Herpesviruses and Latency Flashcards
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)
beta-herpesviruses
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
gamma-herpesviruses
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)
HSV1
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
HSV2
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
VZV
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
acyclovir
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
keratitis
neonatal herpes
sporadic encephalitis
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
keratitis
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
encephalitis
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
VHS
herpes virus tegument protein
virion host shutoff, interferes with cellular protein synthesis
prevents cells from calling out for help or warning other cells
VP16
herpes tegument protein
transcription factor, promotes viral gene expression
US3
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
zoster
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
KSHV
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
LMP1
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
HHV6
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
HHV7
route of entry - not known
primary disease - possibly also roseola
principle site of latency - not known
reactivation disease - not known
