Herpes Simplex Virus Infections

Slide 1 · Herpes Simplex Virus Infections

Oral and orofacial pathology

Primary disease • neural latency • recurrent mucocutaneous lesions • diagnostic morphology

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · What the learner should recognize

Identify the characteristic oral presentations of primary and recurrent HSV.

Explain epithelial lytic infection, sensory-neuron latency, and reactivation.

Recognize vesicular and cytopathic changes in affected epithelium.

Distinguish typical HSV lesions from key oral mimics and high-risk disease.

Slide 3 · The three common oral presentations

Childhood

Acute herpetic gingivostomatitis

Adulthood

Acute or recurrent pharyngitis

Immunocompromise

Chronic mucocutaneous HSV

Slide 4 · HSV-1 and HSV-2: Overlapping syndromes

Dimension

HSV-1

HSV-2

Common association

Orofacial disease

Genital disease

Oral infection

Predominant orofacial type

Also possible

Shared properties

Primary infection, neuronal latency, recurrence

Primary infection, neuronal latency, recurrence

Type distinction

Antibody reactivity to type-specific glycoprotein G

Antibody reactivity to type-specific glycoprotein G

Slide 5 · Oral disease is not exclusive to HSV-1

Anatomic site does not establish HSV serotype.

Most orofacial infections involve HSV-1.

Oral HSV-2 infections are documented.

The two serotypes are genetically related and share pathogenic behavior.

Slide 6 · From exposure to a mucosal lesion

Mucosal contact

Virus encounters susceptible oral epithelium

Lytic replication

Virus produces infectious progeny locally

Cell injury

Epithelial ballooning and cell fusion

Clinical lesion

Intraepithelial vesicle → erosion or ulcer

Slide 7 · The oral epithelium is the first target

Primary HSV replication occurs in skin or mucous membranes at the entry site.

Epithelial infection generates infectious virions and locally destructive lesions.

Vesicles reflect epithelial injury rather than a primary immune-complex eruption.

Clinical disease may remain localized even though neural infection follows.

Slide 8 · Epithelial cytolysis explains vesicle formation

Schematic • epithelial cell injury

Morphologic interpretation

Ballooning degeneration distends infected keratinocytes.

Intracellular and intercellular edema promotes clefting.

An intraepithelial fluid space becomes a visible vesicle.

Slide 9 · HSV enters the sensory nervous system

Mucosal replication

Primary site of infection

Sensory ending

Viral particles enter innervating neurons

Retrograde transport

Nucleocapsids move toward the soma

Sensory ganglion

Viral DNA establishes lifelong latency

Slide 10 · Neural route: Mucosa to sensory ganglion

Oral mucosal

Epithelium

Sensory ganglion

(neuronal soma)

Retrograde axonal transport

HSV DNA

Remains latent

In neuronal nucleus

Schematic • not an anatomical micrograph

Morphologic interpretation

Latency is a neuronal state distinct from productive mucosal infection.

For orofacial lesions, regional sensory ganglia provide the latent reservoir.

Slide 11 · Latency is not eradication

After the initial episode resolves, HSV DNA remains within neuronal nuclei.

The genome is transcriptionally restricted rather than productively replicating.

This persistence allows subsequent recurrence without a new exposure.

Host immune control and the viral latency program coexist.

Slide 12 · Latency-associated transcripts (LATs)

Latent HSV DNA

Remains within neuronal nucleus

LAT expression

Latency-associated RNA transcription

Restricted lytic genes

Silencing of productive viral program

Persistence

Neuronal reservoir maintained

Anti-apoptotic, heterochromatin and microRNA mechanisms as possible LAT contributions.

Slide 13 · Proposed functions of LATs

LATs may reduce apoptosis of infected neurons.

They may promote heterochromatin formation and silencing of lytic genes.

LAT-derived microRNAs may suppress critical HSV lytic transcripts.

These are mechanisms proposed, not deterministic clinical tests.

Slide 14 · Reactivation reverses the direction of spread

Latent genome

Sensory-neuron reservoir

Reactivation

Lytic program resumes

Axonal spread

Virus reaches mucosal surfaces

Recurrent lesion

New focal epithelial cytolysis

Slide 15 · Examples of reactivation triggers

Local injury

Trauma, ultraviolet exposure, temperature extremes

Intercurrent illness

Upper respiratory tract infection and related stress

Physiologic change

Pregnancy or menstruation

Host immunity

Immunosuppression favors more extensive recurrence

Slide 16 · Reactivation may be symptomatic or silent

Viral reactivation does not always produce a visible vesicle.

