human herpes viruses

What is this?

HPV

Pardon Papa as He Has Pox

mnemonic to help remember the DNA enveloped viruses

Herpes, Hepadna, POX

All human herpes viruses

• lrg genome

• linear double stranded DNA

• enveloped viruses

hallmark of HSV

Latent infection

HSV 1

painful vesicles on face

HSV 2

painful vesicles on genitals

VZV

varicella (chicken pox)

zoster (shingles) when it recurs

EBV

infectious mononucleosis

CMV

congenital infections

immunocompetent adults: asymptomatic infections

mononucleosis

HHV 6 & 7

roseola

HHV 8

Kaposi sarcoma (KSHV)

Herpesvirus family structure

Linear, dsDNA

Icosahedral capsid

Tegument “matrix”

Enveloped

What is special about the tegument matrix?

space between nucleocapsid & envelope, contains proteins & enzymes for viral DNA replication after infection

active herpes infection targets

one cell type.

budding & cell lysis of infected cells & Cell mediated immunity (CD8+ & NK cells) to infected cells are responsible for symptoms & host mediated destruction

Herpes latent infection targets

a different cell type & is associated w asymptomatic carriage

herpes virion assembly occurs in

nucleus, ER, GOLGI

virus is release by exocytosis or cell lysis

herpes cell-cell release enables

infections without virus exposure to extracellular environment – EVASION OF IMMUNE SYSTEM

Herpes replication steps simplified

attachment

penetration

uncoating

synthesis

assembly

release

each herpes virus has

a number designation & are divided by host cell targets

HHV genome encodes

viral DNA polymerase that are often drug-able targets

HHV replication occurs in

nucleus

herpes voirus packaging occurs in

nucleus, ER, and Golgi apparatus

herpes virus is release through

exocytosis or lysis

herpes viruses establishes

lytic, persistent & latent infections

what herpes virus are associted w cancer development?

EBV KSV

Herpes is

ubiquitous

HSV 1 & 2

“Mixing and matching of mucous membranes” or via direct contact of infected fluid from vesicles

VSV

Aerosol or direct contact of infected fluid from vesicles

CMV

Aerosol (saliva), sexual, vertical or parental transmission

EBV

saliva aka kissing disease

HHV 6 7 8

unknown relating to ubiquitous

Herpes simplex Type 1 HHV1 primary target cell

mucoepithelial cells

Herpes simplex Type 1 HHV1 site of latency

neuron- trigemial ganglia

Herpes simplex Type 1 HHV1 means of spread

close contact (sexuallry transmitted)

alpha herpes virinae

HHV 1: herpes simplex type 1

HHV 2: HSV type 2

HHV 3: varicella-zoster virus (VZV)

Betaherpes viriniae

HHV5: cytomegalovirus (CMV)

HHV6a, 6b, 7: genus roseolovirus

gammaherpesvirinae

HHV 4: EBV epstein-barr virus

HHV8: kaposi sarcoma-related virus

HHV 2: HSV type 2 targets

mucoepithelial cells

HHV 2: HSV type 2 site of latency

neuron- lumbar or sacral ganglia

HHV 2: HSV type 2 means of spread

close contact (sexually transmitted)

HHV 3: varicella-zoster virus (VZV) targets

mucoepithelial & T cells

HHV 3: varicella-zoster virus (VZV) site of latency

neuron: cranial or thoracic ganglia

HHV 3: varicella-zoster virus (VZV) means of spread

respiratory & close contact

HHV5: cytomegalovirus CMV targets

monocytes, grnaulocytes, lymphocytes, epithelial cells

HHV5: cytomegalovirus CMV site of latency

monocyte, myeloid stem cell & T cells

HHV5: cytomegalovirus CMV means of spread

close contact, transfusions, tissue transplant, congenital

HHV 6a, 6b, 7: genus roseolovirus targets

lymphocytes

HHV 6a, 6b, 7: genus roseolovirus site of latency

T cells

HHV 6a, 6b, 7: genus roseolovirus means of spread

saliva

HHV 4: Epstein-Barr virus (EBV) targets

B cells & epithelial cells

HHV 4: Epstein-Barr virus (EBV) site of latency

B cell

HHV 4: Epstein-Barr virus (EBV) means of spread

saliva (kissing disease)

HHV 8: Kaposi sarcoma-related virus target cell

lymphocytes

HHV 8: Kaposi sarcoma-related virus site of latency

B cell

HHV 8: Kaposi sarcoma-related virus means of spread

close contact

sexual

saliva

HSV 1 clinical presentation/ primary infection

Gingivostomatitis, keratoconjunctivitis, pharyngitis

HSV 1 clinical presenation recurrent infection

cold sores

HSV 2 clinical presentation/ primary infection

Genital herpes, neonatal herpes

HSV 2 clinical presentation recurrent infection

genital herpes

VZV clinical presentation/ primary infection

chickenpox

VZV clinical presentation recurrent infection

shingles (zoster)

EBV clinical presentation/ primary infection

Mononucleosis (heterophile-positive)

