Herpetovirdae Lecture 5 and 6 Flashcards
Herpetoviridae genus
Herpesvirus: alpha=HSV, VZ; Beta= CMV; Gamma = EB
General properties of herpetovirdae
Double stranded DNA wound around protein core. 4 configurations of DNA: alternative arrangements of unique large and unique small, Ul and Us, respectively.
Icosahedral capsid composed of capsomers
envelope with glycoprotein spikes on its surface
Four configurations of HSV DNA
prototype P (Normal), Inverted Short (IS), Inverted Long (IL) and inverted IS and Inverted IL (ISL)
Replication of herpes simplex virus: Initial steps
Herpes simplex virus particle first attaches to receptor on surface of permissive cell (for HSV, Heparan sulfate is believed to act as the receptor.) Following attachment, the virus envelop fuses with the cell membrane to enable penetration. The capsid containing the genomic DNA moves to the nucleus of the cell and the genome is released in to the nucleus, which is the site of viral replication.
Viral DNA replication HSV
Inside the nucleus, the linear genomic DNA circularizes, which results from terminal and internal nt sequence redundancies.
concatemer formation by rolling circle mechanism
specific cleavage of concater into unit size DNAs with reorientation, Ul and Us, to yield the 4 configurations of DNA.
Transcriptional and translational events
alpha then beta then gamma proteins are made. Alpha and beta are immediate early and early, respectively; gamma is late; a temporal cascade of mRNAs and the corresponding proteins.
transcription and translation: alpha proteins
alpha proteins are regulatory in nature
Transcription and translation: beta proteins
beta proteins are enzymatic and are required for DNA replication. (DNA dependent DNA polymerase and thymidine kinase
transcription and translational: gamma proteins
primarily structural and are used to form progeny virus, some are glycoproteins that are inserted into both the nuclear membrane and plasma membranes; by definition late proteins are synthesized following viral DNA synthesis.
Assembly and death of cell
nucleocapsid formation in nucleus
capsid passes through nuclear membrane site. acquires envelop from modified membranes of cytoplasmic vesicles having inserted of viral glycoproteins
disruption of chromosomes, margination of cell DNA along the inner surface of the nuclear membrane
shut off of cell synthetic events (cell protein synthesis)
cell death occurs via different routes, including rounding of cells, syncytia
HSV: Diseases
Disease of type 1 (HSV-1) oral
Disease of type 2 (HSV-2) genital
Primary disease of HSV and how they are acquired
gingivostomatitis, keratitis, skin, central nervous system
A. HSV-1 as children; most are inapparent 6-18 months, Ab formation indicative of infection
B. HSV-2 after puberty through sexual contact, also at birth from infected brith canal
C. HSV-1 followed by HSV-2
D. Primary sites of infection, transmitted via oral or genital secretions
Gingivostomatitis (HSV)
vesicular lesions in all part of oral cavity (HSV-1)
Eye-dendritic keratitis (HSV)
stromal involvement, HSV strains determined (HSV-1)
Skin (HSV)
gladiatorum, herpetic whitlow, cold sores, herpeticum (HSV-1)
CNS: HSV-2
infected brith canal > transmission to neonate > viremia > brain (HSV-2)
Adult > spread along olfactory nerve > temporal lobe (HSV-1) (neurogenic spread)
Congenital (HSV)
fetus CNS, liver (HSV-2)
Immunosuppressed (HSV)
(aids patients or malnourished > disseminated (HSV-1 or 2)
Establishment of latent state (HSV)
after primary infection HSV transported up nerves to ganglia, trigeminal HSV-1, sacral ganglia HSV-2
at 0-7 day virus is present in ganglionic cells as seen by electron microscopy
after 14 days only HSV DNA present in cells, virus is not observed, episomal state of DNA in nuclei
trigeminal ganglia (HSV-1)
sacral ganglia (HSV-2)
Recurrent disease in presence of Ab (HSV) 1
and cell immunity virus can be still be reactivated due to hormonal changes, chemotherapy, mafunctioning immune system, aging, UV light, etc.
Recurrent disease: Activation of HSV from latency 2
DNA harbored in ganglia > activation > virus travel along nerves back to original site of infection, squestered away from immune sytem
Recurrent disease: Vesicular stage and regression.
Strain (HSV) 3 caveat
frequency of reactivation variable, may depend on the viral strain; eg. HSV-1 may exist as a variety of strains which differ in their pathogenicity
Recurrent disease in skin or eye, ocular herpes (HSV) 4 caveat
infection can cause corneal blindness after numerous recurrences, cause stromal scarring
Immunity and epidemiology (HSV)
70-90% of adults have been infected with HSV-1 as detected by neutralizing Ab’s
one third to one half develop recurrent disease sometime during their life
Incidence of HSV-2 infections increasing and supporting of other diseases
common veneral disease
transmitted by intercourse
possibly related to the incidence of cervical carcinoma: DNA tumor virus, may potentiate human papilloma virus in causing cervical cancer.
HSV-1 transmitted by saliva
contaminated eating utensils
socioeconomic association, less hygienic conditions correleted with increased spread.
Immunity not fully protective (HSV)
recurrences still occur.
antibody important in resistance
cellular immunity important in recovery
vaccination, experimental, split vaccine
Other diseases HSV can cause
may initiate erythema multiforme: up to 75% of these cases are preceded by recurrence of HSV infection
HSV infection may initiate idiopathic neuropathies: bell’s palsy, trigeminal neuralgia, temporal lobe epilepsy
Laboratory diagnosis: Tzanck smear (HSV)
scrape cells from base of lesion, stain and look for nuclear inclusions, EM (not specific)
Laboratory diagnosis: Virus isolation (HSV)
In cell culture
vesicular fluid best for isolations of virus
virus is very heat sensitive. Care in transport to lab 4C.
