Herpes Viruses

Herpesviridae key features

- dsDNA genome, linear

- Icosahedral

- Enveloped

- Tegument layer between capsid and envelope

- Lytic replication

- Latency (once infected, infected for life)

- Has its own DNA polymerase which can be a drug target

Tegument layer

Layer between capsid and envelope of herpes viruses

Human herpes virus subfamilies

- Alpha herpesvirus

- Beta herpesvirus

- Gamma herpesvirus

Alpha herpesvirus

HHV1, HHV2, and VZV (Varicella Zoster)

Short reproductive cycle (12-18 hours for the cycle), latency in sensory nerve ganglia

Beta herpesvirus

CMV (Cytomeaglovirus), HHV-6, HHV-7

Longer reproductive cycle (over 24 hours), latency in stem cells

Gamma herpesvirus

EBV (Epstein-Barr Virus), HHV8

Infect T or B cells, latency in lymphoid tissue

Alpha herpesvirus latency

Latency in sensory neuron cells which are cells that do not divide

Viral genome exists as non-integrated piece of DNA that is hiding out and not producing new virions

CMV latency

Latency in hematopoietic stem cells which are cells that do divide

Viral genome passed down in new cells but not producing virus or lysing cells during latency

HHV6/HHV7 latency

Latency in T cells which are cells that do divide

The viral genome is integrated into the host genome and those cells are replicated, can be passed to germ line

EBV latency

Latency in B cells which are cells that do divide

New viral genome goes into daughter cells

Natural reservoir of alpha herpesviruses

Humans

Transmission of alpha herpesviruses

HHV1: Direct contact (saliva, kissing), can be spread when someone is asymptomatic

HHV2: Direct contact (sexual, vertical)

VZV: Respiratory droplets or direct contact with open wound

Latency site of alpha herpesviruses

HHV1: Trigeminal ganglia

HHV2: Sacral ganglia

VZV: Dorsal root ganglia

All in sensory ganglia just in different places, for HHV1 and 2 it is close to the site of innoculation!

Vaccines for alpha herpesviruses

Only for VSV

Which virus causes oral/genital sores from the alpha herpesviruses

HHV1 more commonly making mouth sores, HHV2 making genital sores, but both can do either

HSV1 and HSV2 pathogenesis

- Close contact (kissing, etc) allows virus to go in and invade epithelial cells at the site of innoculation and undergo the lytic cycle quickly (12-18 hours)

- Lytic cycle causes syncytia formation, and when that lyses leads to fluid filled vesicles

- Vesicles can pop leading to ulcerations

- Virus goes up trigeminal ganglia by retrograde transport up the axon and establishes latency

Where can HSV1 and 2 have inoculation at

- Oral mucosa

- Genital skin

- Conjunctiva (from horizontal transmission)

HSV1/2 latency

Virus goes up axon into the trigeminal ganglia and establishes latency by the LAT gene. Keeps sensory neurons which they reside in from dying. Hangs out until reactivation (stress, UV light, etc.)

Latency is permanently established, cannot be removed

Herpetic whitlow

HSV1 or HSV2 goes into the finger (autoinoculation)

Virulence factors of HSV1 and HSV2

- Hijacking host cell machinery

- Viral DNA polymerase

- Neuronal trophism (immune cells do not go here)

- Restricted genome expression (maintains inactive state and maintains life of neuron)

HSV1 and HSV 2 samples

Skin swabs or scrapings, can sometimes look at CSF, blood, or tissue but not common unless dissemination has happened (mainly in immunocompromised people)

HSV1 and HSV2 testing methods

PCR is main form of testing, can be done on swabs, blood, or CSF. Can detect virus and differentiate between HSV1 and HSV2

Serology can also be done for screening in those with high risk of reactivation, transplant, and pregnancy

Culture and microscopy can be done but rarely are

VZV transmission

Transmitted through respiratory droplets

VZV pathogenesis

- Virus breathed in by respiratory droplets and infect tonsils and lymphnodes at first, doing lytic cycle and causing damage to those tissues

- Lysis of cells in the tonsular crypt allows virus to get into bloodstream (primary viremia)

- From there it gets into other organs and replicates more (secondary viremia)

- Skin and mucous membranes are involved, leading to fluid filled lesions and ulceration, as well as pain and itching

- During secondary viremia, it goes to the dorsal root ganglion and becomes latent

