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141 Cards in this Set

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herpes virus (virion)
enveloped
single molecule of linear dsDNA
icoadehdral nucleocapsid
herpes virus (site of nucleocapsid assembly)
nucleus

resulting in a nuclear inclusion body
herpes virus (replication steps)
a) an extracellular virion adsorbs to a susceptible cell
b) virion envelope fuses and penetrates the plasma membrane of the host cell
c) nucleocapsid goes to the nucleus and releases its DNA into the nucleus
d) the DNA becomes circular
e) synthesis of mRNA, viral proteins, and viral DNA takes place
f) progeny nucleocapsids are assembled in the nucleus, large arrays of nucleocapsids result in characteristic nuclear inclusion bodies
g) virus-encoded glycoproteins inserted into nuclear membrane and plasma membrane
i) virus encoded glycoproteins in plasma membrane can result in cell fusion to produce multinucleate giant cells (compare measles)
in replication of Herpes Virus, when does the DNA cyclize?
after the nucleocapsid goes to and releases its DNA into the nucleus

[DNA becomes circular]

followed by mRNA synthesis, viral proteins and viral DNA
where are herpes nucleocapsids assembled?
in the nucleus
Herpes virus (inclusion bodies)
large arrays of nucleocapsids, found in the nucleus result in characteristic nuclear inclusion bodies
why can herpes virus result in multinucleate giant cells
virus-encoded glycoproteins in the plasma membrane can result in cell fusion to produce multinucleate giant cells
how are infectious herpes virus virions produced?
by nucleocapsid budding through the nuclear membrane
single most important biological characteristic of herpes viruses
LATENCY: herpes viruses are not eliminated on recovery from primary infection, but remain in a clinically "latent" state that can subsequently result in recurent disease
how is the herpes virus maintained in small populations?
patients with latent infection may sporadically produce infectious virions (while remaining asymptomatic)

this latent state-recurrent infection allows parent --> child transmission and maintenance of virus in small populations
Number of herpes viruses known to infect humans
8, (5 to be considered in detail:
Herpes simplex virus type-1
Herpes simplex virus type-2
varicella-zoster virus
cytomegalovirus
Epstein Barr (EB) virus)
How are Herpes Simplex type-1 and type-2 distinguised
closely related antigenically

distinguished by type-specific monoclonal antibodies of PCR
viruses that remian latent in sensory ganglion cells
Herpes simplex type-1
Herpes simplex type-2
and Varicella-zoster viruses

(when infection is reactivated, virus makes its way to skin by neural pathway causing unilateral skin lesions, whereas primary lesions are often bilateral)
populations affected by recurrent herpes simplex type 1 and type 2 and varicella-zoster virus infections
seen in immunologically normal persons, pathology more severe in immunosuppressed
latent EB virus is found
within B lymphocytes
latently infected cell type in cytomegalovirus infection
uncertain
recurrent disease (w/ EB and cytomegalovirus) almost entirely seen in what population
immunosuppressed patients
Herpes Simplex Type 1 (primary infection)
often subclinical

virions produced at site of initial infection infect the sensory nerves there and infection ascends the nerve (probably in the form of nucleocapsids) to establish a latent infection in the sensory ganglion that corresponds to the initial site

some infants get somatitis with vesicles throughout the mouth

other sites of primary infection (nose, eyes, fingers, etc.)
Herpes Simplex Type 1 (incubation period)
1-2 weeks
Herpes Simplex Type 1 (latent virus isolated from...)
sensory ganglia
Herpes Simplex Type 1 (reccurent infection begins when...)
extensive viral multiplication is "turned on" in the nucleus of a senosry ganglion cell

resulting virions are transported down the axon to the cutaneous site (corresponding to the primary infection)

local infection with vesicular lesions (cold sores) results

cold sores are self-limiting local lesions
cold sores in Herpes Simplex Type 1
are self-limiting local lesions

