Herpes Simplex Virus

Slide 1 · Herpes Simplex Virus

HERPES SIMPLEX VIRUS

Pathogenesis • Morphology • Clinicopathologic correlations

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Distinguish productive epithelial infection from neuronal latency

Explain reactivation and HSV immune evasion

Recognize the characteristic cytopathic morphology

Relate the lesions to oral, genital, corneal, neurologic and disseminated disease

Slide 3 · HSV: Acute disease and lifelong persistence

HSV-1 and HSV-2 cause primary and recurrent infections

Productive replication occurs in skin and mucosal epithelium

The viral genome persists latently in sensory neurons

Clinical recurrence can follow reactivation from latency

Epithelial replication

Vesicles + shedding

Sensory axonal transport

Latent neuronal genome

Reactivation

Return to surface

Slide 4 · HSV belongs to the α-herpesvirus group

The group includes HSV-1, HSV-2 and varicella-zoster virus

α-Herpesviruses infect epithelium and establish neuronal latency

Epithelial damage and neuronal persistence are biologically distinct phases

HSV-1

HSV-2

VZV

Slide 5 · Herpesviruses: A latency-defining family

Large, enveloped double-stranded DNA viruses

Latency means genomic persistence without infectious virus production

Reactivation causes productive infection and infectious shedding

Neuronal cell body

Latent HSV DNA

Nuclear reservoir

Slide 6 · HSV-1 and HSV-2: Closely related viruses

The two viruses are genetically closely related

Both cause overlapping primary and recurrent syndromes

Virus type does not define an exclusive anatomic site

HSV-1

Often orofacial

Shared infection spectrum

HSV-2

Often genital

Slide 7 · Type-specific distinction: Glycoprotein G

Antibodies to variant forms of viral glycoprotein G distinguish the types serologically

Type-specific antibody response is distinct from identifying the site of active disease

Either viral type may infect oral or genital mucosa

HSV-1

Glycoprotein G

Type-specific

Antibody

HSV-2

Glycoprotein G

Slide 8 · Worldwide burden

The 11th-edition chapter estimates approximately 4 billion HSV infections globally

The figure conveys the enormous scale of persistent infection

Do not interpret this textbook estimate as a real-time 2026 surveillance count

Slide 9 · Sites of entry and early viral replication

Typical entry sites are the oropharynx and genital tract

Replication at entry produces infectious virions

Vesicles arise from injured epithelial cells

The local lesion also provides access to sensory nerve endings

Oropharyngeal

Mucosa

Genital

Mucosa

Slide 10 · Productive epithelial infection

The epithelial phase generates newly infectious virus

Virus-induced cytolysis damages infected epithelial cells

Tissue destruction accounts for vesicles and superficial ulcers

Subepithelial tissue

Vesicle

Slide 11 · Neuronal entry: The transition to persistence

HSV reaches sensory neurons innervating the infected surface

Viral nucleocapsids travel along axons toward neuronal cell bodies

Replication at the surface and latency in the neuron have different outcomes

Epithelial

Site

Sensory

Ganglion

Retrograde nucleocapsid transport

Slide 12 · Retrograde transport toward sensory ganglia

Transport is directed from peripheral axons to cell bodies

Sensory neurons connect the primary epithelial site with the latent reservoir

This neural route explains the relationship between initial and recurrent locations

Epithelial

Site

Sensory

Ganglion

Retrograde nucleocapsid transport

Slide 13 · HSV latency: A precise definition

Latent viral DNA persists inside the neuronal nucleus

Latency is not the same as continuing production of virions

Viral persistence remains possible after epithelial lesions heal

Neuronal cell body

Latent HSV DNA

Nuclear reservoir

Slide 14 · Why clinical healing is not eradication

Primary infection typically resolves within weeks in immunocompetent hosts

Resolution of visible vesicles does not remove latent neuronal DNA

Consequently, prior infection can be followed by further reactivation

Epithelial replication

Vesicles + shedding

Sensory axonal transport

Latent neuronal genome

Reactivation

Return to surface

Slide 15 · Latency-associated transcripts (LATs)

