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1

HERPESVIRUSES:

General:

Fall into 3 subfamilies based on genetic and biological properties:

Over 100 herpesviruses known; 8 are considered human herpesviruses

Alphaherpesviruses
Betaherpesviruses
Gammaherpesviruses

2

HERPESVIRUSES

Subfamilies:
Alphaherpesviruses (3 or 4)
Betaherpesviruses (4)
Gammaherpesviruses (2)

Alphaherpesviruses:
o HSV 1
o HSV 2
o VZV
o Note: B virus, a monkey alphaherpes virus, can infect humans (ie. via a bite); usually results in fatal encephalitis

Betaherpesviruses:
o CMV
o HHV-6A
o HHV-6B
o HHV-7

Gammaherpesviruses:
o Epstein Barr Virus (EBV)
o HHV-8/Karposi’s sarcoma associated herpesvirus

3

Herpes Simplex Infections (HSV)

Incubation Period:
Primary Infection:
Recurrent Infections:

Incubation Period: 4-5 days on average (can be longer or shorter)

Primary Infection: takes ~2 weeks to run its course

Recurrent Infections: are typically shorter and involve fewer lesions

4

Gingivostomatitis OR
Orofacial Herpes OR
Herpes Labialis (recurrent form) OR
“Cold sores”

Typical age:
Frequency:
Usual severity:
Type:

Typical age:
Primary Infection: child/adolescent
Recurrent: any age

Frequency:
Very common

Usual severity:
Mild (asymptomatic) to moderate (infection with painful lesions)

Type:
1>2

5

Genital Herpes

Typical age:
Frequency:
Usual severity:
Type:

Typical age: Once sexually active
Frequency: Common
Usual severity: Moderate to severe
Type: 2>1

6

Keratoconjunctivitis (ocular infection)

Typical age:
Frequency:
Usual severity:
Type:

Typical age: Any
Frequency: Fairly common
Usual severity: Moderate to severe (can penetrate stroma and cause blindness)
Type: 1

7

Dermatitis (other than face or genitals)

Typical age:
Frequency:
Usual severity:
Type:

Typical age: Any
Frequency: Uncommon
Usual severity: Mild
Type: 1 or 2

8

Encephalitis

Typical age:
Frequency:
Usual severity:
Type:

Typical age: Any
Frequency: Rare
Usual severity: Severe (over 50% death rate; those that don’t die have severe SEs)
Type: 1 or 2 (in neonates)
1 (everyone else)

9

Disseminated HSV

Typical age:
Frequency:
Usual severity:
Type:

Typical age: Any (associated with immunosuppression)
Frequency: Rare
Usual severity: Severe
Type: 1>2

10

Neonatal Herpes (from infected mother during/after birth)

Typical age:
Frequency:
Usual severity:
Type:

Typical age: Newborn
Frequency: Uncommon
Usual severity: Severe (disseminates because immune system not developed yet)
Type: 2>1

11

Herpevirus Latency (General):
Definition:
Mechanism:

Definition:
- Continued presence of viral genome
- Absence of viral replication and viral particles

Mechanism:
- Lytic cycle genes not expressed during latency
- Latent virus can reactivate, causing recurrent disease or subclinical virus shedding (most common reactivation); latent viruses last lifetime of host

12

Which herpesviruses establish latent infections?

Primary herpesvirus result in:

All

Primary herpesvirus infections always result in latent infections
(However, different herpesviruses establish latency in different cell types)

13

HSV Latency (Specifically):

Entry into nerve cells:

Transport to nerve cell body:

Virus replication:

Entry into nerve cells: at primary site of infection

Transport to nerve cell body: in ganglion; via retrograde transport
- Oral infection (trigeminal ganglion)
- Genital infection (sacral ganglion)

Virus replication in ganglion: occurs for several days, followed by latency

14

HSV Reactivation:

Frequency depends on:

Stimuli:

Results in:

Frequency: depends on individual; ranges from never to monthly

Reactivation stimuli: often spontaneous; others include sunlight, menstruation, infections, compromised immune system

Reactivation results in: replication in ganglion and travel back down the axon, causing infection near site of primary infection

15

HSV Structure:

Large, enveloped, DNA virus (linear, dsDNA; 75-80 genes)

Icosahedral capsid

16

HSV Replication:

Entry

Gene expression, DNA replication, and Capsid assembly

Envelopment and release

17

Entry:
Primary and Secondary Route:

Primary Route: attachment to host cell via glycoproteins (on virus) and fusion of viral envelope with plasma membrane

Secondary Route: endocytosis followed by fusion with endocytic vesicle

18

Gene expression, DNA replication, and capsid assembly occurs:

Gene expression, DNA replication, and capsid assembly occurs in the nucleus.

