Latent Infections Herpesvirus Infections

Slide 1 · Latent Infections

(Herpesvirus Infections)

Persistence • Reactivation • Clinicopathologic consequences

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes

Define latency by viral-genome persistence and absence of infectious virion production.

Classify the eight human herpesviruses by α-, β-, and γ-group tropism.

Explain how reactivation links a silent reservoir to tissue injury.

Apply reservoir–disease correlations to HSV, VZV, CMV, and EBV.

Slide 3 · What makes an infection latent?

Viral genome persists; Infectious virus is not produced.

The latent cell retains viral genetic material.

Reactivation can restore replication and infectious virion release.

Slide 4 · Latency is not continuous productive infection

Latent state

Viral genomes persist inside host cells.

No production of infectious virions.

Symptoms may be absent despite persistence.

Productive infection

Viral replication generates infectious virus.

Virions can spread to new cells or hosts.

Tissue injury may accompany replication.

Slide 5 · The three-state herpesvirus course

Primary infection

Viral entry and replication in susceptible host cells

Latency

Persistence in a noninfectious cellular form

Reactivation

Replication resumes, with possible shedding or disease

A clinically silent interval does not imply eradication.

Slide 6 · Reactivation is the proximate source of recurrent injury

Dormancy itself does not release infectious virions.

Reactivation generates progeny virus capable of tissue spread.

The resulting infection can injure target tissue directly or trigger immune-mediated damage.

Slide 7 · Why “recovered” may not mean “cleared”

Resolution of the first episode ≠ elimination of the reservoir.

Initial illness can subside while the viral genome persists.

The same host may subsequently shed virus or develop recurrent disease.

Slide 8 · Different compartments perform different roles

Entry / replication

Epithelium, mucosa, or other permissive tissues

Cellular reservoir

Neuron, monocyte lineage, or B cell, depending on virus

Recurrent disease

Tissue injury after reactivation and spread

Reservoir location and lesion location are not always the same.

Slide 9 · Shedding and visible disease are not equivalent

Reactivation may occur with or without symptoms in HSV infection.

Shedding demonstrates release of infectious virus, not necessarily overt tissue damage.

Clinical silence should not be used to infer absence of reactivation.

Slide 10 · Herpesvirus latency: A family-level strategy

Human herpesviruses frequently establish acute infection followed by lifelong persistence.

The group contains large double-stranded DNA viruses.

The Robbins overview describes approximately 70 encoded proteins.

All three subgroups can reactivate; Their reservoirs are different.

Slide 11 · The eight human herpesviruses

α-Herpesviruses

HSV-1, HSV-2, VZV

β-Herpesviruses

CMV, HHV-6, HHV-7

γ-Herpesviruses

EBV, KSHV / HHV-8

Subgroups are parallel classes defined by cell tropism and latency site.

Slide 12 · Classification by predominant latency compartment

Subgroup

Members

Dominant latency pattern

α

HSV-1; HSV-2; VZV

Postmitotic neurons

β

CMV; HHV-6; HHV-7

Diverse cell types

γ

EBV; KSHV (HHV-8)

Mainly lymphoid cells

Slide 13 · Subgroup terminology predicts cellular tropism

α group epithelial infection, then neuronal latency.

β group infection and latency across diverse cell types.

γ group predominant lymphoid-cell latency.

The preferred reservoir helps predict the form of recurrence.

Slide 14 · Site of initial disease versus site of persistence

Infection can be visible

Mucocutaneous blisters during productive α-herpesvirus infection.

Multiorgan CMV infection with nuclear inclusion-bearing cells.

Lymphoid expansion during symptomatic EBV infection.

Persistence may be hidden

Sensory neurons for HSV/VZV.

Monocyte and precursor compartments for CMV.

A restricted population of EBV-infected B cells.

Slide 15 · α-Herpesvirus: The conceptual blueprint

Epithelial replication

Infectious virions at entry site

Neuronal entry

Spread into sensory nerve endings

Neuronal latency

Genome persists without virion production

Return to epithelium

Reactivation produces recurrent lesions

HSV is the best-described model of this sequence.