During neuronal latency, latency-associated RNAs are transcribed

The text describes no apparent viral protein production during latency

LATs are associated with maintenance of the nonproductive state

Neuronal cell body

Latent HSV DNA

Nuclear reservoir

Slide 16 · LATs: A proposed anti-apoptotic role

LATs may protect infected neurons from apoptosis

Survival of the host neuron helps preserve the latent genome

This is a proposed contribution to latency, not a demonstrated sole mechanism

Proposed anti-apoptotic

Role

Proposed chromatin-mediated

Lytic silencing

Proposed miRNA-mediated

Lytic gene repression

Slide 17 · LATs: Transcriptional silencing

LATs may promote heterochromatin-associated repression of lytic genes

Silencing of lytic gene expression favors the latent state

This mechanism with appropriate uncertainty

Proposed anti-apoptotic

Role

Proposed chromatin-mediated

Lytic silencing

Proposed miRNA-mediated

Lytic gene repression

Slide 18 · LAT-derived microRNAs

LAT transcripts may serve as precursors for microRNAs

These microRNAs can downregulate critical HSV lytic genes

Reduced lytic gene expression can reinforce viral latency

Proposed anti-apoptotic

Role

Proposed chromatin-mediated

Lytic silencing

Proposed miRNA-mediated

Lytic gene repression

Slide 19 · From latent genome to reactivation

Reactivation may occur repeatedly during the infected person’s life

Neuronal stress-response pathways have been implicated

The chapter proposes release from epigenetic silencing during reactivation

Neuronal stress

Response

Proposed reversal

Of epigenetic silencing

HSV lytic genes

And reactivation

Slide 20 · Epigenetic model of reactivation

A proposed methylation/phosphorylation process releases lytic genes from repression

The process is linked to cellular stress responses in neurons

Exact mechanistic links should be understood as proposed, not settled

Neuronal stress

Response

Proposed reversal

Of epigenetic silencing

HSV lytic genes

And reactivation

Slide 21 · Recurrence need not be clinically obvious

Reactivation may produce typical recurrent lesions

Reactivation also occurs without symptoms

Asymptomatic episodes matter because active shedding can transmit infection

Epithelial replication

Vesicles + shedding

Sensory axonal transport

Latent neuronal genome

Reactivation

Return to surface

Slide 22 · Return of virus from neuron to epithelium

Reactivated infection leads to spread from neurons toward skin or mucosa

Infectious viral release again occurs at a peripheral epithelial site

The surface–neuron–surface cycle produces recurring disease

Epithelial replication

Vesicles + shedding

Sensory axonal transport

Latent neuronal genome

Reactivation

Return to surface

Slide 23 · Immunity restrains HSV but does not clear latency

Immune control usually limits primary epithelial disease

HSV has mechanisms that impair both cellular and humoral responses

These mechanisms help explain recurrence despite pre-existing host immunity

MHC I pathway

GE → IgG Fc

GC → C3

Slide 24 · HSV interference with CD8 T-cell recognition

HSV inhibits the MHC class I antigen-recognition pathway

Reduced recognition impairs antiviral cytotoxic T lymphocytes

The target is an important mechanism of cellular immune surveillance

HSV protein effects

MHC class I recognition ↓

CTL recognition ↓

Slide 25 · Glycoprotein gE binds the Fc region of IgG

Viral gE binds the Fc domain of IgG

The interaction interferes with C1q binding and antibody-dependent cellular cytotoxicity

Antibodies can therefore be less effective at antiviral clearance

HSV glycoprotein gE

IgG Fc binding

C1q / ADCC effects ↓

Slide 26 · Glycoprotein gC counteracts complement

HSV gC binds complement component C3 and its activation products

It accelerates decay within the alternative complement pathway

Complement interference is a separate route of immune evasion

HSV glycoprotein gC

C3 interactions

Alternative pathway activity ↓

Slide 27 · HSV immune evasion is multi-layered

Evasion mechanism

Host defense disrupted

MHC class I inhibition

CTL antigen recognition

gE: IgG Fc binding

C1q binding; antibody-dependent cytotoxicity

gC: C3 interactions

Alternative complement pathway

Slide 28 · Dendritic cells and antiviral defense

HSV can infect multiple cellular lineages

Dendritic cells are among the susceptible cell types

Infection of antigen-presenting cells has relevance to antiviral immune responses

