Herpes Simplex Virus (Lecture 2)

Slide 1 · HERPES SIMPLEX VIRUS

Genital infection of the female reproductive tract

Pathogenesis • morphology • clinical interpretation

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Describe HSV-1/HSV-2 infection in vulvar, vaginal and cervical tissues.

Explain epithelial replication, neuronal latency and recurrent shedding.

Recognize viral cytopathic changes and compare diagnostic approaches.

Connect maternal genital HSV to neonatal transmission and prevention.

Slide 3 · Why HSV matters in lower genital tract pathology

HSV causes painful genital ulceration and may also present as cervicitis.

Clinical findings must be linked to epithelial cytopathic injury and viral detection.

Latency creates recurrent disease despite resolution of visible lesions.

Slide 4 · Anatomic distribution of genital HSV

Vulva

Visible skin and mucosal lesions

Vagina

Internal lesions may produce discharge

Cervix

Internal lesions may produce pelvic pain

Conceptual site overview — not to anatomical scale

Slide 5 · Two closely related herpes simplex viruses

Feature

HSV-1

HSV-2

Usual association

Perioral infection

Genital infection

Possible genital disease

Yes

Yes

Possible oral disease

Yes

Yes

Slide 6 · HSV type does not rigidly predict anatomic site

HSV-1 can be recovered from genital lesions.

HSV-2 can also infect the oral region.

Type-specific identification is distinct from recognizing HSV cytopathic effect.

Slide 7 · HSV is a latent double-stranded DNA virus

DNA-containing virion

Replication in epithelium

Persistence in sensory neurons

Primary infection and lifelong persistence are separate biologic states.

Slide 8 · Productive infection versus neuronal latency

Property

Productive infection

Latency

Main location

Epithelial entry sites

Sensory neuron

Viral output

Infectious progeny

No infectious virions

Clinical consequence

Lesions and shedding

Potential future reactivation

Slide 9 · Textbook epidemiology: Seropositivity is not the same as symptoms

Roughly 30% HSV-2 seropositivity among females by age 40.

Seropositivity reflects immune recognition, not necessarily visible genital lesions.

The quoted figure is a textbook population estimate, not a universal prevalence rate.

Slide 10 · Most newly infected people do not have recognized symptoms

At acquisition

Approximate source description

Symptomatic

About one-third of newly infected individuals

Without recognized symptoms

Remaining newly infected individuals

Slide 11 · Acquisition begins at a mucosal or cutaneous entry site

Exposure to HSV

Replication at entry site

Mucocutaneous injury

Slide 12 · Initial lesions generally appear within days

3–7 days

Typical source interval between transmission and lesion appearance

The clinical interval cannot establish viral type by itself.

Slide 13 · Primary symptomatic infection has systemic correlates

Fever and malaise may accompany a first symptomatic episode.

Tender inguinal lymph nodes support a regional inflammatory response.

Systemic symptoms should be interpreted with the local genital findings.

Slide 14 · Genital HSV lesions follow a characteristic sequence

Erythematous papule

Vesicle

Painful coalescent ulcer

Healing

Slide 15 · Vulvar HSV: Visible mucocutaneous ulceration

Vesicles and ulcers are often readily appreciated on vulvar skin or mucosa.

Painful clustered lesions support the clinical suspicion of HSV.

Clinical recognition is helpful, but laboratory detection can establish infection.

Slide 16 · Cervical and vaginal HSV may not look like external ulcers

Internal lesions may manifest as purulent discharge and pelvic pain.

The absence of an obvious vulvar eruption does not exclude genital HSV.

The location of lesions determines whether clinical visualization is straightforward.

Slide 17 · Periurethral lesions can impair micturition

Urethral-adjacent ulceration

Pain during urination

Possible urinary retention

Slide 18 · Clinical pain reflects an ulcerative mucosal process

Epithelial injury

Ulceration and acute inflammation

Pain and local tenderness

Slide 19 · Active vesicles and ulcers contain infectious virus

Vesicles and ulcer exudates can contain numerous viral particles.

Active mucosal lesions are associated with efficient transmission.

Reducing symptomatic lesions is not identical to abolishing viral shedding.

Slide 20 · Visible lesions heal, but infection is not eliminated

1–3 weeks

Typical source duration for spontaneous healing of cutaneous and mucosal lesions

The virus can already have established latency during the acute episode.