Recurrent HSV can spread from sensory neurons to epithelium repeatedly.

Symptoms vary with local replication and host response.

A previous infection explains renewed disease at familiar mucosal sites.

Slide 17 · HSV survives despite immune responses

Cell-mediated recognition

HSV may interfere with MHC class I presentation.

Antibody responses

Viral glycoprotein gE can bind the Fc domain of IgG.

Complement pathways

Viral glycoprotein gC interacts with C3 and activation products.

Slide 18 · Reduced CD8+ T-cell recognition

Viral immune evasion

MHC-I recognition pathway inhibited

Altered antigen display

Less efficient recognition by antiviral CTLs

Continued infection

Partial escape despite host immune memory

Slide 19 · Glycoprotein gE interferes with antibody function

GE binds IgG Fc

Antibody effector region is engaged

Effector interference

C1q binding and ADCC can be impaired

Immune evasion

Virus is less effectively cleared

Slide 20 · Glycoprotein gC interferes with complement

GC binds C3

Interaction with complement component

Complement decay

C3 / activation product decay accelerated

Reduced protection

Alternative pathway efficacy impaired

Slide 21 · Primary infection versus recurrence

Feature

Primary HSV infection

Recurrent HSV

Timing

First encounter with virus

Reactivation of persistent viral genome

Clinical expression

Often asymptomatic; may cause gingivostomatitis

Localized clustered vesicles

Anatomic pattern

Initial inoculation site

Same site or mucosa served by same ganglion

Underlying process

Mucosal replication plus neural seeding

Neural reactivation followed by mucosal infection

Slide 22 · Childhood acquisition: The textbook pattern

Primary oral HSV is particularly frequent between ages 2 and 4 years.

A large proportion of childhood infections are asymptomatic.

Symptomatic primary disease is acute herpetic gingivostomatitis.

Age and clinical morphology should be interpreted together.

Slide 23 · Why many primary infections go unrecognized

Primary HSV may occur without a clinically obvious oral eruption.

Absence of recalled gingivostomatitis does not exclude prior exposure.

Latency can be established after subclinical mucosal replication.

Future recurrence can be the first memorable manifestation.

Slide 24 · Acute herpetic gingivostomatitis: Lesion evolution

1

Abrupt onset

Multiple mucosal vesicles

2

Fragile epithelium

Vesicles break and erode

3

Active stomatitis

Painful oral ulceration

4

Resolution

Mucosa regenerates as infection recedes

Slide 25 · Primary gingivostomatitis: Three tissue findings

Mucosa

Vesicles and ulcerations involving the oral surface

Gingiva

Diffuse inflammation contributes to gingivostomatitis

Regional nodes

Cervical lymphadenopathy may accompany the eruption

Slide 26 · Systemic symptoms contextualize primary oral HSV

Fever may accompany symptomatic childhood primary infection.

Anorexia or reduced oral intake can result from painful lesions.

Regional lymphadenopathy reflects local immune activation.

Systemic findings are not mandatory for every infection.

Slide 27 · The textbook’s symptomatic-frequency statement

Up to 20% of childhood primary cases may present with acute gingivostomatitis.

This statement refers to the source’s pediatric presentation, not all HSV infections.

Avoid applying this figure to adult recurrence or population-wide prevalence.

The remaining infections are commonly clinically silent.

Slide 28 · Adult oral HSV can involve the pharynx

Acute herpetic pharyngitis is common in adults.

The adult clinical phenotype differs from classic childhood gingivostomatitis.

Acute pharyngeal involvement may recur.

Etiology cannot be inferred from sore throat alone.

Slide 29 · The pathogenesis of a recurrent oral episode

Ganglionic latency

HSV persists after the primary episode

Trigger / reactivation

Lytic transcription restarts

Epithelial reinfection

Nearby mucosa is seeded

Grouped vesicles

Superficial blisters and ulcers recur

Slide 30 · Anatomic recurrence follows neural territory

Recurrences favor the initial site or mucosa supplied by the same ganglion.

Recurrence does not require a second exogenous exposure.

A repeated distribution supports reactivation of latent infection.

The precise mucosal point of recurrence can vary.

Slide 31 · Small grouped vesicles are a major visual clue

Grouped superficial vesicles

(schematic distribution; Not a patient photograph)

Morphologic interpretation

Typical recurrent oral HSV vesicles measure about 1–3 mm.

They are clustered rather than solitary.

Rupture can replace a vesicular surface with shallow ulceration.