Slide 16 · HSV begins with mucocutaneous replication

HSV-1 and HSV-2 usually replicate at oropharyngeal or genital entry sites.

Epidermal and mucosal infection can generate intraepithelial vesicles.

New virions are available to spread to adjacent neural structures.

Slide 17 · HSV uses sensory neurons to establish latency

Mucocutaneous focus

Local HSV replication

Sensory nerve terminal

Nucleocapsids enter neurons

Axonal transport

Transport toward neuronal cell body

Ganglion neuron

Latent genome in the nucleus

Anatomic transport explains persistence away from a healed lesion.

Slide 18 · The HSV latent genome remains nuclear

Viral DNA persists in the sensory-neuron nucleus.

Latency is nonproductive despite persistence of the viral genome.

The neuron is a long-lived cellular reservoir.

Slide 19 · Latency-associated transcripts are a distinctive HSV feature

During HSV latency, latency-associated transcripts (LATs) are expressed.

The source reports no detectable viral-protein production during this state.

LAT expression distinguishes latent transcription from full lytic viral replication.

Slide 20 · How LATs may promote HSV persistence

Proposed antiapoptotic activity may preserve infected neurons.

Proposed chromatin-based silencing suppresses lytic gene expression.

LAT-derived microRNAs may downregulate essential HSV lytic genes.

Slide 21 · HSV reactivation: A proposed molecular sequence

Cellular stress

Neuronal stress-response pathways

Chromatin change

Release from epigenetic silencing

Lytic program

Renewed viral replication

Clinical consequence

Return toward mucocutaneous sites

Proposed mechanism; Not a universally specified trigger.

Slide 22 · Reactivation can recur despite existing immunity

HSV-1 and HSV-2 may reactivate repeatedly.

Recurrences may be symptomatic or asymptomatic.

Host immunity controls infection but may not remove the latent neuronal reservoir.

Viral mechanisms impede both cellular and humoral immune recognition.

Slide 23 · Primary HSV infection and recurrent HSV infection

Primary episode

Entry-site epithelial replication.

Local lesion with access to sensory nerves.

Establishment of neuronal persistence.

Recurrent episode

Virus emerges from an already infected neuronal reservoir.

Transport to epithelial target tissue.

Often localized; May be clinically silent.

Slide 24 · HSV lesions are consequences of active replication

Ballooning degeneration and intracellular edema produce intraepithelial vesicles.

Vesicle rupture can leave crusted lesions or superficial ulcers.

The infectious lesion is distinct from the silent ganglionic reservoir.

Slide 25 · HSV cytopathic changes: What a schematic can show

Simplified cell schematic — not diagnostic histology

Epithelial cell

Nuclear inclusion

Fusion / cytopathic effect

Intranuclear Cowdry type A inclusions accompany productive HSV infection.

Cell fusion can produce multinucleated epithelial syncytia.

Slide 26 · Why HSV inclusions are intranuclear

Viral replication components and assembling virions accumulate in the nucleus.

The host chromatin is displaced toward the nuclear margin.

The resulting Cowdry type A inclusion is a sign of active infection, not latent carriage.

Slide 27 · HSV vesicular lesions need clinical context

Oral / facial disease

Cold sores favor skin bordering mucosal openings.

Often bilateral and not dermatomally restricted.

Gingivostomatitis may be prominent in children.

Genital disease

Genital mucosal vesicles evolve into superficial ulcers.

HSV-2 is more frequent than HSV-1 as a cause.

Primary and recurrent patterns are possible.

Slide 28 · HSV keratitis: Two mechanisms of damage

Epithelial keratitis

Direct viral cytolysis injures superficial epithelium.

Active replication is central to tissue injury.

Stromal keratitis

Mononuclear infiltration and neovascularization.

Immune-mediated tissue injury drives scarring and opacification.

Slide 29 · HSV encephalitis can cause severe CNS injury

HSV-1 is an important cause of sporadic fatal encephalitis.

Brain involvement often favors temporal lobes and orbital frontal gyri.

Defects in TLR3 or its signaling components increase susceptibility.

Slide 30 · Impaired host defenses change HSV severity

Neonates may develop disseminated infection with multiorgan necrosis.

