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Describe the four types of infection and how the virus production manifests over time.

acute infection - fast peak and then destruction of virus

persistent infection - constant presence of virus before death

latent, reactivating infection - virus peaks up at various times in life accompanied by an immune response

slow virus infection - virus infects certain cells and lays dormant until a later time period where it explodes and causes death


herpesvirus family

eight different herpesviruses isolated from humans

classified into three subfamilies based on biological properties and genomic analyses

certain genes are conserved among members of all three subfamilies

depending on the particular virus and the population studied, infection rates are generally between 60-90%


Name the eight different herpesviruses isolated from humans.

HSV-1, HSV-2, HCMV (human cytomegalovirus), VZV (varicella-zoster virus), EBV (Epstein-Barr virus), HHV6, HHV7, and KSHV (Kaposi's sarcoma associated herpesvirus)

HHV6 has recently been split into HHV6a and HHV6b


human alpha--herpesviruses

neurotropic, characterized by a broad host range and are highly litic in cell culture

short reproduction cycles

includes HHV1, HHV2, and HHV3 (VZV)



restricted host range and grow more slowly in culture

cells infected with beta subfamily members often display an enlarged cytoplasm, referred to as cytomegaly

members include cytomegalovirus, HHV6, and HHV7



lymphotropic and can be oncogenic

severe diseases arises from latency

members include Epstein-Barr virus and Kaposi's sarcoma associated herpes virus


genes conserved among members of all three subfamilies

genes for structural proteins and enzyme enzymes for DNA replication


hallmarks of all herpesvirus infections

the ability of the virus to establish latent infections during the primary encounter with the host and to reactivate to cause secondary disease long after recovery from primary disease


three classes of herpesviruses

class I - herpesviridae (mammals, reptiles, birds)

class II - alloherpesviridae (amphibians, fish)

class III - (malacoherpesviridae, bivalves)



route of entry - exposure of broken skin or mucosa to oral or genital secretions

primary disease - gingivostomatis, pharyngotonsilitis, keratitis, encephalitis (rarely)

principle site of latency - neurons of sensory or autonomic ganglia

reactivation disease - cold sores/fever blisters (herpes labialis), keratitis, encephalitis (rarely)

above the waist

leading cause of blindness in the developed world



route of entry - exposure of broken skin or mucosa to oral or genital secretions

primary disease - meningitis, disseminated disease

principle site of latency - neurons of sensory or autonomic ganglia

reactivation disease - recurrent mucocutaneous lesions (genital sores)

below the waise



route of entry - respiratory

primary disease - chicken pox

principle site of latency - neurons of sensory ganglia

reactivation disease - zoster

causes systemic primary disease instead of localized disease

cutaneous lesions in the outer layers of the stratified squamous epithelium produces infectious virus that can spread through air

incubation and acute illness

live attenuated vaccine for general use


receptors required for HSV viral entry

nectin-1 - a cell adhesion molecule expressed in epithelial cells and neurons

HVEM - a member of the TNF receptor family expressed in leukocytes and epithelial cells

PILRalpha - a co-receptor also required for virus entry and may simultaneously trigger the cell to be more permissive to the subsequent infection


HSV latency

virus enters the endings of adjacent neurons and transports within axons to the sensory ganglia

viral DNA is injected into the nuclei after viral particles arrive at the neural somas

latent infection of neurons is characterized by the absence of viral gene expression except for the latenct-associated transcript (LAT)


latency-associated transcript (LAT)

encodes a stable intron that accumulates in the nuclei of latently infected neurons and microRNAs that interfere with teh TGF-beta pathway

protects latently infected neurons from apoptosis



treatment of choice for life-threatening HSV infection

can be used prophylactically to reduce the frequency and severity of recurrent lesions


HSV severe disease

sporadic encephalitis


neonatal herpes


sporadic encephalitis


no strong predispositions

most often involves temporal lobe

highly fatal

permanent neural damage in survivors

CNS latency allows for recurrence

presentation is similar to stroke an may include confusion, reduction in consciousness, difficulty speaking, change in personality, and seizures



leading cause of infectious blindness in USA

corneal scarification and neovascularisation are conesquences of the immune response


neonatal herpes

mostly HSV-2

predominantly spread during birth

infection can also be in utero or postnatally

1 in 1,200-2,000

three forms include:

localized mucocutaneous disease


disseminated disease


primary (natural host)

species that maintains virus in nature

typically experiences relatively benign recurrent infections resulting from successful establishment of latency


secondary (dead-end host)

virus causes a typically fatal encephalitis


Herpes B

herpes virus that usually infects resus macac monkeys

very severe for humans, goes straight to the brain and kills the person


describe the structure of herpesvirus.

