DNA Viruses — Herpesviruses, HPV and Others

• Herpesviridae — enveloped, and defined by lifelong latency.
• HSV-1 and HSV-2: latent in sensory ganglia (trigeminal and sacral respectively). Gingivostomatitis, herpes labialis, genital ulcers that are painful, herpetic whitlow, and temporal lobe encephalitis (HSV-1). Tzanck smear shows multinucleated giant cells.
• VZV: chickenpox, then latency in dorsal root ganglia and reactivation as shingles in a dermatome.
• EBV: infects B cells via CD21; infectious mononucleosis with atypical (reactive) T lymphocytes, positive heterophile antibody, splenomegaly (avoid contact sport), and association with Burkitt and nasopharyngeal carcinoma. An ampicillin rash follows β-lactam exposure.
• CMV: owl-eye inclusions; congenital infection with periventricular calcifications; retinitis, colitis and pneumonitis in immunosuppression.
• HHV-8: Kaposi sarcoma.
• HPV: E6 degrades p53 and E7 inactivates Rb — the mechanism of cervical, anal and oropharyngeal carcinoma; low-risk types cause warts. Koilocytes are the cytological clue.
• Hepatitis B, the one with reverse transcriptase; adenovirus; parvovirus B19 (slapped cheek, aplastic crisis, hydrops fetalis).

Structural framework

• Herpesviridae: enveloped, icosahedral, linear double-stranded DNA with a proteinaceous tegument between capsid and envelope. Envelope derives from host nuclear membrane, which is why these viruses are labile and require close mucosal or secretion contact for transmission.
• Papillomaviridae/Polyomaviridae: naked, circular dsDNA — non-enveloped and therefore environmentally stable (fomite spread of warts).
• Poxviridae: the largest viruses, brick-shaped, complex rather than icosahedral, and the sole DNA family replicating in the cytoplasm because they encode their own DNA-dependent RNA polymerase.
• Hepadnaviridae (HBV): partially double-stranded circular DNA replicated through an RNA intermediate by a virally encoded reverse transcriptase — the basis for nucleos(t)ide analogue therapy.

Laboratory identification

• Cytopathology: Tzanck smear is insensitive and cannot distinguish HSV from VZV, since both produce multinucleated giant cells with Cowdry type A intranuclear inclusions. CMV gives the owl-eye intranuclear inclusion with a perinuclear halo; poxviruses give cytoplasmic Guarnieri bodies; HPV produces koilocytes (perinuclear halo, raisinoid nucleus).
• Culture: HSV grows readily in conventional cell culture; CMV is slow-growing and traditionally required shell-vial assay; HPV and parvovirus B19 are effectively non-culturable, so nucleic acid amplification and serology dominate.
• Molecular: PCR has displaced culture and Tzanck as the confirmatory method for essentially all herpesviruses.

Virulence factors

• Immune evasion: HSV ICP47 blocks TAP-mediated peptide loading onto MHC I; CMV downregulates MHC I broadly; both blunt CD8 recognition and enable persistence.
• Tropism-determining receptors: EBV gp350 binds CD21 (CR2) on B cells — this is the B-cell entry mechanism; entry into pharyngeal epithelium uses distinct receptors (ephrin receptor A2, integrins) rather than CD21. Parvovirus B19 binds the P antigen (globoside) on erythroid precursors.
• Oncoproteins: HPV E6 targets p53 for proteasomal degradation and E7 displaces E2F from Rb; HHV-8 encodes homologues of cyclin D and vIL-6.
• Latency programs: HSV latency-associated transcripts (LATs) permit genome maintenance with minimal antigen expression.

Herpesvirus latency and reactivation

• Primary infection occurs at a mucosal or cutaneous surface, where lytic replication produces the intraepidermal vesicle — ballooning degeneration of keratinocytes with intercellular edema, hence the thin-walled, painful, clustered vesicle on an erythematous base.
• Virions enter free nerve endings and travel by retrograde axonal transport to sensory ganglia: trigeminal for HSV-1, sacral (S2–S4) for HSV-2, dorsal root and cranial ganglia for VZV. Because latency resides in a neuron and reactivation travels anterograde down a single sensory axon, recurrent disease is confined to the territory that neuron supplies — a fixed labial site for HSV-1, a single dermatome for zoster.
• Reactivation triggers (UV light, fever, stress, waning cell-mediated immunity with age, HIV, transplant immunosuppression) all converge on reduced CD8/NK surveillance. This is why zoster incidence rises steeply with age and why disseminated or multidermatomal zoster signals immunodeficiency.
• HSV-1 encephalitis reflects spread along trigeminal or olfactory pathways to the temporal and inferior frontal lobes, producing hemorrhagic necrosis and the personality change, aphasia and focal seizures seen clinically.

