Herpes Simplex Virus — HSV-1 and HSV-2

Primary Infection and Viral Entry Mechanism

Latency Establishment and Molecular Mechanisms

Reactivation and the "Reactivation Trigger" Phenomenon

Immune Evasion and Host Response

Cellular and Tissue-Level Damage

Neuroinvasion and CNS Involvement

Transmission and Primary Acquisition

• Direct contact with viral lesions or asymptomatic viral shedding is the fundamental mechanism of HSV transmission. Approximately 50% of genital HSV transmission occurs during asymptomatic viral shedding—when the infected individual has no visible lesions—making prevention through barrier methods and antiviral suppressive therapy important counseling points. Primary HSV-1 acquisition most commonly occurs in childhood (50-90% by age 5 in some populations) through saliva exposure, while primary HSV-2 acquisition typically occurs in adolescence or adulthood through sexual contact. Notably, previous HSV-1 infection may partially protect against severe primary HSV-2 infection due to cross-reactive antibodies and cell-mediated immunity, though type-specific immunity is ultimately superior.

Immunocompromise and Reactivation Risk

• HIV/AIDS (particularly CD4 <50 cells/μL) represents the most clinically significant risk factor for severe, disseminated, or atypical HSV disease. In this population, HSV may present with massive erosive lesions, retinitis, esophagitis, colitis, or hepatitis. Disseminated disease with viral isolation from blood cultures, though rare, is a marker of profound immunosuppression and carries high mortality if untreated. Other immunocompromised states—including chemotherapy recipients, solid organ or hematopoietic stem cell transplant recipients, and patients on immunosuppressive therapy (TNF-α inhibitors, high-dose corticosteroids)—carry significantly elevated risk for severe HSV disease and warrant consideration of antiviral prophylaxis.

Genetic and Demographic Risk Factors for Reactivation

• Female gender is associated with higher frequency of genital HSV-2 reactivation compared to males, likely due to hormonal influences (progesterone appears protective; estrogen may trigger reactivation in some studies). Menstrual cycle phase influences genital HSV-2 reactivation rates, with increased shedding in the perimenstrual period. Genetic polymorphisms in IL-10, TNF-α, and TLR-2 have been associated with differences in reactivation frequency, though clinical utility is limited. Age influences reactivation rates, with older individuals generally experiencing fewer symptomatic recurrences, though viral shedding continues.

Environmental and Triggering Factors

• Physical trauma (including dental procedures, sexual intercourse, or sunburn for orofacial HSV) triggers reactivation through local inflammatory responses and viral migration along nerve pathways. Psychological stress consistently correlates with HSV reactivation in prospective studies, with cortisol elevation and catecholamine signaling implicated in disrupting latency repression. Fever from any cause (including influenza, pneumonia, or other infections) represents a well-documented reactivation trigger. Ultraviolet light exposure (particularly UVB) triggers reactivation in approximately 40% of individuals with recurrent orofacial herpes, warranting sunscreen use as a preventive measure.

Primary Orofacial HSV-1 Infection (Gingivostomatitis)

• Prodromal symptoms (fever, malaise, headache, lymphadenopathy) typically precede mucosal involvement by 1-2 days; these symptoms reflect the profound systemic inflammatory response to primary viral infection. Severe oral pain develops as mucosal ulcerations appear, often making eating and drinking difficult; this pain is mediated by exposed nerve endings in denuded epithelium and high local concentrations of inflammatory cytokines. Characteristic intraoral vesicles and erosions appear first on the hard palate, gingiva, and dorsal tongue as clusters of small fluid-filled blisters that rapidly rupture to form painful shallow ulcers with erythematous halos. Bilateral cervical lymphadenopathy with nodes often >2 cm and tender to palpation occurs in up to 80% of primary infections, representing reactive hyperplasia of draining lymph nodes. Fever (often 38.5-40°C) may persist 5-10 days in primary infection, significantly longer than in recurrences. Halitosis develops secondary to bacterial overgrowth in areas of oral ulceration. Primary gingivostomatitis is most severe in children aged 6 months to 5 years and may be complicated by dehydration from reduced oral intake.