core, capsid, tegument, and envelope


herpes core

viral DNA ranging from 120-240 kbp

double-stranded linear DNAs

tightly packaged inside capsid under high pressure


herpes capsid

125 nm diameter icosahedron with 162 capsomers

composed predominantly of 4 viral proteins

encases viral DNA

visible as a multi-faceted ball in the center of the image, and the capsomers are the very small shapes composing the capsid surface


herpes tegument

viral proteins located between the capsid surface and the envelope

these proteins do not make a structure that is easily visible with a standard electron microscope


herpes envelope

lipid bilayer containing about a dozen viral membrane proteins and glycoproteins

some glycoproteins can be seen as spikes emanating from the lipid envelope


herpesvirus infectious cycle

virus attaches to cell surface receptors and fuses with the cell membrane

capsid transported to the nucleus via microtubules

viral genome injected into th enucleus through pores

tegument proteins transported to the nucleus, direct cell RNA polymerase to transcribe immediate-early (IE) viral genes

IE mRNAs encode viral regulatory proteins that induce the expression of early (E) and late (L) genes

E mRNAs encode enzymes required for viral DNA replication

viral DNA is replicated, providing template for L gene expression and progeny viral genomes for packaging

capsids assemble in the nucleus, where viral DNA genomes are packaged into the performed capsids

capsids acquire temprary envelop by budding through the inner nuclea rmembrane



herpes virus tegument protein

virion host shutoff, interferes with cellular protein synthesis

prevents cells from calling out for help or warning other cells



herpes tegument protein

transcription factor, promotes viral gene expression



herpes tegument protein

protein kinase, blocks apoptosis pathway


TK mutant herpes virus

lack of thymidine kinase prevents activation of acyclovir

gradually expanding superficial ulcerated lesion on face that does not response to high-dose acyclovir

not a problem because they are no longer neurotropic so no more latency

treatment through alternative anti-virals that do not require TK activation


latent infections

viral genome persists in the cell nucleus as an autonomous episome

replication is not necessary for maintentance

in replicating cells, virus expresses EBNA1 that attaches the episomes to cell chromosomes to ensure partitioning of viral genomes to daughter cell nuclei

EBNA1 has a repeating amino acid sequence that prevents it from being presented by MHC molecules to the immune system


incubation period of VZV

inhalation of virus

replication in lymph nodes

primary viremia

replication in liver and spleen


acute illness of VZV

secondary viremia

virus-infected monocytes go to skin

lesions in epidermis

neurotropic transmission to dorsal root ganglia


cell surface proteins that serve as receptors for VZV

myelin-associated glycoprotein (MAG)

cell surface heparan sulfate

can infect leukocytes, leads to replication in spleen and liver which then distribute to skin and cause lesions


chicken pox

most dramatic form of primary VZV infection, usually requires no specific treatment

in more severe cases, acyclovir or derivatives are the treatment of choice



many years after primary infection, some stimulus to the nerves and a waining of immunity permits reactivation of VZV replication

acute inflammation of the sensory nerves and ganglia is accompanied by mcuh pain and eruption of lesions on the body surface following the dermatome of the affected nerve


site of VZV latency

sensory pseudounipolar neurons int he dorsal root ganglion


cytomegalovirus (HCMV)

route of entry - exposure to oral or genital secretions, transplanted organs, parenteral, in utero, perinatal

primary disease - usually sublinical, fetal infections can cause wastage, mental retardation, hearing defects, and vision defects

principle site of latency - cells of monocytic lineage

reactivation disease - usuall yonly in immunocompromised

almost universal, with 90-95% of adults infected

infects salivary glands, lungs, and kidneys

shed in secretions

transmission by oral/respiratory route

generally benign unless person is immunocompromised

fetal infections, transmission from mother can lead to congenital abnormalities

therapy is glancyclovir



route of entry - sexual transmission

primary disease - Kaposi's sarcoma

principle site of latency - not known

reactivation disease - Kaposi's sarcoma

infections typically only seen in elderly men prior to AIDS epidemic

secondary infection common in AIDS patients


Epstein-Barr Virus (EBV)

route of entry - exposure to oral secretions

primary disease - infectious mononucleosis

principle site of latency - B lymphocytes

reactivation disease - lymphoproliferative disease and oral hairy leukoplakia in the immunocompromised, cofactor in several cancers

classif feature of mononucleosis is lymph node swelling

associated with Burkitt's lymphoma and nasopharyngeal carcinoma

XLP (X-linked lymphoproliferative syndrome) characterized by fulminant fatal EBV-induced infectious mononucleosis, B cell lymphoma, and dys-gammaglobulinemia


receptor for EBV infections

interaction with CD21 and MHC Class II molecules



a viral gene that promotes proliferation in the host cells


EBV life cycle


three sets of active EBV genes

promotes T cell response

EBNA1 - partitions viral genomes

LMP2 - blocks signaling through BcR

LMP1 0 induce cell proliferation (very immunogenic)

latent cells only express EBNA1 and LMP2



route of entry - probably by oral secretions

primary disease - roseola infantum

principle site of latency - not known

reactivation disease - perhaps pneumonitis and hepatitis in teh immunocompromised



route of entry - not known

primary disease - possibly also roseola

principle site of latency - not known

reactivation disease - not known