Slide 21 · HSV gains access to sensory neuronal pathways

Mucosal / skin replication

Sensory axonal entry

Transport to ganglion cell body

Slide 22 · Genital HSV establishes latency in lumbosacral ganglia

Genital epithelial site

Sensory axon

Regional lumbosacral ganglion

The neuronal reservoir persists after surface healing.

Slide 23 · Latency means persistence without productive virion release

Viral genomes persist in neuronal nuclei.

No infectious virions are produced during true latency.

Reactivation restarts productive replication and can restore mucosal shedding.

Slide 24 · The HSV genome remains in the neuronal nucleus

Sensory neuron nucleus

Persisting HSV DNA

Latent viral state

Slide 25 · Latency-associated transcripts distinguish the latent state

Latency-associated transcripts (LATs) are expressed in neurons.

No detectable viral protein production during latency.

LATs are implicated in maintaining a nonproductive infection state.

Slide 26 · LATs may support survival and silence lytic viral genes

Anti-apoptotic effects

Resistance to neuron apoptosis

Chromatin-based silencing

Reduced lytic gene expression

MicroRNA precursors

Downregulation of selected lytic genes

Slide 27 · Reactivation can follow reduced immune control

Stress, trauma, concurrent infection and hormonal change as triggers.

Trigger-associated reactivation resumes productive viral replication.

Not all reactivation episodes produce recognizable symptoms.

Slide 28 · Reactivation reverses the direction of viral travel

Latent neuronal HSV

Reactivation

Axonal return to mucosa

Recurrent shedding / lesion

Slide 29 · Recurrent episodes arise from a persistent neural reservoir

Epithelial replication

Ganglionic latency

Reactivation

Epithelial recurrence

Conceptual cycle of persistence and recurrence

Slide 30 · Subclinical shedding separates infectivity from visible disease

State

Visible lesions

Potential shedding

Symptomatic active infection

Often present

Yes

Subclinical reactivation

Absent

Possible

Latency itself

Absent

No virion production

Slide 31 · Immunosuppression makes recurrence more consequential

Reactivation and recurrent lesions are particularly common with impaired immunity.

Control of cell-mediated responses is important in HSV infection.

Disseminated infection is a recognized risk in severely immunocompromised hosts.

Slide 32 · HSV can evade cytotoxic T-cell recognition

HSV interference with MHC class I

Reduced CTL recognition

Improved viral persistence / escape

Slide 33 · HSV glycoprotein gE disrupts antibody functions

Viral gE binds IgG Fc

Interference with selected antibody effector actions

Reduced complement / cellular targeting

Slide 34 · HSV glycoprotein gC interferes with complement

Viral gC

Interaction with complement C3 products

Attenuation of alternative-pathway activity

Slide 35 · Why immunity does not guarantee viral eradication

Neuronal persistence

Viral DNA remains latent

Immune evasion

MHC-I and antibody/complement interference

Periodic reactivation

Local shedding may recur

Slide 36 · Early HSV epithelial injury produces intraepithelial vesicles

Epithelial cell ballooning

Intraepithelial fluid space

Vesicle → rupture / ulcer

Schematic mechanism; Not a histologic image.

Slide 37 · Late biopsy may primarily show ulceration

Biopsied genital lesions have often progressed beyond the vesicular stage.

Surface epithelium may be desquamated or absent.

Marked acute inflammation is commonly present in the ulcer bed.

Slide 38 · The ulcer bed is not the same as the diagnostic infected cell

Lesion compartment

Expected interpretive finding

Ulcer bed

Acute inflammatory exudate and epithelial loss

Residual infected squamous cells

HSV-specific cytopathic alteration

Practical limitation

Advanced ulceration may reduce intact diagnostic epithelium

Slide 39 · HSV induces multinucleated squamous cells

Schematic illustration — not a clinical or cytologic specimen

Multinucleation

Cells may fuse to form syncytia.

This is characteristic but must be interpreted in context.

Slide 40 · Ground-glass nuclei are a key cytologic clue

Peripheral chromatin rim

Schematic illustration — not a clinical or cytologic specimen

Ground-glass chromatin

HSV-infected nuclei may show homogenized pale nuclear interiors.

Observe the entire pattern, rather than one isolated feature.

Slide 41 · HSV produces intranuclear inclusions

Intranuclear body with surrounding clearing

Schematic illustration — not a clinical or cytologic specimen

Cowdry type A inclusions

Pink to purple intranuclear material may displace normal chromatin.