19

Envelopment and Release:

How do capsids first acquire envelope?

Envelope fuses:

Capsid buds:

What release virions from the cell? How?

Capsids first acquire envelope by budding through inner nuclear membrane

Envelope fuses with outer nuclear membrane, and naked capsid released into cytoplasm

Capsid buds into vesicles from cytoplasmic membrane (acquires envelope again)

Enveloped virions release from cell via fusion of vesicles with plasma membrane

20

Antivirals Against HSV DNA Replication:

HSV encodes its own DNA replication system:

Steps of Activation (Phosphorylation):

How does triphosphate form inhibit DNA synthesis? (2)

HSV encodes its own DNA replication system:

DNA polymerase is the target for most anti-herpes drugs (most are nucleoside analogs)

Steps of Activation (Phosphorylation):
- HSV-encoded TK phosphorylates acyclovir (or other) to monophosphate-acyclovir
- Cellular kinases synthesize di- and triphosphate forms

Triphosphate form inhibits DNA synthesis by:
- Inhibiting viral DNA polymerase
- Becoming incorporated into DNA, resulting in termination of strand

21

Varicella-Zoster Virus

Primary VZV Infection:

Reactivation of Latent Virus:

Current vaccine:

Primary VZV Infection: typically manifests as varicella (chickenpox)
- Worse in adulthood than in children
- Latent infections established in dorsal root ganglia

Reactivation of Latent Virus: causes zoster (shingles)
- Incidence increases with age

Now use a live attenuated vaccine against VZV in the United States

22

Varicella

Portal of Entry:

Viremia:
First, second stages
Lesions appear where first?
Lesion stages:
Healing

Incubation Period:

Portal of Entry:
- Primary: upper respiratory tract (some replication occurs here)
- Secondary: fluids from vesicles containing high concentrations of infectious particles

Viremia:
- First Stage: spread to lymphoid organs (replication)
- Second Stage: spread to epithelial tissue (lesions) and respiratory tract (more transmission)
- Lesions appear on trunk first, spread outward (centrifugal spread)
- Lesion stages: macule, papule, vesicle, crusting
- Typically heal without scarring (unless secondary bacterial infection)

Incubation Period: 14-21 days

23

Zoster

Reactivation of latent VZV:

Lesions:

What is possible?

Reactivation of latent VZV: causes unknown; can happen more than once

Prodromal syndrome may exist: nerve pain/tingling before outbreak

Lesions: generally limited to skin/mucous membranes innervated by the reactivated ganglion (sharply demarcated areas)

Post-Herpetic Neuralgia is possible: persistent nerve pain after lesions disappear (can last for months)

24

Betaherpesvirus Infections:
• General:

Types:

Slow replication cycle (many days vs. ~24hrs for alphaherpesviruses)

Restricted host range and cell type specificity

CMV
HHV-6
HHV-7

25

CMV:

Causes cell enlargement (cytalomegaly)

Latent infections in cells of myeloid lineage

26

HHV-6:

How common?

T cell tropic?

2 subtypes:

Common: by 12 months of age, nearly everyone is seropositive for HHV-6

T cell tropic

2 Subtypes:

HHV-6A: not associated with disease

HHV-6B:
- Establishes latency/replicates in monocytes and macrophages

27

Primary HHV-6B- Exanthem Subitum (Roseola):

Common? Age?
Incubation period:
Transmission:
Symptoms:
Complications

- Common childhood infection
- Incubation Period: 5-15 days
- Transmission: saliva?
- Symptoms: fever (3-5 days), rash developing over trunk/face and spreading to limbs as fever diminishes
- Possible Complications: very high fever, neurological symptoms (convulsions, aseptic meningitis), hepatitis, mononucleosis-like syndrome

28

HHV-7:

- Also T cell tropic
- Establishes latency in T cells
- May also cause exanthem subitum (roseola)

29

Gammherpesvirus Infections:

Epstein Barr Virus (EBV)

HHV-8/Karposi’s sarcoma associated herpesvirus

30

Epstein-Barr Virus:

- B cell tropic
- Latent in B cells