Slide 32 · Common sites of recurrent orofacial HSV

Lips

Herpes labialis / “cold sores”

Nasal orifices

Periorificial vesicular clusters

Buccal mucosa

Recurrent focal mucosal eruption

Attached oral mucosa

Gingiva and hard palate

Slide 33 · Herpes labialis: The classic recurrence

Clusters of small vesicles involve the labial or perioral surface.

Lip lesions may rupture and subsequently crust.

Oral/facial HSV is often bilateral or not dermatomally restricted.

This pattern contrasts with zoster distribution.

Slide 34 · Recurrent disease may involve multiple oral zones

The buccal mucosa, gingiva and hard palate are documented sites.

The nasal orifices are another frequent orofacial site.

A typical recurrent outbreak remains a clustered, superficial epithelial process.

The lesion site is informative but not uniquely diagnostic.

Slide 35 · Typical recurrent lesion: Visible natural history

1

Early

Small grouped vesicles

2

Breakdown

Epithelial roof ruptures

3

Surface repair

Crusting or mucosal erosion resolves

4

Usual endpoint

Healing in approximately 7–10 days

Slide 36 · An unusually persistent lesion changes the risk assessment

HSV lesions may remain active longer in immunocompromised hosts.

Prolonged ulcers should not automatically be labeled benign recurrent herpes.

Persistent HSV can require systemic antiviral treatment.

The clinical setting is as important as morphology.

Slide 37 · Immune status modifies the phenotype

Feature

Immunocompetent host

Immunocompromised host

Typical course

Self-limited oral episodes

Prolonged or chronic mucocutaneous lesions

Viral control

Cellular immunity restricts spread

Control may be impaired

Major concern

Local pain and recurrence

Persistent disease or dissemination

Clinical implication

Recognize the usual recurrent pattern

Assess for severe or disseminated involvement

Slide 38 · Clinical settings that favor severe HSV

HIV-related impairment of cellular immunity may permit unusually severe infection.

Chemotherapy and other immunosuppressive states increase vulnerability.

Neonates are also at risk of disseminated infection.

Disseminated disease lies beyond uncomplicated oral herpes.

Slide 39 · How ballooning degeneration produces a blister

Schematic • epithelial cell injury

Morphologic interpretation

Cytolysis causes swollen epithelial cells.

Edema and intercellular separation generate a cleft.

Coalescing spaces create an intraepithelial vesicle.

Slide 40 · HSV vesicle: Tissue-level architecture

Schematic • epithelial cell injury

Morphologic interpretation

The blister lies within the stratified squamous epithelium.

Injured keratinocytes can remain near the vesicle margin.

Inflammatory cells appear as the lesion evolves.

Slide 41 · Vesicle rupture creates a shallow ulcer

1

Intracellular injury

Ballooning of keratinocytes

2

Surface separation

Fragile fluid-filled vesicle

3

Epithelial loss

Rupture and superficial erosion

4

Inflammation / repair

Red rim; Epithelial regeneration

Slide 42 · Cowdry type A inclusions: Nuclear HSV effect

Characteristic infected cells have large pink-to-purple intranuclear inclusions.

Inclusions represent viral proteins and virions during assembly.

Host chromatin is pushed toward the nuclear periphery.

Recognition is a cytopathic clue, not an HSV serotype test.

Slide 43 · Cowdry type A inclusion: Conceptual cell

Intranuclear inclusion

Morphologic interpretation

Peripheral chromatin forms a dense rim.

An inclusion lies within the nucleus, sometimes with surrounding clearing.

Appearance here is explanatory artwork, not an H&E specimen.

Slide 44 · Cell fusion creates multinucleated syncytia

HSV can produce multiple nuclei inside a single infected epithelial cell.

Syncytia result from virus-mediated cell fusion.

Infected nuclei may also contain herpetic inclusions.

Multinucleation and inclusions are complementary morphologic observations.

Slide 45 · HSV syncytium: Conceptual cell fusion

A single fused cell with several nuclei

(schematic, not microscopic evidence)

Morphologic interpretation

Adjacent infected keratinocytes fuse into a multinucleated polykaryon.

A multinucleated cell may be seen in vesicle material.

Such changes support a herpesvirus cytopathic pattern.

Slide 46 · Cytology can show herpetic cytopathic effect

Active vesicular material can contain infected epithelial cells.

Multinucleated cells and intranuclear inclusions are diagnostic clues.

Demonstration of multinucleate cells on a Tzanck preparation.