Nuclear inclusions support herpesvirus cytopathic infection.

Slide 42 · Nuclear molding reflects close apposition of fused nuclei

Abutting nuclei with locally flattened interfaces

Schematic illustration — not a clinical or cytologic specimen

Nuclear molding

In multinucleated epithelial cells, nuclear contours press against each other.

Chromatin can be marginated at the nuclear periphery.

Slide 43 · Read the full pattern of HSV cytopathic effect

Cell architecture

Multinucleated squamous cells

Nuclear texture

Ground-glass change and chromatin margination

Inclusions

Cowdry A-type intranuclear material

Slide 44 · A positive morphologic pattern does not establish HSV type

HSV-1 and HSV-2 share similar cytopathic alterations.

Virologic methods or type-specific assessment are needed for serotype attribution.

A smear is a morphologic clue; It is not equivalent to viral genotyping.

Slide 45 · Clinical recognition and direct detection are complementary

Suggestive genital lesions

Collect lesion material

Detect HSV by laboratory method

Integrate with site and history

Slide 46 · Traditional viral culture demonstrates replication

Lesional exudate is inoculated into a permissive tissue culture.

Growing virus produces an observable cytopathic effect.

Viral isolates can subsequently be typed.

Slide 47 · Culture-based cytopathic effects take time to develop

48–72 hours

Time interval given by Robbins for observing culture cytopathic effect

Culture-based detection is not the only laboratory option.

Slide 48 · PCR detects HSV nucleic acid in lesion material

PCR as a more sensitive option for lesional secretions.

The result confirms HSV nucleic acid detection rather than proving a visible ulcer is present.

Type-specific assays may further distinguish HSV-1 from HSV-2.

Slide 49 · Immunologic assays may detect HSV in lesions

Test approach

Target / interpretive role

Direct immunofluorescence

Viral antigen in lesion-associated material

ELISA

Assay-dependent viral or antibody detection

Serologic type specificity

Antibodies against variant HSV glycoprotein G

Slide 50 · Serum antibodies reflect immune history, not an active lesion

Early primary infection may precede development of detectable anti-HSV antibodies.

Once developed, anti-HSV antibodies support prior exposure and persistence.

Seropositivity alone does not localize active infection or prove a particular lesion is herpetic.

Slide 51 · A source-grounded diagnostic reasoning pathway

Typical genital lesion or cervicitis?

Sample appropriate lesion material

PCR / culture / antigen-based methods

Interpret results with clinical findings

Slide 52 · Transmission is most efficient during active disease

Active vesicles and ulcers contain abundant infectious virus.

HSV can pass between sexual partners during symptomatic episodes.

Viral activity at mucosal surfaces underlies transmission risk.

Slide 53 · Subclinical shedding maintains risk between episodes

Shedding may occur without an apparent genital lesion.

An interval without symptoms does not guarantee absence of transmission.

Latency and subclinical reactivation should not be conflated.

Slide 54 · Barrier measures and antiviral therapy lower—but do not abolish—risk

Condom use

Reduces contact-associated transmission risk

Antiviral therapy

Reduces the symptomatic phase and transmission risk

Residual hazard

Incomplete protection, including silent shedding

Slide 55 · Prior HSV-1 infection may modify HSV-2 acquisition risk

Reduced HSV-2 susceptibility after previous HSV-1 infection.

This represents partial protection, not reliable immunity to HSV-2.

Anatomic distribution and viral type should remain conceptually separate.

Slide 56 · HSV transmission has sex-related asymmetry

Genital HSV is more readily transmitted to females than males.

This is a broad epidemiologic observation, not a patient-specific prediction.

Risk counseling must still account for shedding without symptoms.

Slide 57 · Maternal genital HSV can be transmitted at birth

Maternal genital HSV

Exposure during passage through birth canal

Neonatal infection

Slide 58 · Primary maternal infection near delivery has special importance

Greatest neonatal risk when maternal infection is active at delivery.

The risk is particularly concerning with maternal primary infection.

Clinical classification of maternal infection therefore matters for perinatal risk.

Slide 59 · Neonatal HSV may produce disseminated organ injury

Lymphoreticular involvement

Lymphadenopathy and splenomegaly

Visceral necrosis

Lung, liver and adrenal involvement

Central nervous system

CNS involvement in severe disease

Slide 60 · Delivery planning is an important preventive intervention

Robbins recommends cesarean delivery when active genital infection is present at delivery, especially primary infection.