Patients receiving chemotherapy or with impaired cellular immunity may develop widespread disease.

HSV may produce esophagitis, necrotizing bronchopneumonia, or hepatitis.

Slide 31 · HSV evasion of cellular immunity

Activated CD8⁺ T cell

Antiviral cytotoxic recognition

HSV interference

Inhibits MHC class I presentation

Host consequence

Reduced recognition of infected targets

Slide 32 · HSV evasion of antibody and complement

Viral glycoprotein gE

Binds Fc portion of IgG.

Interferes with complement C1q engagement.

Disrupts antibody-dependent effector responses.

Viral glycoprotein gC

Interacts with complement C3 / activation products.

Accelerates decay of complement components.

Weakens alternative-pathway defense.

Slide 33 · Why HSV can recur in an immune host

Immune control is not sterilizing eradication.

Neuronal latency shields a persistent genetic reservoir.

Reacting to reactivation may limit disease without preventing the next episode.

Slide 34 · VZV separates primary and recurrent syndromes

Acquisition

Respiratory infection and dissemination

Varicella

Widespread chickenpox vesicles

Ganglionic latency

Persistence in sensory ganglia

Zoster

Localized dermatomal reactivation

Slide 35 · Primary VZV follows a systemic dissemination route

VZV is spread through respiratory aerosols.

Hematogenous dissemination causes widespread vesicular lesions.

This differs from the usually localized mucocutaneous entry-site disease of HSV.

Slide 36 · VZV latency resides in sensory ganglia

VZV persists in ganglionic neurons and/or nearby satellite cells.

Dorsal root and trigeminal sensory ganglia are important reservoirs.

A long interval may separate chickenpox from shingles.

Slide 37 · Anatomic origin of a zoster eruption

Latent ganglion

Virus persists after chickenpox

Reactivation

Infection of sensory nerve structures

Nerve distribution

Spread along a dermatome

Skin lesion

Painful vesicles in the innervated skin

Slide 38 · Why shingles hurts

Ganglionic and neural inflammation accompanies reactivation.

The source describes mononuclear infiltrates and neuronal injury in affected ganglia.

Pain, burning, and itching can accompany the cutaneous vesicles.

Slide 39 · Varicella and zoster share a cytopathic lesion

Both can generate intraepithelial vesicles with intranuclear inclusions.

Primary varicella crops are generalized and may appear in successive waves.

Zoster is usually localized to the distribution of affected sensory nerves.

Slide 40 · HSV versus VZV: Important differences

HSV

Usually replicates at oral or genital entry sites.

Recurrent episodes may be frequent and nondermatomal.

Latent HSV DNA is retained in sensory neurons.

VZV

Primary infection includes viremia and widespread varicella.

Reactivation typically produces a dermatomal shingles eruption.

Pain reflects concomitant neural inflammation.

Slide 41 · β-Herpesviruses differ in cellular reservoirs

A diverse cell repertoire replaces a single neuron-centered model.

CMV, HHV-6, and HHV-7 are the named β-group members.

The subgroup infects and establishes latency in several cell types.

Slide 42 · CMV has a hematopoietic reservoir

CMV latency occurs in monocytes and bone marrow progenitors.

Depression of cellular immunity may allow CMV reactivation.

Productive disease can involve epithelial, endothelial, and other parenchymal cells.

Slide 43 · CMV: Reservoir to opportunistic disease

Latent CMV

Monocytes / marrow progenitors

Immune perturbation

Weakened cellular control

Reactivation

Productive infection

Organ injury

Pneumonitis, colitis, or visceral disease

Slide 44 · CMV virulence depends strongly on immune status

Many immunocompetent hosts have asymptomatic or mononucleosis-like illness.

Neonates may develop serious congenital or perinatal infection.

Transplant recipients and severely immunosuppressed patients risk organ disease.

Slide 45 · CMV “owl’s-eye” change is a productive-infection clue

Simplified cell schematic — not diagnostic histology

Uninfected cell

Enlarging infected cell

Prominent nuclear inclusion

Affected cells and nuclei enlarge; An inclusion has a clear peripheral halo.