Primary Genital HSV-2 Infection

• Dysuria and severe genital pain are the most bothersome symptoms, often described as burning or throbbing and exacerbated by urination or local contact; pain severity in primary genital herpes often exceeds that of other sexually transmitted infections. Grouped vesicles on erythematous base appear on the external genitalia, perineum, buttocks, and potentially the lower abdomen in primary infection; these lesions are typically 2-3 mm and extremely tender. Systemic symptoms including fever (38-40°C), malaise, myalgias, and headache occur in 50-75% of women with primary HSV-2 but are less common in men—a sex difference attributed partly to reduced viral burden in men. Bilateral inguinal lymphadenopathy with nodes often 2-3 cm develops in 50-80% of cases. Urinary retention may develop in women from severe urethritis, occasionally requiring catheterization; hematuria may occur from urethral or bladder involvement. Vaginal discharge (often purulent or hemorrhagic) develops as secondary epithelial damage and bacterial overgrowth occur. Constitutional symptoms may be severe enough to prompt hospitalization, particularly in pregnant women with primary infection. Aseptic meningitis complicates primary genital herpes in approximately 10% of women and 1% of men, presenting with headache, photophobia, neck stiffness, and pleocytosis on lumbar puncture.

Recurrent Orofacial Herpes (Herpes Labialis)

• Prodromal paresthesia or tingling at the site of recurrence occurs in 50-80% of individuals in the 6-48 hours before visible lesions appear, representing viral reactivation in the axon before widespread lytic infection; this prodrome provides an opportunity for early antiviral treatment. Grouped vesicles on the vermillion border of the lip or perioral skin represent the classic presentation; the single or clustered small blisters rapidly progress through pustule, ulcer, and crust stages over 7-10 days. Local pain and mild systemic symptoms (myalgias, low-grade fever) accompany recurrence, though systemic symptoms are substantially milder than in primary infection. Rapid progression compared to primary infection reflects the dampening effect of pre-existing immunity, with lesions typically progressing through all stages in 7-10 days versus 2-3 weeks for primary infection.

Recurrent Genital Herpes

• Brief prodrome (2-24 hours) of localized tingling, itching, or burning precedes lesions; women are more likely to experience prodromal symptoms than men. Fewer, smaller, more localized lesions compared to primary infection—typically 3-5 versus 20+ lesions in primary disease. Quicker progression to crusting with total healing in 5-10 days compared to 2-3 weeks for primary infection. Minimal or absent systemic symptoms in most recurrences, though some individuals report mild dysuria and myalgias. Highly variable frequency of recurrences—some patients experience monthly episodes while others have one or two episodes lifetime; HSV-2 recurs approximately 4-6 times per year on average compared to HSV-1 at 1-2 times per year.

Atypical Presentations

• Herpes gladiatorum (herpes rugborum in rugby players) involves HSV-1 transmission through abraded skin during contact sports, presenting as vesicular lesions on areas of trauma (face, arms, torso) with associated lymphadenopathy and systemic symptoms. Herpetic whitlow (occupational herpes affecting healthcare workers) involves HSV infection of the finger,

Initial and confirmatory testing of mucocutaneous lesions

• Nucleic acid amplification testing (PCR) of a lesion swab: the diagnostic test of choice per the CDC STI Treatment Guidelines, 2021. Unroof a fresh vesicle and swab the base — viral DNA concentration is highest in intact vesicles and falls sharply once lesions crust. PCR is type-specific (distinguishes HSV-1 from HSV-2), which matters for prognosis since HSV-2 recurs far more often.
• Viral culture: historical gold standard, now largely supplanted; sensitivity is poor in recurrent and crusted lesions and it is the only method that permits phenotypic resistance testing.
• Tzanck smear: rapid bedside scraping showing multinucleated giant cells and Cowdry type A intranuclear inclusions. Insensitive and cannot distinguish HSV from VZV — never accept it as confirmation.
• Direct fluorescent antibody: faster than culture, type-specific, but less sensitive than PCR.