EBV clinical presentation recurrent infection

Asymptomatic shedding of virus

CMV clinical presentation/ primary infection

Mononucleosis (heterophile-negative), cytomegalic inclusion disease

CMV clinical presentation recurrent infection

Asymptomatic shedding of virus

HSV 6 & 7 clinical presentation/ primary infection

Roseola infantum/exanthem subitum/6th disease

HSV 6 & 7 clinical presentation recurrent infection

Asymptomatic shedding of virus

HSV 8 clinical presentation/ primary infection

Kaposi sarcoma, primary effusion lymphoma (rare B cell), multicentric Castleman disease (lymphoma?)

herpes family sites of latency

neurotropic or lymphotropic

neurotropic latency

HSV 1 & 2, VZV

lymphotropic latency: EBV

B cells

Lymphotropic latency: CMV

T cells, monocytes

Lymphotropic latency: HHV 6 & 7

T cells

lymphotropic latency: HHV 8

probably B cells

HHV (HSV, VZV, CMV and EBV) can

cause recurrent lytic infection

HHVs remain silent in latency until

stress signal AND lower T cell activity trigger activation.

HHV reactivation is often associated w

depressed T cell response

Herpes Family are responsible for TORCH congenital infections

Toxoplasmosis

Other (VZV, Parvo, Syphillus)

Rubella

Cytomegalovirus

Herpes (type 2)

HSV-1, HSV-2, and VSV target

Mucoepithelial cells for lytic primary infection and

Nerve cells for latent infection

HSV pathogenesis

Direct contact- sexual, other intimate

Enter in the mucous membranes or through skin breaks

Virus replicates in cells at base of lesion

infects the innervating neuron and travels to the ganglion

Trigeminal ganglia for HSV-1 (face)

Sacral for HSV-2 (genitalia)

Virus then returns to the initial site of infection

HSV clinical syndrome

Herpatic vesicular lesion

“dew drop on a rose petal”

Usually clustered

Painful, fluid-filled blisters

Preceded by tingling

Accompanied by fever

Symptoms last 3-7 days

HSV 1 & 2 is highly labile

most primary infections are acquired through direct contact with a lesion or contaminated secretions.

HSV 1 vs HSV 2

1 above the belt

2 below the belt lesions not always true

HSV-1 is often acquired early in life, while HSV-2 often appears after the onset of sexual activity.

HSV 1 transmitted in

in vesicle fluid, saliva, and vaginal secretions

“Mixing and matching of mucous membranes”

HSV 1 latency

in trigeminal ganglia

Herpes pharyngitis and gingivostomatitis

Swollen gums or throat

Lesions in mouth

Fever

Painful eating/drinking

Differentials

HPV (no pain)

Canker sores (no fever)

Foot and mouth disease

Herpes Labialis “Cold sores”

was in romeo & juliet

Lesions occur at the corners of the mouth or next to the lips.

Benign and self-resolving

Recurrent episode

less severe and shorter

more localized

herpetic whitlow

finger

establishes infection through cuts

Common in health care workers

thumb-sucking children

Herpes gladiatorum

body

establishes infection through cuts or abrasions in the skin

acquired during wrestling or rugby.

Herpetic keratitis HSV-1

most common cause of corneal blindness in USA

Typically limited to one eye

Pain

Photophobia

Blurred vision

Tearing

Redness

Recurrent disease

permanent scarring

corneal damage

Blindness

Eczema herpeticum

Acquired by children with active eczema

Underlying disease promotes the spread of the infection

Skin

adrenal glands

Liver

other organs

Herpes encephalitis typically HSV-1

Immunocompromised patients

Viral pathology and immunopathology (CMI) cause

Personality alterations

Fever and headache

Destruction of the temporal lobe

Erythrocytes in the cerebrospinal fluid

Seizure

Focal neurologic abnormalities

Genital herpes – typically HSV-2

Vesicular lesions (blisters) last for 10-15 days

1-2% individuals transmit virus though asymptomatic

HSV-2 and host interactions in nerve root ganglia

DRG are clusters of sensory neuron cell bodies located in the dorsal roots of the spinal column

neonatal herpes HSV-2

Often fatal or chance of chronic carriage

Contract from HSV+ mother

Most commonly contracted during passage through vaginal canal

Baby initially appears septic

Vesicular lesions may/may not be present

UNDERDEVELOPED CMI leads to Virus disseminates to the liver, lung, etc., and CNS

High risk of developmental complications

immunity to HSV

Th1, CTL and NK cells are critical for controlling active infection. ~80% infections are asymptomatic.

IFN and CD8+ cells are important for limiting herpesviruses.

Suppression of immunity triggers reactivation, spread, and severe disease.

Establishment of memory CTL reduces the severity of flare-ups

antiviral response for HSV

Th1 lead to CTL activation

(IFN-a, -b, and TNFa) are important players in CMI response

Entry of herpes viral DNA results in :

Active infection targets one cell type. Lysis of infected cells and CMI to infected cells are responsible for symptoms.

Latent infection targets another cell type and is associated with asymptomatic carriage.

herpes virion assembly occurs in

nucleus, ER, GOLGI

cell-cell release for herpes ensures

infections without virus exposure to extracellular environment – EVASION OF IMMUNE SYSTEM