The drawing is schematic; Definitive morphologic recognition requires genuine tissue.

Slide 46 · CMV may damage tissue with little inflammation

The source describes focal necrosis in many different organs.

Some infected tissues show comparatively little inflammatory response.

This explains why severe organ injury can coexist with limited cellular reaction.

Slide 47 · CMV control: Virus versus immune host

Viral immune evasion

Downmodulates MHC I and II molecules.

Modulates cytokine signaling and NK-cell recognition.

Can impair dendritic-cell function.

Host control

CD8⁺ T cells are important effectors.

CD4⁺, γδ T cells, and NK cells also contribute.

Cellular immunodeficiency facilitates organ disease.

Slide 48 · Two clinically distinct CMV contexts

Congenital CMV

Fetal acquisition via transplacental spread.

Possible microcephaly, calcifications, or sensorineural deficits.

Not necessarily a reactivation syndrome.

Post-transplant CMV

May represent new infection or latent-virus reactivation.

Can cause pneumonitis and severe colitis.

Quantitative PCR is used in monitoring.

Slide 49 · CMV diagnosis depends on the clinical question

Tissue histology can show characteristic cytomegalic inclusions.

PCR detects CMV DNA; Quantitative PCR supports transplant monitoring.

Congenital CMV can be diagnosed by PCR testing of urine or saliva.

Detection and attributable organ disease are not identical questions.

Slide 50 · HHV-6 and HHV-7 complete the β group

Both are classified with CMV in the β-herpesvirus subgroup.

They cause exanthem subitum (roseola infantum, sixth disease).

These infections exemplify viral latency beyond HSV, VZV, and CMV.

Slide 51 · HHV-6/7 reactivation may affect multiple organs

The textbook associates reactivation with encephalitis.

Pneumonitis and hepatitis are also described associations.

Myelitis is among the reported neurologic complications.

An association in the overview should not be mistaken for a universal outcome.

Slide 52 · γ-Herpesviruses favor lymphoid latency

Persistent infection is mainly maintained in lymphoid cells.

The γ group includes EBV and Kaposi sarcoma herpesvirus (KSHV / HHV-8).

EBV illustrates how latency intersects with lymphocyte activation.

Slide 53 · EBV-infected B cells: Two outcomes

Lytic EBV infection

Minority of infected B cells undergo productive replication.

Cell lysis releases new virions.

Latent EBV infection

Most infected B cells support persistent viral genomes.

The genome persists as an extrachromosomal episome.

Slide 54 · EBV latency can initially promote B-cell expansion

Latent viral products include LMP1 and EBNA2.

These proteins support activation and proliferation of infected B cells.

The ensuing polyclonal B-cell response produces diverse antibodies.

Slide 55 · Why EBV mononucleosis yields atypical T cells

EBV infects B cells

Latent activation and expansion

Cellular response

Expansion of EBV-specific CD8⁺ T cells

Tissue manifestation

Lymphadenopathy and splenomegaly

Blood finding

Reactive atypical lymphocytes

Slide 56 · The conspicuous EBV blood cell is often not infected

The large atypical lymphocytes in mononucleosis are mainly reactive CD8⁺ T cells.

These lymphocytes respond to EBV-infected B cells.

The diagnostic appearance reflects the host response, not direct infection of every atypical cell.

Slide 57 · Reactive EBV lymphadenopathy can mimic lymphoma

Expansion of T-cell-rich paracortical areas may be striking.

A minority of EBV-infected B cells express latency-associated proteins.

The exuberant reactive appearance may require discrimination from malignant lymphoma.

Slide 58 · Immune surveillance changes EBV persistence

Effective host responses restrict viral shedding and highly immunogenic infected B cells.

Some B cells reduce expression of viral proteins and survive indefinitely.

Acquired cellular immune dysfunction can permit pathologic B-cell expansion.

Slide 59 · EBV links latency to a neoplastic risk context

EBV is associated with certain lymphomas and nasopharyngeal carcinoma.

Immunosuppression can release restraint on EBV-infected B-cell populations.

Latent EBV infection alone is not equivalent to a cancer diagnosis.

