---|---|---|---|
| HSV-1 | Gingivostomatitis, herpes labialis | Trigeminal ganglion | “Cold sores” recur with stress, fever, sunlight |
| HSV-2 | Genital herpes, neonatal herpes | Sacral dorsal root ganglia | Painful genital vesicles; recurs with stress/immunosuppression |
| VZV | Varicella (chickenpox) | Dorsal root ganglia | Zoster (shingles) in a dermatomal distribution |
| EBV | Infectious mononucleosis | B cells | Reactivation rare clinically; assoc. with malignancies |
| CMV | Often asymptomatic; mono-like illness | Monocytes / bone marrow progenitors | Reactivation in transplant/HIV → retinitis, esophagitis, pneumonitis |
HSV-1 and HSV-2 (Herpes Simplex): The “Painful Vesicles” Viruses
Definition + Pathophysiology (what Step 1 wants)
- Entry via mucosal surfaces or abraded skin → local replication
- Travels retrograde along sensory nerves → latency in sensory ganglia
- Reactivation → anterograde transport → recurrent lesions
- HSV can cause multinucleated giant cells and Cowdry type A intranuclear inclusions
First Aid cross-reference: HSV-1/2 under DNA viruses; “painful vesicles,” encephalitis, neonatal disease, Tzanck smear
Clinical presentations (Step 2 patterns)
HSV-1
- Herpes labialis: grouped vesicles on erythematous base (“cold sores”)
- Herpetic gingivostomatitis (kids)
- Temporal lobe encephalitis (HSV-1 is classic)
- Fever, headache, seizures, personality changes
- Can see hemorrhagic necrosis of temporal lobes
HSV-2
- Genital herpes: painful vesicles/ulcers + tender lymphadenopathy
- Neonatal herpes (high stakes):
- Acquired intrapartum during vaginal delivery
- Can cause disseminated disease, encephalitis, vesicular rash
HY association: “Painful” helps distinguish HSV lesions from syphilis (painless chancre) and H. ducreyi (painful chancroid but different context).
Diagnosis (HY tests)
- PCR from lesion swab is best in practice (and commonly tested)
- Tzanck smear: multinucleated giant cells (supportive, not specific for HSV vs VZV)
- CSF PCR for HSV encephalitis
Treatment
- Acyclovir / valacyclovir / famciclovir
- Mechanism (Step 1): activated by viral thymidine kinase → inhibits viral DNA polymerase (chain termination)
- Foscarnet for acyclovir-resistant HSV (often due to altered/deleted thymidine kinase)
HY adverse effect callout: Acyclovir can cause crystalluria → hydrate.
VZV (Varicella-Zoster): Chickenpox Now, Shingles Later
Pathophysiology (what matters)
- Primary infection: varicella (chickenpox)
- Latency: dorsal root ganglia
- Reactivation: zoster (shingles)—dermatomal, painful vesicular eruption
First Aid cross-reference: VZV section—varicella vs zoster, dermatomal rash, complications (pneumonia, encephalitis), shingles vaccine
Clinical presentation
Varicella (primary)
- Fever + malaise → pruritic vesicular rash in crops
- Lesions in different stages at the same time (papules, vesicles, crusts)
- More severe in adults, pregnant patients, immunocompromised
Zoster (reactivation)
- Painful unilateral dermatomal rash
- Often preceded by neuropathic pain/tingling
- Complications:
- Postherpetic neuralgia (esp. older adults)
- Herpes zoster ophthalmicus (V1 distribution—vision risk)
- Disseminated zoster in immunocompromised
Diagnosis
- Usually clinical
- PCR from lesions if needed
- Tzanck smear: multinucleated giant cells (again, not specific)
Treatment + Prevention
- Acyclovir/valacyclovir (best early, esp. zoster)
- VZIG (varicella-zoster immune globulin) for post-exposure prophylaxis in high-risk patients (e.g., immunocompromised, pregnant, certain neonates)
- Vaccines:
- Live-attenuated varicella vaccine (avoid in pregnancy/immunocompromised)
- Recombinant zoster vaccine used for prevention of shingles (clinical emphasis)
EBV (Epstein–Barr Virus): Mono + Onc Associations
Pathophysiology (Step 1 gold)
- Infects B cells via CD21 (CR2) receptor
- Leads to B-cell proliferation → atypical lymphocytes are actually reactive CD8+ T cells responding to infected B cells
- Latency in B cells
First Aid cross-reference: EBV—CD21, mono triad, heterophile antibody test, associated cancers
Clinical presentation: Infectious mononucleosis
Classic triad:
- Fever
- Pharyngitis
- Posterior cervical lymphadenopathy
Other HY findings:
- Splenomegaly (avoid contact sports—risk of rupture)
- Fatigue
- Palatal petechiae
- Mild hepatitis (↑ LFTs)
Ampicillin rash pearl (HY!)
- Giving amoxicillin/ampicillin in EBV can cause a diffuse maculopapular rash (not a true allergy).
Diagnosis
- Heterophile antibody test (Monospot): commonly positive (esp. adolescents/young adults)
- EBV-specific serologies when needed (VCA IgM, EBNA, etc.)