EBV mononucleosis

• EBV drives polyclonal B-cell proliferation; the resulting CD8 cytotoxic T-cell response is what produces the illness. The atypical lymphocytes are reactive T cells, not infected B cells, and the same expansion explains lymphadenopathy, splenomegaly (with capsular stretch and rupture risk) and transaminitis.

HPV carcinogenesis

• Microtrauma exposes basal keratinocytes, notably at the cervical transformation zone. Episomal infection yields warts and koilocytosis; integration disrupts the E2 repressor, derepressing E6 and E7. Loss of p53-mediated arrest/apoptosis plus Rb inactivation permits accumulation of mutations — the stepwise progression from CIN to invasive carcinoma over years.

Parvovirus B19

• Lysis of P-antigen–bearing erythroid precursors halts erythropoiesis; healthy hosts tolerate this, but shortened red-cell survival (sickle cell, hereditary spherocytosis) converts it into aplastic crisis, and fetal infection causes high-output failure and hydrops.

HSV

• Primary herpetic gingivostomatitis: toddlers, fever with painful oral vesicles and ulcers; recurrences appear as herpes labialis at the vermilion border.
• Genital herpes: grouped painful ulcers with tender inguinal adenopathy — contrasted with the painless chancre of syphilis and the painful, ragged ulcer of chancroid.
• Herpetic whitlow (dentists, respiratory therapists), herpes gladiatorum (wrestlers), and eczema herpeticum in atopic dermatitis.
• HSV encephalitis: fever, altered mentation, aphasia and temporal-lobe seizures; the most common sporadic fatal encephalitis in the US.
• Neonatal HSV: skin-eye-mouth, CNS, or disseminated disease, usually from HSV-2 acquired intrapartum from a mother with primary infection.

VZV

• Varicella: crops of lesions in different stages simultaneously (macule, vesicle, crust).
• Zoster: unilateral dermatomal pain preceding vesicles. Hutchinson sign (nasal tip lesions) predicts herpes zoster ophthalmicus; Ramsay Hunt syndrome combines facial palsy with ear canal vesicles. Postherpetic neuralgia is the major sequela in the elderly.

HSV/VZV lesions

• Initial: clinical recognition; Tzanck smear is fast but neither sensitive nor type-specific and is no longer the standard of care.
• Confirmatory: PCR of vesicle fluid or lesion swab (direct fluorescent antibody as an alternative), which distinguishes HSV-1, HSV-2 and VZV. Type-specific glycoprotein G serology answers which HSV a patient carries but not whether the current lesion is herpetic; CDC STI guidelines advise against routine population screening with serology.

HSV encephalitis

• CSF: lymphocytic pleocytosis, normal glucose (a normal CSF glucose helps exclude bacterial, fungal and tuberculous causes; mild reduction is uncommon), elevated protein, and often red cells or xanthochromia from hemorrhagic necrosis.
• CSF HSV PCR is the gold standard; MRI shows temporal-lobe hyperintensity and EEG may show periodic lateralized epileptiform discharges. Per IDSA encephalitis guidance, start acyclovir before the PCR returns — a negative PCR very early in illness may warrant repeat testing.

EBV

• Initial: CBC with lymphocytosis and >10% atypical lymphocytes, plus the heterophile (Monospot) test, which agglutinates horse or sheep erythrocytes. False negatives occur in the first week and in children under about 4 years.
• Confirmatory: EBV-specific serology — VCA IgM with negative EBNA indicates acute infection, since EBNA antibodies appear only months later.

CMV

• Quantitative plasma CMV DNA PCR for viremia and for surveillance in transplant recipients; tissue biopsy showing owl-eye inclusions confirms end-organ colitis or esophagitis. Retinitis is a clinical, dilated-funduscopic diagnosis — vitreous PCR is not required.
• Congenital CMV must be confirmed by urine or saliva PCR within the first 3 weeks of life; later testing cannot separate congenital from perinatal acquisition.