Slide 60 · KSHV / HHV-8 belongs in the γ-group map

KSHV is the eighth named human herpesvirus in this taxonomy.

Its classified latency is mainly lymphoid, as for other γ-group viruses.

Detailed KSHV-associated neoplasia is beyond the cited latency overview.

Slide 61 · Monkey B virus: A zoonotic boundary case

Herpesvirus simiae can cause severe neurologic disease after monkey bites.

It is an Old World monkey virus with similarities to HSV-1.

Animal handlers may acquire a potentially fatal neurologic infection.

It is separate from the eight listed human herpesviruses.

Slide 62 · Synthesis: Reservoir, reactivation, and pathology

Virus

Predominant reservoir

Illustrative consequence

HSV-1 / HSV-2

Sensory neuron

Recurrent mucocutaneous infection

VZV

Sensory ganglion

Dermatomal shingles

CMV

Monocyte / progenitor

Pneumonitis or colitis under immunosuppression

EBV

B lymphocyte

Mononucleosis; pathologic B-cell expansion

Slide 63 · Evidence of prior infection versus active disease

Historical / reservoir evidence

Past infection may leave viral genomes in host cells.

Some antiviral antibodies persist after recovery.

Persistence need not be symptomatic.

Evidence of productive pathology

Compatible tissue injury or cytopathic change.

Appropriately interpreted virologic detection.

Clinical distribution and immune status.

Slide 64 · Select testing to match the herpesvirus syndrome

VZV PCR is the principal diagnostic method in the adjacent description.

CMV tissue morphology and PCR; Quantitative PCR for transplant monitoring.

EBV mononucleosis atypical lymphocytes, heterophile testing, and EBV-specific serology.

Morphology and laboratory detection require appropriate clinicopathologic interpretation.

Slide 65 · Application: Recurrent oral vesicles

CLINICAL VIGNETTE

An otherwise healthy person has episodic vesicles near the lip after a prior similar episode.

Where is the most relevant silent reservoir?

Interpretation: Sensory neurons

Reasoning: HSV can remain latent in the sensory ganglia after mucosal or skin lesions heal.

Slide 66 · Application: Painful unilateral rash

CLINICAL VIGNETTE

An older adult develops a painful vesicular eruption confined to a band of skin on one side.

Which mechanism best explains the distribution?

Interpretation: Reactivated VZV in a sensory ganglion

Reasoning: The virus spreads to skin through the innervating sensory pathway.

Slide 67 · Application: New colitis after transplantation

CLINICAL VIGNETTE

A transplant recipient has severe colitis and a positive CMV tissue study.

Why may a previously controlled virus become pathogenic?

Interpretation: Loss of cellular immune control

Reasoning: CMV latency in hematopoietic cells can reactivate during immunosuppression.

Slide 68 · Application: Atypical lymphocytosis

CLINICAL VIGNETTE

A young adult has fever, enlarged cervical nodes, splenomegaly, and many atypical peripheral lymphocytes.

What does the atypical lymphocyte population mainly represent?

Interpretation: Activated cytotoxic T cells

Reasoning: EBV infection of B cells elicits an expanded host CD8⁺ response.

Slide 69 · Four errors to avoid in interpreting latency

Calling latent viral DNA equivalent to continuous infectious virion production.

Assuming the anatomical reservoir is identical to the active lesion site.

Attributing every recurrent rash to the same herpesvirus without distribution/context.

Equating virus detection with proof that it caused the presenting organ injury.

Slide 70 · The unifying clinicopathologic model

A persistent genome becomes dangerous when productive infection resumes.

The affected cell type determines the reservoir.

Tissue tropism, immune control, and reactivation determine clinical expression.

Specific organisms differ sharply in their target organs and injury patterns.

Slide 71 · Primary reference and source scope

Robbins, Cotran & Kumar: Pathologic Basis of Disease

11th edition (2026) · Infectious Diseases

Core source: Latent Infections (Herpesvirus Infections).

Contextual textbook sections: Herpes Simplex Virus, Varicella-Zoster Virus, Cytomegalovirus, and Epstein-Barr Virus.

The supplied Markdown text does not contain reusable diagnostic micrographs or the original printed chapter pages.