- CBC: atypical lymphocytosis
EBV malignancy associations (very testable)
- Burkitt lymphoma: classically t(8;14) involving c-MYC; “starry sky”
- Hodgkin lymphoma (subset; Reed–Sternberg cells)
- Nasopharyngeal carcinoma
HY concept: EBV drives B-cell proliferation; your immune system (CD8+ T cells) is responsible for many symptoms.
Treatment
- Supportive care (fluids, rest)
- Avoid contact sports if splenomegaly
- Steroids only for serious complications (e.g., impending airway obstruction)
CMV (Cytomegalovirus): The “Mono but Heterophile-Negative” + Opportunistic Giant
Pathophysiology (Step 1 essentials)
- Latency in monocytes and bone marrow progenitors
- Causes disease in:
- Congenital infection
- Transplant recipients
- Advanced HIV/AIDS
- Histology: owl eye intranuclear inclusions
First Aid cross-reference: CMV—mono-like illness, congenital triad-ish findings, retinitis, transplant complications, owl-eye inclusions, treatment
Clinical presentation
Mono-like illness (immunocompetent)
- Fever, fatigue, malaise
- Heterophile-negative mononucleosis (Monospot negative)
- Can see atypical lymphocytes too, but key clue is heterophile-negative
Congenital CMV (classic Step question)
- Most common congenital viral infection
- Findings can include:
- Sensorineural hearing loss
- Seizures
- Petechial “blueberry muffin” rash
- Periventricular calcifications
- Chorioretinitis
- Jaundice, hepatosplenomegaly, microcephaly
Opportunistic CMV
- CMV retinitis: floaters, blurry vision; “pizza pie / cottage cheese with ketchup” fundus
- Esophagitis: large, shallow linear ulcers (contrast with HSV: small deep “volcano” ulcers)
- Pneumonitis in transplant patients
- Colitis in immunosuppressed
Diagnosis
- PCR for CMV DNA (blood/CSF depending on syndrome)
- Tissue biopsy can show owl eye inclusions
- Fundoscopy is key for retinitis
Treatment
- Ganciclovir / valganciclovir
- Foscarnet if resistant or severe (also covers acyclovir-resistant HSV)
- Cidofovir is another option in select cases
HY adverse effects:
- Ganciclovir: bone marrow suppression (neutropenia, thrombocytopenia)
- Foscarnet: nephrotoxicity, electrolyte abnormalities
Rapid-Fire Differentials the USMLE Loves
HSV vs VZV on smear
- Both: multinucleated giant cells, Cowdry A inclusions on Tzanck
- Differentiate clinically (dermatomal shingles vs oral/genital grouped vesicles)
HSV encephalitis vs other causes
- HSV-1: temporal lobe involvement → personality changes, seizures
- Diagnosis: CSF PCR; treat emergently with IV acyclovir
EBV mono vs CMV mono
| Feature | EBV | CMV |
|---|---|---|
| Monospot | Positive | Negative |
| Lymph nodes | Posterior cervical LAD common | Less prominent |
| Sore throat | Prominent | Less prominent |
| Key receptor | CD21 on B cells | Broad tropism; latency in monocytes |
Congenital infections: CMV vs others
- CMV: periventricular calcifications + hearing loss
- Toxoplasmosis (not a virus but tested alongside): diffuse intracranial calcifications + hydrocephalus + chorioretinitis
- Rubella: cataracts, PDA, deafness (“eye-heart-ear”)
High-Yield One-Liners (Memorize These)
- HSV-1: trigeminal ganglion; oral lesions; temporal lobe encephalitis
- HSV-2: sacral ganglia; genital lesions; neonatal herpes
- VZV: dorsal root ganglia; varicella → shingles (dermatomal pain + vesicles)
- EBV: infects B cells via CD21; heterophile-positive mono; Burkitt (t(8;14)), nasopharyngeal carcinoma
- CMV: heterophile-negative mono; congenital hearing loss + periventricular calcifications; owl eye inclusions; retinitis in AIDS
Treatment Snapshot Table (USMLE-Friendly)
| Virus | First-line | Key alternatives/notes |
|---|---|---|
| HSV-1/2 | Acyclovir/valacyclovir | Foscarnet if acyclovir-resistant |
| VZV | Acyclovir/valacyclovir | VZIG for high-risk exposures; vaccines for prevention |
| EBV | Supportive | Avoid ampicillin/amoxicillin; no contact sports if splenomegaly |
| CMV | Ganciclovir/valganciclovir | Foscarnet/cidofovir in resistance; watch marrow suppression |
Final Exam Strategy: How to Nail Herpesvirus Questions
When you see a herpesvirus stem, immediately ask:
- Where is latency? (trigeminal, sacral, dorsal root, B cells, monocytes)
- Is the patient immunocompromised/pregnant/newborn? (CMV and HSV neonatal jump up)
- What’s the signature syndrome? (temporal encephalitis, dermatomal zoster, heterophile+ mono, retinitis)
- Which drug fits—and what’s the toxic effect? (acyclovir crystalluria; ganciclovir marrow suppression; foscarnet nephrotoxicity)
If you can answer those four quickly, you’ll rarely miss these.