produce many infectious virions
what prevents disseminated infection in recurrent Herpes Simplex Tyle 1 infection
circulating Ab already present as result of primary infection
small amounts of infectious virus sporadically released in latent Herpes Simplex Type 1 do what?
do NOT produce lesions
what can activate latent Herpes Simplex Type 1 infections to produce cold sores?
fever, UV light, emotion
Herpes simplex type 2 (disease)
STD with lesions on the genitalia
Herpes simplex type 2 (population infected)
seroconversion is seen in populations after the age of puberty

currently ~20% of US population is seropositive (latently infected)
Herpes simplex type 2 (primary infection)
may be severe with multiple BILATERAL lesions

but many are asymptomatic

reulsts in a latent infection of the sensory ganglia cells that innervate the genitalia (SACRAL GANGLIA)
Herpes simplex type 2 (incubation period)
1-2 weeks
Herpes simplex type 2 (characteristics of recurrent disease)
fewer lesions, generally unilateral
Herpes simplex type 2 (how is recurrent disease prevented)
chemotherapy with acyclovir
most persons latently infected with Herpes simplex type 2
sporadically produce small amts of infectious virus

even though they have no overt lesions
Herpes simplex type 2 (transmission)
Sexual Transmission
Perinatal transmission (via virions in vaginal secretions of latently or acutely infected mother)
neonatal herpes simplex
caused by perinatal infection
systemic disease
appears ~6 days pp
often fatal
most organs are invaded by the virus in neonatal disease
marked by HEPATO-ADRENAL NECROSIS

highest risk of perinatal infection and fatal outcome when mother has acute primary Herpes Simplex Type 2 infection
HEPATO-ADRENAL NECROSIS
destruction of liver and adrenals characteristic of neonatal herpes simplex
prevention of neonatal herpes simplex
if vaginal lesions are present before delivery, strong indication for C-section
most common cause of sporadic (non-epidemic) encephalitis
Herpes simplex (mostly type 1)

route to CNS is probably neural
Herpes simplex encephalitis is seen in what patient populations
primary infection
and
in patients with history of recurrent lesions
Herpes simplex encephalitis (site of infection/symptoms)
temporal lobe is most commonly infected, may give rise to temporal lob symptoms

(auditory or olfactory hallucinations)
Herpes simplex encephalitis (diagnosis)
formerly required biopsy

now PCR detection of herpes simplex DNA in CSF

rapid diagnosis is important because chemo is available (acyclovir)
Herpes simplex encephalitis (treatment)
chemotherapy with acyclovir

sometimes administered on clinical suscpicion of herpes simplex encephalitis
HERPES SIMPLEX KERATITIS
herpes infection of the eye can lead to keratitis affecting:
the conjunctiva, eyelids, and cornea
HERPES SIMPLEX KERATITIS (typical presentation)
unilateral "red eye" with a variable degree of pain or ocular irritation

often associated with photophobia
HERPES SIMPLEX KERATITIS (complications, prognosis)
can spread to deeper levels of the eye and cause permanant damage

risk of corneal damage
HERPES SIMPLEX KERATITIS (treatment)
topical trifluridine or systemic acyclovir
Varicella-Zoster Virus (primary infection)
chicken pox
Varicella-Zoster Virus (epidemics)
winter-spring epidemics in children are seen every few years
Varicella-Zoster Virus (site of primary infection)
by way of respiratory tract, with subsequent viremia
Varicella-Zoster Virus (incubation period)
2-3 weeks
Varicella-Zoster Virus (symtoms)
fever and rash appear after 2-3 week incubation period

lesions are small itchy vesicles

characteristically lesions are in different states of developmentin the same area of skin
Varicella-Zoster Virus (transmission)
spread probably spread primarily by viruses shed from skin lesions

virus-containing vesicles in the mucosa rupture shorly after they form

shed virus from respiratory tract may also spread the infection
Varicella-Zoster Virus (in patients with impaired immune response)
get a severe and often fatal chicken pox on primary infection

if exposed can be passively immunized with IgG from donors with high known titers of neutralizing Ab (VZIG: Varicella-Zoster Immune Globulin)

less common now, bc available vaccine and chemotherapy and chemprophylaxsis with acyclovir works well
VZIG
Varicella-Zoster Immune Globulin:

IgG from donors known to have high titers of neutralizing Ab to Varicella-Zoster virus

before Varicella-Zoster Virus vaccine and effective chemotherapy was used to prevent severe/fatal infections in immune compromised patients
CONGENITAL VARICELLA SYNDROME
rare (0.5-2%) fetal infection, when pregnant mother is infected with Varicella-Zoster Virus in first or early 2nd trimester

characterized by limb atrophy, scarring of skin on the affected limb

MUCH LESS COMMON THAN congenital cytomegalovirus infection
Latent infections with Varicella-Zoster Virus are established where?
sensory ganglia

(same as with herpes simplex virus)
ZOSTER
(aka SHINGLES) disease resulting from reactivation of latent Varicella-Zoster infection

virions move down the axons, produce vesicular lsions at cutaneous site

unilateral, dermatomal distrubution

(may produce pain before lesions appear)
SHINGLES
(aka Zoster) disease resulting from reactivation of latent Varicella-Zoster infection

virions move down the axons, produce vesicular lsions at cutaneous site

unilateral, dermatomal distrubution

(may produce pain before lesions appear)
Post-Herpetic Neuralgia
severe local pain at sites of healed lesions after recovery from Zoster (shingles)

adverse outcome increases with age at which the zoster attack takes place

Acyclovir given in the first 1-2 days can reduce the risk of post-herpetic neuralgia
Post-Herpetic Neuralgia (prevention)
Acyclovir given in the first 1-2 days of Zoster infection can reduce the risk of post-herpetic neuralgia
dermatomal distribution of Zoster
patients who get zoster are seropositive as a result of original chicken pox, Ab prevents viremic spread and results in this distribution
Disseminated Zoster
virus is spread by viremia and produces lesions beyond the original dermatome

immunsosuppressed patients at risk

disseminated disease can be treated with acyclovir
Zoster characterized by:
monocyte infiltration of the involved ganglion

pain that may precede the cutaneous lesions
Zoster (population affected)
all ages are affected, but..

attack frequency increases with age after 50 (probably related to age-related decline in cell-mediated immunity)

higher incidence also seen in those with reduced cell-mediated immunity (AIDS, anti-cancer drugs, other immunosuppresive drugs)
Zoster vesicles contain what?

what can they be the source of?
vesicles contain virus

a case of zoster may be the source of a chicken pox epidemic
explain survival of VARICELLA ZOSTER virus in small populations
a case of zoster can cause a chicken pox epidemic

latent/recurrent infection resultant transmission
Ab titers in patients recovered from zoster
VERY HIGH antiviral Ab titers
VARICELLA-ZOSTER Vaccine
live-attenuated vaccine is available and recommended for routine pediatric use

vaccine reduces clinical infections by 85% and reduces severe infections by 97%
CYTOMEGALOVIRUS (reason for name)
infected cells are much enlarged

and have nuclear inclusion
CYTOMEGALOVIRUS (primary infections)
before puberty-- usually subclinical

teens/adults-- mono-like syndrome (but with negative heterophile test)
CYTOMEGALOVIRUS (incubation period)
difficult to measure
probably bt 3-12 weeks
CYTOMEGALOVIRUS-caused mononucleosis-like syndrome

seen in:
primary cytomegalovirus infection

or as post-blood-transfusion complication
CYTOMEGALOVIRUS (transmission)
requires close contact

viruses excreted in naso-pharyngeal fluid, semen, urine, and vaginal secretions

breast milk (40% transmission by seropositive nursing moms, probably due to recurrent asymptomatic infection)

person-to-person transmission is common in nursery schools
CYTOMEGALOVIRUS (infection of nursing infants)
40% risk of infection by seropositive mothers who breast-feed for several months

infection of nursing infants general ASYMPTOMATIC
person-to-person transmission of this virus is common in nursery schools
CYTOMEGALOVIRUS
CONGENITAL INFECTION with CYTOMEGALOVIRUS
realtively common

symptoms of maternal infection are unknown (subclinical?)

