Herpesviruses and Latency

Question 1

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

Answer 1

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

Question 2

herpesvirus family

Answer 2

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%

Question 3

Name the eight different herpesviruses isolated from humans.

Answer 3

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

Question 4

human alpha–herpesviruses

Answer 4

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

short reproduction cycles

includes HHV1, HHV2, and HHV3 (VZV)

Question 5

beta-herpesviruses

Answer 5

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

Question 6

gamma-herpesviruses

Answer 6

lymphotropic and can be oncogenic

severe diseases arises from latency

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

Question 7

genes conserved among members of all three subfamilies

Answer 7

genes for structural proteins and enzyme enzymes for DNA replication

Question 8

hallmarks of all herpesvirus infections

Answer 8

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

Question 9

three classes of herpesviruses

Answer 9

class I - herpesviridae (mammals, reptiles, birds)

class II - alloherpesviridae (amphibians, fish)

class III - (malacoherpesviridae, bivalves)

Question 10

HSV1

Answer 10

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

Question 11

HSV2

Answer 11

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

Question 12

VZV

Answer 12

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

Question 13

receptors required for HSV viral entry

Answer 13

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

Question 14

HSV latency

Answer 14

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)

Question 15

latency-associated transcript (LAT)

Answer 15

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

Question 16

acyclovir

Answer 16

treatment of choice for life-threatening HSV infection

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

Question 17

HSV severe disease

Answer 17

sporadic encephalitis

keratitis

neonatal herpes

Question 18

sporadic encephalitis

Answer 18

rate

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

Question 19

keratitis

Answer 19

leading cause of infectious blindness in USA

corneal scarification and neovascularisation are conesquences of the immune response

Question 20

neonatal herpes

Answer 20

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

encephalitis

disseminated disease

Question 21

primary (natural host)

Answer 21

species that maintains virus in nature

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

Question 22

secondary (dead-end host)

Answer 22

virus causes a typically fatal encephalitis

Question 23

Herpes B

Answer 23

herpes virus that usually infects resus macac monkeys

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

Question 24

describe the structure of herpesvirus.

Answer 24

core, capsid, tegument, and envelope

Question 25

herpes core

Answer 25

viral DNA ranging from 120-240 kbp double-stranded linear DNAs tightly packaged inside capsid under high pressure

Question 26

herpes capsid

Answer 26

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

Question 27

herpes tegument

Answer 27

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

Question 28

herpes envelope

Answer 28

lipid bilayer containing about a dozen viral membrane proteins and glycoproteins some glycoproteins can be seen as spikes emanating from the lipid envelope

Question 29

herpesvirus infectious cycle

Answer 29

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

Question 30

VHS

Answer 30

herpes virus tegument protein virion host shutoff, interferes with cellular protein synthesis prevents cells from calling out for help or warning other cells

Question 31

VP16

Answer 31

herpes tegument protein transcription factor, promotes viral gene expression

Question 32

US3

Answer 32

herpes tegument protein protein kinase, blocks apoptosis pathway

Question 33

TK mutant herpes virus

Answer 33

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

Question 34

latent infections

Answer 34

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

Question 35

incubation period of VZV

Answer 35

inhalation of virus replication in lymph nodes primary viremia replication in liver and spleen

Question 36

acute illness of VZV

Answer 36

secondary viremia virus-infected monocytes go to skin lesions in epidermis neurotropic transmission to dorsal root ganglia

Question 37

cell surface proteins that serve as receptors for VZV

Answer 37

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

Question 38

chicken pox

Answer 38

most dramatic form of primary VZV infection, usually requires no specific treatment in more severe cases, acyclovir or derivatives are the treatment of choice

Question 39

zoster

Answer 39

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

Question 40

site of VZV latency

Answer 40

sensory pseudounipolar neurons int he dorsal root ganglion

Question 41

cytomegalovirus (HCMV)

Answer 41

**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

Question 42

KSHV

Answer 42

**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

Question 43

Epstein-Barr Virus (EBV)

Answer 43

**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

Question 44

receptor for EBV infections

Answer 44

interaction with CD21 and MHC Class II molecules

Question 45

LMP1

Answer 45

a viral gene that promotes proliferation in the host cells

Question 46

EBV life cycle

Answer 46

Question 47

three sets of active EBV genes

Answer 47

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

Question 48

HHV6

Answer 48

**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

Question 49

HHV7

Answer 49

**route of entry** - not known **primary disease** - possibly also roseola **principle site of latency** - not known **reactivation disease** - not known