Morphology must be interpreted with lesion distribution and clinical findings.

Slide 47 · What a Tzanck preparation does and does not show

Can demonstrate

Cannot establish alone

Multinucleated epithelial cells

HSV-1 versus HSV-2 serotype

Herpesvirus-type cytopathic morphology

A definite distinction between HSV and VZV

Rapid morphologic clue from a vesicle

Extent of latent infection in sensory ganglia

Slide 48 · A late biopsy may no longer show an intact blister

HSV vesicles rupture rapidly, exposing superficial ulcerated mucosa.

Biopsied lesions may contain desquamated epithelium and acute inflammation.

Infected epithelial cells at the margin may preserve cytopathic changes.

Specimen timing can influence morphologic yield.

Slide 49 · HSV versus recurrent aphthous ulceration

Discriminator

Herpes simplex

Aphthous ulcers

Initial surface

Clusters of vesicles

Shallow ulcers with exudative surface

Distribution

Labial / gingival / palatal and other oral sites

Variable oral mucosal sites

Etiology

Persistent latent neurotropic virus

Cause uncertain in Robbins

Course

Recurrent, often same neural territory

Often recurrent; not a herpesvirus infection

Slide 50 · HSV versus oral candidiasis

Discriminator

Herpetic lesion

Oral thrush

Common surface

Vesicles or superficial ulcers

Gray-white pseudomembrane

Key tissue change

Viral epithelial cytolysis

Fungal organisms in surface exudate

Removal of surface

Fragile blister / erosion

Pseudomembrane readily scraped

Shared context

Can worsen with immunosuppression

Commonly promoted by immunosuppression

Slide 51 · HSV versus herpes zoster

Discriminator

HSV recurrence

Reactivated VZV / zoster

Cutaneous pattern

Often periorificial; not restricted to dermatome

Characteristic segmental / dermatomal eruption

Recurrence

Repeated episodes possible

Less frequent in immunocompetent persons

Neural correlate

Sensory-ganglion reservoir

Dorsal root or cranial sensory ganglia

Cytology

Herpesvirus inclusions and multinucleation

Similar herpesvirus cytopathic effect

Slide 52 · Other oral infections in the differential

Enteroviruses

Herpangina and hand-foot-and-mouth disease may involve the oral region.

EBV

Hairy leukoplakia produces white lateral tongue plaques, not vesicular clusters.

Cytomegalovirus

Included among oral/head-and-neck viral infections.

Rubeola / measles

A separate viral disease that may affect the oral cavity.

Slide 53 · Oral hairy leukoplakia is not recurrent oral HSV

EBV-associated hairy leukoplakia typically forms white lateral-tongue plaques.

The white plaque generally cannot be scraped off.

HSV recurrence instead produces vesicles that ulcerate.

The setting of immunosuppression can occur in both entities.

Slide 54 · Reasoning from a painful oral lesion

Morphology

Grouped vesicles? Superficial ulcer? White plaque?

Site and pattern

Periorificial cluster, recurrent site, or dermatomal?

Clinical context

Age, immune status, systemic symptoms

Diagnostic category

HSV likely vs alternative oral disease

Slide 55 · Anatomy plus morphology is stronger than either alone

Interpret the visible lesion in its clinical and neural context.

Grouped small vesicles at a recurrent site strongly support HSV.

A solitary shallow fibrin-covered ulcer raises other possibilities.

A persistent atypical ulcer in an immunocompromised host requires careful evaluation.

Slide 56 · Type-specific serology addresses a different question

Morphology

Type-specific antibody assessment

Characterizes local cytopathic changes

Uses type-specific glycoprotein G antigenicity

Can support a herpesvirus-induced lesion

Can distinguish immunologic recognition of HSV-1 / HSV-2

Does not reliably separate HSV types

Does not itself localize the active oral lesion

Slide 57 · Two mechanisms of HSV keratitis

Corneal epithelial keratitis

Corneal stromal keratitis

Direct virus-induced epithelial cytolysis

Immune-mediated stromal injury

Loss of superficial epithelial integrity

Mononuclear inflammatory infiltration

Reflects active epithelial infection

Can cause vessels, opacity and scarring

Slide 58 · Ocular extension matters clinically

Recurrent HSV can cause corneal ulcerations.

Corneal epithelial damage can be directly viral.

Stromal disease can instead reflect a damaging immune response.

Corneal scarring and loss of transparency threaten vision.

Slide 59 · Herpetic whitlow: A nonoral manifestation

HSV can cause painful, erythematous lesions of the fingers or palm.