Slide 29 · The principal HSV epithelial lesion

Intraepithelial vesicles are the defining blister morphology

Cell injury combines ballooning degeneration and intracellular edema

Vesicular fluid contains virus during productive infection

Subepithelial tissue

Vesicle

Slide 30 · Ballooning degeneration of epithelial cells

Infected epithelial cells enlarge as they accumulate intracellular fluid

Swelling disrupts normal epithelial cohesion

Grouped swollen cells contribute to intraepithelial blister formation

Subepithelial tissue

Vesicle

Slide 31 · Intraepithelial blister to superficial ulcer

HSV vesicles are fragile and frequently rupture

The denuded surface may form a superficial erosion or ulcer

Healing lesions often crust over in exposed skin

Papule

Vesicle

Erosion /

Ulcer

Crust / heal

Slide 32 · Cowdry type A: The nuclear inclusion

Infected nuclei contain large pink-to-purple intranuclear inclusions

The inclusion consists of viral replication proteins and assembling virions

The finding points to a productive viral cytopathic effect

Intranuclear inclusion with rim of chromatin

Schematic — not a clinical or histologic specimen

Slide 33 · Margination of nuclear chromatin

Intranuclear viral material pushes host chromatin toward the nuclear periphery

Peripheral chromatin accentuates the abnormal inclusion-bearing nucleus

The appearance may be described as a ground-glass nuclear change

Intranuclear inclusion with rim of chromatin

Schematic — not a clinical or histologic specimen

Slide 34 · Multinucleated syncytia from cell fusion

HSV induces fusion of infected epithelial cells

The fused cells contain multiple nuclei

Several nuclei may show herpetic intranuclear changes simultaneously

Fused multinucleated epithelial cell

Schematic — not a clinical or histologic specimen

Slide 35 · Recognition pattern of HSV cytopathology

Morphologic element

Interpretive significance

Ballooning + vesicle

Lytic epithelial injury

Cowdry type A inclusion

Intranuclear viral replication material

Multinucleation

Cell fusion / syncytial cytopathic effect

Slide 36 · Orofacial cold sores: Preferred location

Cold sores occur around mucosal orifices

Lips and the skin around the nose are common locations

Perioral lesions are not necessarily restricted to one side

Lips

Nostrils

Oral mucosa

Slide 37 · Distribution: HSV is not a typical dermatomal rash

Feature

HSV

VZV reactivation

Latency

Sensory neurons

Sensory neurons

Typical lesion pattern

Recurrent orofacial/genital

Painful dermatomal zoster

Recurrence

May recur repeatedly

Usually later in life

Slide 38 · Primary gingivostomatitis in children

Primary oral disease is usually associated with HSV-1

Vesicles and ulcers may extend from tongue toward the retropharynx

Cervical lymphadenopathy accompanies the oral inflammatory process

Tongue / gingiva

Lips / hard palate

Pharynx

Slide 39 · The oral spectrum changes with age

Context

Typical manifestation

Children

Acute gingivostomatitis

Adults

Acute herpes pharyngitis

Immunosuppression

Persistent mucocutaneous disease

Slide 40 · Recurrent oral herpes: Sites and timing

Grouped small vesicles may involve lip, nostrils, buccal mucosa, gingiva or hard palate

Recurrences arise in the area of primary inoculation or territory of the same ganglion

The oral chapter describes usual resolution within 7–10 days

Lips

Nostrils

Oral mucosa

Slide 41 · Herpetic whitlow: Painful digital infection

HSV can cause swollen, erythematous lesions of fingers or palm

Herpetic whitlow occurs in infants and sometimes through occupational exposure

Painful vesicular lesions should prompt consideration of HSV

Slide 42 · Genital HSV: Both virus types are possible

Genital infection is more often caused by HSV-2 than HSV-1

The vulva, vagina, cervix and external genital skin can be involved

Oral–genital site overlap prevents reliable typing by anatomy alone

HSV-1

Often orofacial

Shared infection spectrum

HSV-2

Often genital

Slide 43 · Genital lesions progress from papules to ulcers

The genital-tract chapter describes early erythematous papules

Papules become vesicles and then painful confluent superficial ulcers

Inflammatory response contributes to the rim and ulcer-bed exudate

Papule

Vesicle

Erosion /

Ulcer

Crust / heal

Slide 44 · Symptoms may reflect lesion location

Acute genital disease may cause fever, malaise and tender inguinal nodes

Vaginal or cervical disease may present with discharge and pelvic pain

Periurethral ulcers may cause dysuria or urinary retention

Slide 45 · Genital HSV and lumbosacral latency

During genital infection HSV travels to regional lumbosacral ganglia

The virus then persists in a neuronal reservoir

Reactivation can produce mucosal or cutaneous lesions at related sites

Neuronal cell body

Latent HSV DNA

Nuclear reservoir

Slide 46 · What can precipitate recurrence?