- It takes 10-20 days to see a rash occur

Radiation of VZV on the skin

Goes to trunk first and then spreads to the extremities

VZV primary infection

Consists of scalp involvement, exanthem, oral mucosa involvement

Very important to check for oral mucosa involvement as these virus can go into the lungs, invading pulmonary epithelial and endothelial cells and lead to VZV associated lung infection which can cause death

Incubation period of 10-21 days

VZV reactivation

High risk of reactivation due to waning cell mediated immunity with age, immunosuppression, or other stressors. CD8+ cells kill cells displaying viral antigen become less effective over time

Once reactivated, it affects a specific dermatome that is associated with the dorsal root ganglion where the virus went latent, can lead to pain/chronic pain syndrome

VZV samples

Tissue swab or scraping, biopsy, blood, CSF

Testing for VZV

Serology

Does not show if someone has risk of reactivation of shingles, even with high titres for VZV this only protects from primary infection, not reactivation

VZV vaccines

Live attenuated vaccine (childhood) and recombinant vaccine (adulthood)

Live attenuated VZV vaccine

- 2 doses, one at 12-15 months, and one at 18 months

- 98% effective

Recombinant VZV vaccine

- Glycoprotein + Adjuvant

- 2 doses, 2-6 months apart

- For people over 50 or immunocompromised

- More than 90% effective

Epstein Barr Virus Pathogenesis

Spread by saliva, coughing, or talking

- Gets into susceptible host leading to lytic cycle in the throat/tonsils which produces lots of new virions and puss, ulceration, inflammation, etc.

- Then infects B cells where latency occurs in lymphoid tissue

- Reactivation occurs when memory B cells differentiate into plasma cells, reactivation asymptomatic but can spread virus

EBV hallmarks

Atypical blood lymphocytes on a smear

EBV chronic complications

Oncogene virus, can cause different types of cancer

- Epithelial malignancy

- Malignant lymphoma

- TK T cell lymphoma

EBV samples

Tissue biopsy or blood (most common)

EBV testing

Serology is most common, PCR can be used in disseminated infection

EBV antibody testing

- Monospot

- EBV specific antibodies

Monospot testing

Old way of testing for EBV, looking at patients non-specific antibodies to EBV

Add to sheep RBC and see clumping in presence of nonspecific EBV antibodies, but has low sensitivity and can produce false positives or negatives

EBV specific antibody testing

Looking for viral nucleocapsid antigen (VCA) and nuclear antigen (EBNA)

Viral nucleocapsid antigen:

IgM: Within 2 days, disappear in 6 weeks (active infection)

IgG: Positive forever (recent or latent infection)

Nuclear antigen:

IgG: Positive forever (latent infection)

CMV transmission

Contact with any bodily fluid, most common in childhood with saliva/urine and in adults by sexual contact, transfusion, or organ transplant

CMV pathogenesis

- Invades epithelial cells with no clinical manifestation

- Goes into the bloodstream and activates monocytes and T lymphocytes and goes around the body in these cells

- Then goes into hematopoetic stem cells where it becomes latent and can be transferred to daughter cells/germ line

- Reactivation is linked to immunosuppression or severe inflammation where it can go into retina, lung, colon, genitourinary organs

CMV samples

CSF, tissue biopsy, blood (most common)

CMV testing

PCR is gold standard for monitoring infection

Serology for screening and risk stratification

HHV 6 and 7

AKA "Roseola", a common childhood illness

Belongs to beta herpesvirus subfamily, latency in T cells and integrates genome into host genome. Reactivation is common but there is no sign for it.

HHV6 in early childhood due to waning maternal antibodies, HHV7 later in childhood

Infects CD4+ cells leading to fever, immune activation, and a rash once the fever is broken

Transmission of HHV6 and HHV7

Saliva (parent to child, child to child)

HHV8

AKA Kaposi Sarcoma-Associated Herpesvirus

Belongs to gamma herpesvirus and establishes latency in B cells

Complications of HHV8

Causes soft tissue cancer (Kaposi's sarcoma) and B-cell cancer (lymphoma)

Virulence factor: Expresses viral genes that mimic host genes leading to cancer

Transmission of HHV8

Close contact, saliva, blood

In non-endemic areas can be spread by sexual contact

Most common in Sub Saharan Africa and Mediterranean