Serology

• Type-specific glycoprotein G assays: gG1 and gG2 ELISAs identify past infection when lesions are absent or PCR is negative; useful for a symptomatic patient with recurrent unexplained ulcers or for a partner of an infected person. Seroconversion takes weeks, so serology is negative early in primary infection. The USPSTF recommends against routine serologic screening for genital herpes in asymptomatic adolescents and adults, including pregnant persons.

CNS and ocular disease

• CSF HSV PCR: the confirmatory test for herpes simplex encephalitis, with high sensitivity and specificity. It may be falsely negative in the first 72 hours — repeat it while continuing acyclovir.
• CSF profile: lymphocytic pleocytosis, elevated protein, normal or mildly low glucose, and red blood cells or xanthochromia reflecting hemorrhagic temporal-lobe necrosis.
• MRI: temporal and orbitofrontal T2/FLAIR hyperintensity, often asymmetric. EEG: temporal periodic lateralized epileptiform discharges (LPDs/PLEDs).
• Slit-lamp with fluorescein: dendritic ulcer with terminal bulbs establishes herpetic epithelial keratitis clinically.

Immediate action when CNS disease is suspected

• IV acyclovir, started empirically before confirmatory results (10 mg/kg IV q8h, adjusted for renal function) — the IDSA encephalitis guideline recommends empiric therapy in any patient with suspected encephalitis, because mortality in untreated herpes simplex encephalitis is very high and delay is the strongest modifiable predictor of poor outcome. Treat 14–21 days and hydrate aggressively.

First-line therapy for mucocutaneous disease

• Guanosine nucleoside analogues (acyclovir, valacyclovir, famciclovir): monophosphorylated only by viral thymidine kinase, then converted by host kinases to the triphosphate that inhibits viral DNA polymerase and terminates the chain. This TK dependence explains their selectivity — and their resistance pattern. The CDC STI Treatment Guidelines, 2021 endorse all three orally for first-episode genital herpes, episodic recurrent therapy (most effective if started during prodrome), and daily suppressive therapy, which also reduces transmission to susceptible partners.
• Valacyclovir: the acyclovir prodrug with far better oral bioavailability; preferred for adherence.
• Topical antivirals for genital or labial lesions: minimal benefit — do not substitute for oral therapy.

Escalation and second-line options

• Acyclovir-resistant HSV (almost always TK-deficient mutants in advanced HIV or transplant recipients; suspect when lesions progress on adequate therapy): treat with foscarnet, a pyrophosphate analogue that inhibits DNA polymerase directly without requiring phosphorylation. Cidofovir is an alternative.

Special populations

• Pregnancy: ACOG recommends suppressive acyclovir or valacyclovir from 36 weeks in women with recurrent genital herpes, and cesarean delivery if genital lesions or prodromal symptoms are present at the onset of labor. Acyclovir is not contraindicated in pregnancy.
• Neonatal HSV: high-dose IV acyclovir (20 mg/kg q8h) per the AAP Red Book, 14 days for skin-eye-mouth disease and 21 days for CNS or disseminated disease, followed by oral suppression.
• Herpetic keratitis: topical antiviral (trifluridine or ganciclovir gel) with ophthalmology involvement. Topical corticosteroids are contraindicated in active epithelial keratitis — they promote geographic ulceration and perforation.

Neurologic — emergencies

• Herpes simplex encephalitis: hemorrhagic necrosis of temporal and orbitofrontal cortex from direct neuronal cytolysis plus interferon-driven neuroinflammation. Signaled by fever with personality change, aphasia, olfactory or gustatory hallucinations, and focal temporal seizures. Empiric IV acyclovir immediately — do not wait for PCR.
• Post-HSE anti-NMDA receptor autoimmune encephalitis: neuronal antigen release primes autoantibodies; suspect when a patient improves after acyclovir then relapses weeks later with movement disorder and psychiatric features. Antivirals do not treat it — immunotherapy does.
• Neonatal HSV, disseminated or CNS: acquired intrapartum; skin vesicles are absent in a substantial minority, so a septic-appearing neonate with seizures, hepatitis, or coagulopathy warrants empiric acyclovir.