The genital chapter associates recurrence with altered immune function

Stress, trauma, concurrent viral infection and hormonal changes are listed

Recurrent episodes are more frequent in immunosuppressed individuals

Neuronal stress

Response

Proposed reversal

Of epigenetic silencing

HSV lytic genes

And reactivation

Slide 47 · Genital biopsy: Stage affects the findings

Lesions are often already ulcerated when biopsied

The epithelial surface may have been lost by desquamation

The ulcer bed may show marked acute inflammation

Papule

Vesicle

Erosion /

Ulcer

Crust / heal

Slide 48 · Genital cytology: Characteristic changes

Exudate may contain multinucleated squamous epithelial cells

Nuclei may contain eosinophilic-to-basophilic inclusions

Ground-glass nuclear change supports HSV cytopathic injury

Intranuclear inclusion with rim of chromatin

Schematic — not a clinical or histologic specimen

Slide 49 · HSV versus VZV: Compare the patterns

Feature

HSV

VZV reactivation

Latency

Sensory neurons

Sensory neurons

Typical lesion pattern

Recurrent orofacial/genital

Painful dermatomal zoster

Recurrence

May recur repeatedly

Usually later in life

Slide 50 · HSV versus CMV: Different nuclear morphology

Feature

HSV

CMV

Prominent cell change

Syncytia / ballooning

Cytomegaly

Nuclear inclusion

Cowdry type A

Haloed owl-eye type

Common context

Skin and mucosal disease

Immunosuppressed visceral disease

Slide 51 · HSV epithelial keratitis: Direct damage

Corneal epithelial disease is associated with viral cytolysis

Infected superficial epithelial cells are injured directly by HSV

Mechanism differs from the stromal form of herpetic keratitis

Corneal epithelium — cytolytic injury

Corneal stroma — immune infiltrate

Slide 52 · Stromal keratitis: Predominantly immune injury

The stromal form shows mononuclear inflammatory infiltration

Cells accumulate around stromal cells and endothelial structures

The text attributes stromal injury mainly to the immune response

Corneal epithelium — cytolytic injury

Corneal stroma — immune infiltrate

Slide 53 · Why herpetic stromal disease threatens vision

Inflammation promotes corneal neovascularization and scarring

Stromal opacification compromises corneal transparency

Repeated or severe injury may culminate in blindness

Corneal epithelium — cytolytic injury

Corneal stroma — immune infiltrate

Slide 54 · HSV-1 encephalitis: Characteristic topography

HSV-1 is an important cause of sporadic fatal encephalitis

The temporal lobes and orbital gyri of frontal lobes are characteristically involved

Recognizing the topography supports the clinicopathologic differential

Temporal lobes

Orbital frontal gyri

Characteristic involvement in HSV-1 encephalitis

Slide 55 · CNS tissue injury in HSV-1 encephalitis

The CNS chapter describes necrotizing infection

Hemorrhage may accompany severe tissue destruction

The anatomic pattern and injury type are more useful than an isolated symptom

Temporal lobes

Orbital frontal gyri

Characteristic involvement in HSV-1 encephalitis

Slide 56 · Clinical clues to HSV-1 encephalitis

Changes in behavior, memory or mood may predominate

Seizures, weakness, lethargy or ataxia may occur

The neurologic presentation relates to the affected temporal and frontal regions

Slide 57 · TLR3 signaling and susceptibility

Inherited changes in TLR3 or components of its signaling pathway raise HSV encephalitis risk

The association implicates innate antiviral defense in the CNS

Genetic susceptibility does not imply that most infections cause encephalitis

Inherited TLR3-pathway

Variant

Altered innate antiviral

Defense

Increased risk of

HSV encephalitis

Slide 58 · HSV-2 can also involve the CNS

HSV-2 may cause meningitis in adults

Neonatal CNS infection can be severe

In patients with active HIV, HSV-2 may cause necrotizing hemorrhagic encephalitis

Slide 59 · Neonatal HSV: Acquisition during birth

Transmission may occur while passing through an infected birth canal

The chapter most often associates neonatal transmission with HSV-2

Active maternal primary genital disease presents particularly serious transmission risk

Maternal genital

HSV

Birth canal

Exposure

Neonatal systemic

Or CNS infection

Slide 60 · Disseminated neonatal disease

Neonatal infection may be fulminant rather than restricted to mucosa

Generalized lymphadenopathy and splenomegaly can occur

Necrotic foci may involve lung, liver, adrenal glands and CNS

Maternal genital

HSV

Birth canal

Exposure

Neonatal systemic

Or CNS infection

Slide 61 · Impaired cellular immunity permits dissemination

Patients receiving chemotherapy or living with HIV may develop extensive HSV

Immunosuppression weakens containment of epithelial infection

Hospitalized individuals with malignancy or immunosuppression are at risk for visceral disease