The purpose is to reduce neonatal exposure during passage through the birth canal.

Patient-specific intrapartum decisions require current obstetric protocols beyond this pathology source.

Slide 61 · Genital HSV increases susceptibility to HIV transmission

Genital ulceration

Compromised mucosal barrier / inflammation

Increased HIV acquisition / transmission risk

Slide 62 · Antivirals reduce episodes but do not remove latent virus

Target

Antiviral effect described in Robbins

Initial symptomatic episode

Shortened duration

Recurrent symptomatic episode

Shortened duration

Neuronal latent infection

Not eradicated

Slide 63 · A preventive HSV vaccine remains an unmet goal

No effective vaccine at the time of publication.

The enduring neuronal reservoir helps explain the need for preventive strategies.

This statement reflects the supplied textbook rather than a real-time vaccine-development review.

Slide 64 · Different lower tract infections produce distinct patterns

Condition

Characteristic presentation

Genital HSV

Painful vesicles / superficial ulcers

Candida vulvovaginitis

Pruritus; erythema; curdlike discharge

Trichomoniasis

Possible frothy discharge; vulvovaginal discomfort

Bacterial vaginosis

Thin, malodorous discharge

Slide 65 · HSV and HPV have different pathologic consequences

Characteristic

HSV

HPV

Lower genital tract concern

Ulcerative infection

Neoplastic transformation

Typical emphasized pathology

Vesicular / ulcerative injury

Cervical, vaginal, vulvar neoplasia

Major virus property in this lesson

Neuronal latency

Oncogenic role of some HPV types

Slide 66 · Clinical case: Painful vulvar lesions

A patient presents with painful clustered genital vesicles and tender inguinal nodes.

What evolution of skin findings would strengthen HSV suspicion?

Which specimen could establish viral detection?

Slide 67 · Case interpretation: Characteristic progression and testing

Papules progressing to vesicles and coalescent painful ulcers support HSV.

Collect material from active lesions for HSV detection.

Symptoms alone cannot reliably distinguish HSV-1 from HSV-2.

Slide 68 · Clinical case: Purulent cervicitis without obvious vulvar vesicles

A patient has purulent cervical discharge and pelvic pain but no visible vulvar ulcers.

Can genital HSV still be considered?

What additional evidence would improve diagnostic specificity?

Slide 69 · Case interpretation: Internal genital HSV is possible

HSV may involve the vagina and cervix without externally obvious lesions.

Direct virologic testing can support suspected HSV infection.

Other causes of cervicitis remain in the differential diagnosis.

Slide 70 · Clinical case: Active lesions at delivery

A pregnant patient has active genital vesicles at the onset of labor.

What is the major pathology-related neonatal hazard?

Why is maternal primary infection especially important?

Slide 71 · Case interpretation: Prevent exposure to infectious genital HSV

Neonatal acquisition can occur during passage through the infected birth canal.

High risk with active primary maternal infection.

The textbook supports cesarean delivery in this setting to reduce exposure.

Slide 72 · Clinicopathologic synthesis: Local infection versus persistence

Stage

Underlying pathology

Clinical consequence

Entry / replication

Epithelial cytopathic injury

Vesicles and ulcers

Neuronal latency

Persisting viral DNA

Asymptomatic reservoir

Reactivation

Return to epithelial sites

Recurrent lesions or silent shedding

Slide 73 · Summary: What a pathologist should recognize

Genital HSV can involve vulva, vagina and cervix.

Multinucleated squamous cells with ground-glass inclusions suggest herpesvirus infection.

Ulcer beds may lack intact diagnostic epithelium.

Viral detection and clinical correlation complete the interpretation.

Slide 74 · Summary: What a clinician should anticipate

Symptomatic disease resolves while neuronal latency remains.

Subclinical shedding limits purely symptom-based prevention.

Maternal active genital infection at delivery creates neonatal risk.

Antivirals shorten symptomatic episodes but do not eradicate latency.

Slide 75 · Source references

Robbins, Cotran & Kumar: Pathologic Basis of Disease. 11th ed. (2026). Chapter 22: The Female Genital Tract, pp. 896–898.

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

Clinical algorithms, drug regimens, and contemporary practice recommendations were not independently reviewed for this source-faithful pathology lecture.