Nucleoside analogues (HSV/VZV)

• Acyclovir, valacyclovir, famciclovir: monophosphorylated by the viral thymidine kinase, then chain-terminate viral DNA polymerase — selective toxicity, and the reason these agents are inert against CMV.
• Oral valacyclovir or acyclovir for orolabial, genital and zoster disease; chronic suppressive therapy reduces recurrences and transmission in frequent genital recurrences (CDC STI Treatment Guidelines). IV acyclovir is mandatory for HSV encephalitis, neonatal HSV and disseminated VZV — for encephalitis the standard adult regimen is 10 mg/kg IV every 8 hours; maintain hydration to prevent crystalline nephropathy.

Resistance

• Acyclovir resistance arises chiefly from thymidine kinase–deficient mutants in heavily immunosuppressed hosts. Switch to foscarnet, a pyrophosphate analogue that inhibits viral DNA polymerase directly without requiring phosphorylation (nephrotoxic, causes electrolyte derangement including hypocalcemia), or cidofovir, a nucleoside phosphonate activated by host kinases alone (no viral kinase required), given with probenecid and IV saline because of dose-limiting nephrotoxicity.

CMV

• Ganciclovir/valganciclovir is first-line; activation requires the viral UL97 kinase, and UL97 mutations confer resistance — the classic pivot to foscarnet. Dose-limiting toxicity is myelosuppression. Letermovir (terminase inhibitor) is used for CMV prophylaxis in allogeneic hematopoietic cell transplant, and maribavir for refractory/resistant CMV. Immune reconstitution with antiretroviral therapy is essential in AIDS-related retinitis.

EBV, HHV-8, HPV

• EBV mononucleosis is supportive; avoid ampicillin/amoxicillin and restrict contact sports while splenomegaly persists. Corticosteroids are reserved for airway compromise, not routine illness.
• Kaposi sarcoma: antiretroviral therapy is the cornerstone, with chemotherapy for visceral disease.
• Warts: destructive or immunomodulatory therapy (cryotherapy, imiquimod, podophyllotoxin); dysplasia is managed by excision/ablation per ASCCP.

Prevention (ACIP)

• 9-valent HPV vaccine routinely at 11–12 years, catch-up through 26, shared clinical decision-making 27–45.
• Recombinant zoster vaccine, two doses, for adults ≥50 and for immunocompromised adults ≥19; it is non-live and preferred over the retired live vaccine.
• Live varicella vaccine in childhood; VariZIG for susceptible high-risk exposures. Hepatitis B vaccine universally in infancy and for all adults 19–59.

• Poxvirus is the cytoplasmic outlier. It replicates outside the nucleus because it brings its own DNA-dependent RNA polymerase; every other DNA virus except this one is nuclear. Parvovirus is the ssDNA outlier; HBV is the one with reverse transcriptase.
• Temporal lobe + altered mental status + RBCs in the CSF = HSV-1 encephalitis, and the single best next step is empiric IV acyclovir, not waiting for the CSF PCR. Delay in starting acyclovir is the tested error.
• Heterophile-negative mononucleosis is CMV (toxoplasmosis and acute HIV are the other distractors). Conversely, VCA IgM positive with EBNA negative means acute EBV; EBNA positivity implies past infection.
• The atypical lymphocytes of mononucleosis are reactive CD8 T cells, not infected B cells — a favorite trap. EBV enters B cells via CD21.
• Tzanck smear cannot distinguish HSV from VZV; both give multinucleated giant cells with Cowdry A inclusions. If the question asks for the confirmatory test, choose PCR.
• E6 → p53 degradation; E7 → Rb inactivation. Do not swap them. Koilocytes signal HPV infection; p16 overexpression signals transforming (high-risk) infection.
• Ganciclovir resistance is UL97; acyclovir resistance is thymidine-kinase deficiency. Both are answered by foscarnet, which needs no viral kinase — remember its hypocalcemia and nephrotoxicity.
• Recombinant zoster vaccine is non-live and therefore usable in immunocompromised adults; the live varicella and live attenuated zoster products are not interchangeable with it.
• Ampicillin rash in mononucleosis is not a penicillin allergy and does not preclude future beta-lactam use.
• Parvovirus B19 targets the P antigen on erythroid precursors — a transient arrest that only becomes an aplastic crisis when red-cell survival is already short (sickle cell disease, spherocytosis).