Cellular immune suppression

Disseminated HSV

Skin + viscera

Slide 62 · HSV esophagitis and superinfection

HSV can cause esophageal disease in susceptible hosts

Damaged mucosa may become secondarily infected by bacteria or fungi

The combination complicates interpretation of an ulcerated lesion

Esophagus

Lung

Liver

Slide 63 · HSV bronchopneumonia may be necrotizing

HSV bronchopneumonia is often a severe necrotizing infection

Some cases follow airway instrumentation when active oral HSV is present

Anatomic setting and host immune status are clinically important

Esophagus

Lung

Liver

Slide 64 · HSV hepatitis and systemic consequences

Disseminated HSV may involve the liver

Severe hepatic tissue damage may produce liver failure

The outcome illustrates how HSV disease differs between host contexts

Esophagus

Lung

Liver

Slide 65 · HSV-2 genital ulceration and HIV risk

The textbook associates HSV-2 with increased HIV transmission

Ulcerated genital epithelium disrupts mucosal barriers

The chapter additionally cites modulation of antiviral host immunity

Slide 66 · Diagnostic assessment begins with the lesion

Clinical morphology and anatomic distribution guide suspicion

HSV detection from active lesions is important for confirmation

Morphology is useful but cannot substitute for all organism-specific tests

Clinical lesion

And site

Collect active lesion

Material

Direct HSV

Detection

Slide 67 · Laboratory detection of HSV

The genital-tract chapter describes viral culture from lesional secretion

PCR assays offer a more sensitive method of detecting HSV

Immunofluorescence and other antigen-based assays are also discussed

Clinical lesion

And site

Collect active lesion

Material

Direct HSV

Detection

Slide 68 · Serology and direct viral detection answer different questions

Method

Primary question

Lesion PCR

Is HSV DNA present in sampled lesion?

Viral culture

Is infectious virus recoverable?

Type-specific serology

Evidence of HSV-type exposure

Slide 69 · Why HSV cytology is suggestive, not site-specific

Morphologic element

Interpretive significance

Ballooning + vesicle

Lytic epithelial injury

Cowdry type A inclusion

Intranuclear viral replication material

Multinucleation

Cell fusion / syncytial cytopathic effect

Slide 70 · Comparing the two forms of herpetic keratitis

Epithelial keratitis

Stromal keratitis

Direct viral cytolysis

Immune-mediated tissue injury

Surface epithelial damage

Mononuclear inflammation

Epithelial lesion

Neovascularization / opacity / scar

Slide 71 · Case: Recurrent perioral vesicles

A patient develops grouped vesicles around the lip after a previous similar episode

The eruption is bilateral rather than limited to one dermatome

Explain the site of viral latency and the route back to epithelium

Discuss

Mechanism → lesion → tissue injury

What observation makes the diagnosis plausible?

Slide 72 · Case: Painful genital ulceration

A patient presents with clusters of painful vulvar ulcers and inguinal tenderness

A cervical smear shows multinucleated squamous cells with abnormal nuclei

Identify the likely infection and the most useful route to viral confirmation

Discuss

Mechanism → lesion → tissue injury

What observation makes the diagnosis plausible?

Slide 73 · Case: Altered behavior and seizures

A young adult develops acute altered behavior and memory disturbance with seizures

A lesion predominantly involves the temporal lobe

Explain why HSV-1 is an important infectious diagnostic consideration

Discuss

Mechanism → lesion → tissue injury

What observation makes the diagnosis plausible?

Slide 74 · Mechanism-to-morphology synthesis

Epithelial viral replication produces ballooning, vesicles and ulcers

Neuronal latency preserves infection after visible recovery

Reactivation recreates epithelial injury, and immune evasion favors persistence

Epithelial replication

Vesicles + shedding

Sensory axonal transport

Latent neuronal genome

Reactivation

Return to surface

Slide 75 · Organ injury: Three different mechanisms

Site

Principal pathology

Skin / mucosa

Cytolysis; vesicles / ulcers

Corneal stroma

Immune-mediated scarring

Brain / viscera

Necrotizing tissue injury

Slide 76 · Essential morphologic recognition points

Intraepithelial vesiculation follows ballooning degeneration

Cowdry type A intranuclear inclusions displace peripheral chromatin

Cell fusion produces multinucleated inclusion-bearing syncytia

Intranuclear inclusion with rim of chromatin

Schematic — not a clinical or histologic specimen

Slide 77 · References

Robbins, Cotran & Kumar: Pathologic Basis of Disease, 11th ed. (2026), Chapter 8: Infectious Diseases, pp. 320–322

Cross-referenced sections: Chapter 16 (oral HSV); Chapter 22 (genital HSV); Chapter 28 (CNS HSV)

Schematic illustrations were constructed as editable PowerPoint shapes; they are not histologic specimens