Laboratory diagnosis: serological (HSV)
neutralization (antibody reduces infectivity of virus as determined by a reduction in # of plaques); fluorescent antibody attached to viral proteins on or in infected cells shows cells are infected.
Laboratory Diagnosis: PCR (HSV)
available for HSV encephalitis diagnosis
Prevention and control: neonatal herpes HSV-2
Caesarean section
Pregenant women with active infection must be delivered by C-section due to possible fatal neonatal infection
neonatal infections tend to be generalized affecting brain and visceral organs
Prevention and control: Chemotherapy (HSV)
Topical for kertoconjunctivits or systemic for encephalitis, nucleoside analogs
- 5-iodo-2’deoxyuridine (idoxuridine, IUDR, stoxil)
- Adenine arabinoside (ara-A, vidarbine)
- Cytosine arabinoside (ara-c)
Prevention and control: Chemotherapy: Acylocivr, valacyclovir, penciclovir Ganiclovir (HSV)
ACV: oral acyclovir reduces severity of recurring disease, inhibits viral DNA polymerase and acts as a chain terminator; ACV is inactive when administered, ACV must be phosphorylated by viral thymidine kinase and then cellular kinases to from triphosphate, ACV good drug model fro establishing other anti viral drugs. Acycloguanosine
Valacyclovir: taken orally and has better absorption characterisitcs. Converts to acyclovir
Penciclovir: must be phosphorylated for activation and has a longer half life than acyclovir
Ganiclovir: more toxic than acylocivr
Prevention and control: Trifluorothymidine, Foscarnet and phosphonoformic acid (HSV)
Trifluorothymidine
Foscarnet and phosphonoformic acid: inhibits viral DNA polymerase, foscarnet resembles diphosphate group and binds to polymerase
Prevention and control: drug resistant mutants (HSV)
can be developed (DNA polymerase gene is mutated so that PFA no longer binds; viral thymidine kinase gene in inactive and fails to phosphorylate drugs- viral TK gene nonessential for virus growth
drug resistant mutants formed against ACG and other nucleoside analogs
Agents which inactivate infectious virus (HSV)
chloroform, ether, glutaraldehyde, detergens: destroy envelop of virus
vaccines, experimental, live virus may have oncogenic potential, split vaccine
Association with human cancer (HSV) and transformations
cervical carcinoma (HSV-2), both types can transform cells in culture (HSV-1 and 2) under certain situations
Varicella Zoster Chicken pox: Varicella zoster. Description. Complications.
Successive crops of lesions in a specfic area of skin
contrasts with smallpox (one crop of lesions in a specific area of the skin)
Complications: pneumonitis in adults, X-ray calcified nodules; encephalitis (children) and males are two times greater incidence than female. Hemorrhgaic varicella causes bleeding in vesicles, GUT, and GU.
Immunologically compormised and non immune neonates, severe, 20% mortality, AIDS patients
REYES syndrome: aspirin related hepatic failure encephalopathy
Herpes Zoster: shingles: varicella zoster
Recurrent infection
Adults: located on area of skin (dermatome innervated by affected sensory nerve, latency in dorsal root ganglia.
lesions are unilateral, severity increases with age.
Pathogenesis and immunity Varicella (primary infections)
Respiratory route (mucosa) > viremia > skin > macular papular, vesicular, not umbilicated > crusts not infectious, each crop of lesions arise in asyncronous progression
two week incubation period > fever with each crop, wide spread rash produces higher fever (spread from trunk > face
fever usually not as high as that associated with smallpox prodrome.
Pathogenesis and immunity Herpes Zoster (recurrent infection)
Occurs only with history of varicella infection, verified by specific antibodies in serum
second attacks unusual, but may occur
1% of population annualy
resides in (dorsal root) ganglia of affected nerve– recurs at dermatomes, thoracic (50%), ophthalmic (15%), lumbar (15%), cervical (10%)
subject usually over 50 years old
Epidemiology and control of herpes zoster. Activation, age range of chicken pox, and TX of zoster lesions
Most children infected in first 6-8 years; chickenpox case
zoster patients can be source of chicken pox epidemic virus in vesicular fluid. Zoster can be activated via x rays, tumor in CNS, trauma, immunosuppression, exposure to CP or zoster all may reactivate VZ virus.
treatment of zoster lesions, zoster immune globulin preventions of complications, ZIG, pooled gamma globulin from patients convalescing from zoster, given IM to immunosuppressed patients within 2-3 days of exposure to VZ, ab neutralizes VZ virus.
Epidemiology and control of herpes zoster 2. Vaccine
Highly contagious chicken pox
vaccine was licensed in US in 1995. Attenuated live vaccine, which is recommended for routine vaccination of children; 2 doses recommended, dose 1 at 12-15 months, dose 2 at 4-6 years and for susceptible older children, adolescents and adults
two varicella vaccines are available, single antigen vaccine (varivax) and a combination vaccine consisting of measles, mumps, rubella, and varicella (MMRv and Proquad)
Zoster vaccine: zostavax for individuals over 60 years, one immunization; reduces likelihood of shingles by about 50%
Epidemiology and control of herpes zoster 3. Other TX for immunosuppressed.
Adenine arabinoside: approved for treatment of immunosuppressed patients with V or Z, oral acyclovir also recommended, IV acyclovir for immunocompromised children.
