Micro Chapter 41: Alphaherpesviruses: Herpes Simplex Viruses and Varicella-Zoster Virus

Herpesviruses are DNA viruses that can establish lifelong latent infections, that can reactivate symptoms
throughout life
The alpha herpesviruses are herpes simplex 1 and 2 (HSV-1 and -2) and varicella zoster (VZV)
Infection with one or more herpesviruses is inevitable for pretty much everyone
- Most of us have probably spread HSV-1 by kissing or exchanging saliva
- HSV-1 can be gotten in childhood or during sex through oral-oral or oral-genital contact
- Most adults have antibodies to HSV-1
- HSV-2 can be gotten oral-oral and oral-genital, but is mainly spread by genital-genital
o So HSV-2 gets more common with sex
- Varicella zoster is gotten mainly through respiration, but you can also get it by touching the
blisters or secretions
o Varicella zoster is much more contagious than HSV
o Adults with no immunity from shots or exposure can have more severe chickenpox
disease than kids do
o A mild version of chickenpox can happen in vaccinated people since the vaccine isnt
100% effective, called breakthrough disease
Breakthrough disease is contagious and can be spread
o Varicella infections are almost always symptomatic, causing chickenpox
Most infections with HSV are asymptomatic (1/3 who have it show symptoms)
- Asymptomatic people can still spread HSV by shedding from epithelial surfaces from lesions too
small to be noticed
Herpesviruses are fragile and susceptible to drying and inactivation by heat, mild detergent, and
solvents, due to their membrane envelope
- So they cant survive well in the environment, and usually need direct contact with saliva or
other secretions from an infected person
HSV likes to infect the mucous membranes of the mouth, eye, genitals, respiratory tract, and anus
- The first line of defense against HSV is the skin, which normally cant be penetrated infected
by HSV
- The thick keratin layer of the superficial epidermis prevents access of HSV, but mucous
membranes dont have a thick layer like that, so theyre easier to infect
The main way to get chickenpox is by inhaling aerosols of varicella, but you can also get it directly
So mucous membranes are the main entry for herpesviruses into us
Herpresvirus infection starts by attaching to cells, which it does by using glycoproteins to bind to our
heparan sulfate on the cell surface
- This isnt enough to enter the cell, but brings the virus close to other parts of the cell
- It then binds to a so called entry receptor on the host cell, causing fusion of the virus envelope
with the cell membrane, which can be either the plasma membrane or an endosome membrane
- This releases viral stuff into the cell, and the nucleocapsid is taken to the nucleus, where cells
that can transcribe herpesvirus DNA, like epithelial cells, will transcribe it to make viral proteins
and do viral DNA replication
- If the cell is latently infected, then the viral genome hangs out in the nucleus as an episome
that only transcribes the minimal amount of genes
- In herpesvirus and varicella, the virus enters nerve cell ending that extend toward the
epidermis, and is sent to the nerve cell bodies in peripheral sensory and autonomic ganglia,
where the latent infection is established
- During productive infection (when virus replication is happening), immediate-early genes are
transcribed to make proteins to help replicate the viral DNA
- After DNA synthesis, late genes are expressed to make progeny virions
- As the new viral nucleocapsids are made int eh nucleus, they bud through the inner nuclear
membrane to get a temporary envelope, which they lose then by fusing with the outer nuclear
membrane
- The final viral envelope with all its glycoproteins is gotten by budding ito cytoplasmic vacuoles
made from the golgi
- These vacuoles take the mature virus to the cell surface and release it through exocytosis
- These new viruses arent good at being released from the cell, so they immediately attach to
and penetrate adjacent cells
o This is why HSV infections are localized and rarely found at many distant sites
o HSV rarely spreads systemically, except in newborns or severely immunocompromised
people
o Varicella though, is very systemic, probably cause it infects & can be carried by WBCs
Host defense to herpesviruses:
- Host defense is usually enough to limit the duration and severity of infection, and can prevent
symptoms and recurrences
- Host defense wont prevent latent infections though, and cant eliminate the virus, because
latently infected cells dont trigger an immune response
- At first, herpesviruses induce immediate innate response with neutrophils and NK cells, and
within days there are antibodies and T cells
o Antibodies dont do much, because herpesvirus doesnt spend much time outside the
cells