Other significant complications

• **Aseptic meningitis and *Mollaret meningitis***: recurrent benign lymphocytic meningitis, classically HSV-2; large mononuclear Mollaret cells in CSF.
• **Sacral radiculitis (Elsberg syndrome)**: autonomic dysfunction with urinary retention and saddle anesthesia after primary genital HSV.
• **Eczema herpeticum (Kaposi varicelliform eruption): HSV disseminating across barrier-defective atopic skin as monomorphic punched-out erosions; can progress to bacteremia and death — treat as an emergency with IV acyclovir**.
• Herpetic keratitis: recurrent stromal disease causes scarring and is a leading infectious cause of corneal blindness in the US.
• Erythema multiforme: HSV is the most common identified trigger of recurrent EM (target lesions); suppressive antivirals prevent recurrence.
• Esophagitis and hepatitis: in immunocompromised hosts and pregnancy; punched-out distal esophageal ulcers, or fulminant hepatitis with markedly elevated transaminases and often anicteric presentation.
• Increased HIV acquisition and transmission: ulceration plus recruitment of activated CD4+ target cells.

Treatment-related

• Acyclovir crystalline nephropathy: drug precipitates in tubules with rapid IV infusion or volume depletion — rising creatinine; prevent with hydration and slow infusion.
• Acyclovir neurotoxicity: confusion, tremor, myoclonus, hallucinations in renal impairment — mimics the encephalitis being treated.
• Foscarnet: nephrotoxicity and electrolyte derangement — hypocalcemia, hypomagnesemia, hypokalemia causing seizures and QT prolongation.
• Cidofovir: dose-limiting proximal tubular injury; requires probenecid and saline prehydration.

• PCR of the lesion base is the single best diagnostic test, and CSF PCR is the test for encephalitis. A Tzanck smear showing multinucleated giant cells is the classic distractor — it cannot separate HSV from VZV and is never confirmatory.
• Fever plus altered mentation, aphasia, or bizarre behavior with temporal lobe changes on MRI = start IV acyclovir now. "Obtain MRI" or "await CSF PCR" is always the wrong next step; empiric therapy precedes confirmation (IDSA).
• Genital ulcer discrimination: HSV gives multiple painful grouped vesicles on an erythematous base with tender bilateral inguinal nodes; primary syphilis gives a single painless indurated chancre; chancroid (H. ducreyi) gives a painful ragged ulcer with suppurative unilateral buboes. Pain plus vesicles is the giveaway.
• Acyclovir requires viral thymidine kinase for the first phosphorylation. Resistance is therefore TK deficiency, and the answer is foscarnet, which inhibits DNA polymerase directly. Expect this stem in advanced HIV or a transplant patient with an enlarging, non-healing ulcer despite acyclovir.
• Pregnancy: suppressive acyclovir from 36 weeks and cesarean delivery for active lesions or prodrome at labor (ACOG). Acyclovir is safe in pregnancy — the drug examiners actually want you to reject in pregnancy is an ACE inhibitor, not an antiviral.
• Recurrent erythema multiforme with target lesions is most often HSV-driven; the management answer is chronic suppressive antiviral therapy, not steroids.
• **Topical corticosteroids in a fluorescein dendritic ulcer cause geographic ulceration and perforation** — the classic "which drug is contraindicated" question.
• Asymptomatic shedding transmits HSV, so condoms plus daily suppressive valacyclovir — which reduces transmission to a susceptible partner — is the counseling answer (CDC 2021). Routine type-specific serologic screening of asymptomatic people is not recommended (USPSTF).