This manifestation occurs in infants and occasionally after occupational exposure.

The same epithelial cytopathic process operates outside the oral mucosa.

It is a clinicopathologic extension, not the central topic of this lecture.

Slide 60 · Dissemination is not routine recurrent herpes

Immunocompromise can permit skin and visceral dissemination.

Robbins documents esophagitis, bronchopneumonia and hepatitis.

Necrotizing pneumonia or hepatitis represents severe organ involvement.

Suspicion rises when mucocutaneous disease is unusually persistent or widespread.

Slide 61 · Local oral HSV versus visceral HSV

Uncomplicated orofacial episode

Severe systemic infection

Grouped vesicles and shallow erosions

Potential visceral organ necrosis

Usually self-limited in intact immunity

Often associated with immunosuppression

Local mucosal epithelial injury

May involve esophagus, lung, liver or CNS

Slide 62 · Neurologic HSV disease: A boundary reminder

Neuronal latency is common; Encephalitis is a separate severe manifestation.

HSV-1 encephalitis preferentially involves the temporal and orbital-frontal regions.

Defects in TLR3 signaling are associated with susceptibility.

Oral recurrence alone is not evidence of encephalitis.

Slide 63 · Case 1: Febrile child with oral erosions

Clinical vignette

A 3-year-old has abrupt oral vesicles progressing to painful erosions, fever, reduced intake, and enlarged cervical nodes.

What presentation best unifies the age, morphology and systemic symptoms?

What local cellular event initially produces the vesicles?

Slide 64 · Case 1 interpretation: Primary gingivostomatitis

A first symptomatic oral HSV episode is the most coherent explanation.

Childhood primary disease can present with acute gingivostomatitis.

Lytic epithelial infection produces fragile intraepithelial blisters.

Fever and regional lymphadenopathy are recognized accompanying features.

Slide 65 · Case 2: Recurrent lip vesicles

Clinical vignette

An otherwise healthy adult describes repeated clusters of tiny vesicles at nearly the same lip site, healing after about a week.

Does repeated disease imply repeated new HSV acquisition?

What explains the similar site and short natural history?

Slide 66 · Case 2 interpretation: Recurrent herpes labialis

Reactivation from a regional sensory-ganglion reservoir explains recurrence.

Small clustered vesicles on the lip are characteristic.

Relapse near the previous inoculation site reflects related neural innervation.

The 7–10-day course is consistent with uncomplicated recurrence.

Slide 67 · Case 3: Prolonged ulceration in immunosuppression

Clinical vignette

An adult receiving immunosuppressive therapy develops persistent orofacial ulceration that does not follow a brief self-limited course.

What makes this scenario different from usual herpes labialis?

Which major complication category deserves particular consideration?

Slide 68 · Case 3 interpretation: Complicated mucocutaneous HSV

Chronic or extensive HSV is a recognized presentation in immunocompromised hosts.

Persistence should trigger careful clinical and etiologic reassessment.

Severe disease may require systemic antiviral therapy.

Disseminated or visceral HSV is a clinically important possibility.

Slide 69 · Connecting mechanisms to observed pathology

Oral entry

Local lytic epithelial replication

Primary lesion

Ballooning, clefting, cytopathic inclusions

Neural latency

HSV DNA persists in sensory ganglia

Reactivation

Recurrent clusters in related mucosal territory

Slide 70 · Four errors worth avoiding

Serotype inference

Do not assume every oral HSV lesion must be HSV-1.

Pattern inference

Do not call a solitary aphthous ulcer recurrent HSV without support.

Microscopy inference

Tzanck morphology is not specific HSV typing.

Severity inference

Do not dismiss chronic ulceration in immunocompromised hosts.

Slide 71 · Integrated clinicopathologic conclusions

HSV causes primary mucosal injury followed by sensory-neuron latency.

Reactivation generates clustered small periorificial or oral vesicles.

Ballooning, intranuclear inclusions, and multinucleation explain the morphology.

Immune status governs persistence and risk of organ involvement.

Clinical distribution and lesion architecture drive the oral differential.

Slide 72 · Textbook source map

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. (2026). Chapter 16: Head and Neck, oral HSV section, p. 666–667.

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. (2026). Chapter 8: Infectious Diseases, HSV section, pp. 321–322.

Adjacent Chapter 16 sections: aphthous ulcers, oral candidiasis, and hairy leukoplakia.

Chapter 22: HSV cytopathic changes in genital-tract specimens (limited supporting comparison).