o The antibodies can prevent primary disease though, which is why we can make a
varicella vaccine
- The ability to mount a good enough immune response to herpseviruses changes with age
o The immune cells are maturing for the first month of life, so herpesvirus infections in
the first month can be devastating, neonatal infections are often fatal
o After 1 month old and up to were old, we tolerate the virus well
o Reactivation of varicella zoster happens more as we get older due to senescence of
antiviral immune responses
Damage from herpesviruses pics page 424, table page 421
- Both HSV and varicella destroy the epithelial cells they replicate in in the skin and mucous
membranes, causing blisters that rupture, leaving shallow gray-white ulcers with an
erythematous base
- As virus replication and spread get contained by immune response, the epithelium fully
regenerates
- HSV lesions are usually localized, with spread of virus restricted to regional nerves
o During primary disease, there can be sequential crops of lesions, resulting from
reseeding of adjacent epithelial sites by neurons infected during earlier waves of
epithelial replication
o Inflammation or damage of the nerves can happen in the acute phase of disease,
causing symptoms of itching, tingling, burning, or pain
o Feeling these same symptoms later, called a prodrome, can indicate that a recurrent
lesion is about to develop
o Things that can trigger the reactivation of latent HSV are sunburn, systemic infections,
immune impairment, emotional stress, and menstruation
o Reactivated HSV travels down the axon process to infect mucocutaneous epithelial
cells
o Page 425 events in HSV infection
o Where HSV enters determines the manifestations of disease
Corneal infections cause immune responses that damage the cornea
irreparably and cause blindness, making you need a corneal transplant to get
vision back
Genital herpes can progress to meningitis, or affect autonomics for urination
and defecation
HSV-1 can pass from peripheral nerves to the CNS to cause life-threatening
encephalitis, characterized by a strongly progressive and destructive
inflammation thats localized and unilateral
HSV-1 encephalitis is rare, but accounts for most cases of sporadic
disease
Newborns are very susceptible to HSV infections that spread or cause neuro
disease, and if they survive they often are developmentally impaired
People with low cell mediated immunity can have HSV spread a lot
o Chickenpox is a systemic disease with mucocutaneous lesions, caused by varicella zoster
Cells of the lymphatic system are infected in the respiratory tract
The spread of virus infected WBCs throughout the lymphatic system induces
cytokine responses that cause fever, malaise, and headache
In secondary viremia, circulating WBCs transmit the virus ot epithelial cells of
the skin and mucosa, causing characteristic chickenpox lesions
Latent infection is established in peripheral ganglia, and then they recover with
no further symptoms
Along with chickenpox lesions, kids can have cerebellar ataxia,
immunocompromised can have encephalitis
o Shingles zoster lesions are similar blisters to the chickenpox ones, but theyre clustered
along the dermatome innervated by the nerve that varicella was reactivated from
The neurosymptoms are mainly pain, and are more severe
o Page 426 course of varicella infection
You usually can diagnose HSV or varicella from history and inspection, but you can also scrape the lesion
for polymerase chain reaction (PCR)
- HSV shows cytopathic effect, where if you take sample and put on a set of cells, it will lyse each
cell, causing plaques that dont stain
o It wipes out only adjacent cells, and not the whole set
Drugs for herpesviruses are usually nucleoside analogs
- Acyclovir guanosine analog that is used only by the herpesvirus enzymes and not cell
enzymes, and then incorporated into viral DNA as a chain-terminating nucleotide
o So acyclovir is active in herpesvirus-infected cells, but has no toxicity for uninfected cells
o Acyclovir is a prodrug that needs thymidine kinase to become active
- Other antiherpesvirus drugs include penciclovir, valacyclovir, and famciclovir
- These drugs can only treat symptoms, and cant cure the infection, because they dont prevent
entry into neurons and so cant get rid of latent infections
- Long term use of acyclovir can suppress recurrent infections
There are no vaccines for HSV, but there is a vaccine for varicella
- A live attenuated vacricella zoster vaccine prevents chickenpox in normal and some
immunocomprommised people
- The vaccine virus establishes latent infection just like normal virus does, and reactivation can
lead to mild cases of shingles
Latency associated transcripts (LATs) micro RNAs that keep the virus from erupting
- When you remove the LATs, you have a herpes eruption