spectrum of signs in sypmtomatic congenital disease:
a. microcephalic mental retardation with intracerebral calcifications
b. neuro-sensory deafness
c. jaundice, enlarged liver/spleen
d. anemia
incidence of symptomatic congenital cytomegalovirus infections in the US
~4,000/year

CMV is the most frequent viral congenital infection now that rubella vaccine has reduced the incidence of rubella
primary cause of congenital CMV
nearly all congenital malformations result from a primary maternal infection

however, fetal infection can follow either primary infection or (asymptomatic) recurrent viremia in a latently infected mom
immune response of fetus infected with CMV
makes anti-CMV IgM

after birth anti-CMV IgG is also made

virus excretion continues for years just as in congenital rubella
best method of CMV detection in neonates
urine
treatment of congenital CMV
neonates treated with ganciclovir have improved outcome:
test of hearing
resolution of hepatitis
and cognitive dvpt
CMV vaccine
live virus vaccine is being used experimentally
Recurrent disease caused by CMV is seen only when:
immune response is defective (immunosuppressive therapy, luekemia, Hodgkins disease, etc..)

such patients get generalized (sometimes fatal) infection (pneumonitis and hepatitis)
AIDS patients have higher incidence of what diseases caused by CMV?
retinitis and gastroenteritis
best treatment for all CMV infections
GANGICLOVIR

(acyclovir is not used for CMV infections)
CMV (in transplantation)
major problem in organ transplants when the donor is seropositive and the recipient is seronegative)

transplanted organ generally contains latently infected cells
EB [EPSTEIN-BARR] VIRUS
most common cause of infectious mononucleosis
MONONUCLEOSIS
disease of teenagers and young adults

infection in young children is subclincal

virus is probably transmitted primarily by saliva transfer during kissing
MONONUCLEOSIS (symptoms)
fever, sore throat, lymphadenopathy

incubation period is 4-6 weeks

acute HIV infection may closely mimic this clinical presentation
MONONUCLEOSIS (blood contains..)
"abnormal" lymphocytes

cytotoxic T-lymphocytes produced in high numbers to attack the circulating B-lymphocytes that are infected with EB virus
MONONUCLEOSIS (diagnostic test)
detects short term increase in heterophile Ab to sheep red cells

heterophile Ab is presumably induced by an EB virus antigen that happens to cross-react with sheep red cells

heterophile Ab does NOT neutralize EB virus
heterophile Ab
induced by an EB virus antigen

but does NOT neutralize EB virus

happens to cross-react with sheep red cells

provides a cheap diagnostic test for mononucleosis
What dose EB virus do to lymphocytes
"Transforms" lymphocytes making them into actively dividing cells

a rare human mutation blocks the cell-mediated immune response to EB virus (resulting in fatal lymphoproliferative disease)
fatal lymphoproliferative disease
caused by EB infection in individuals with a rare mutation that blocks the cell mediated immunse response to EB
proof that EB virus is the most common cause of mononucleosis
obtained by cohort analysis

(remember CMV also causes infectious mono, but with (-) Heterophile Ab Test)
compare antibody to EB with heterophile Ab
Ab to EB virus rises during course of infectious mononucleosis (patients seroconvert) Ab continues to be made

Whereas heterophile Ab rapidly disappears
Procedure equivalent to virus isolation of EB virus
virus-producing B-lymphocytes can be cultured during acute disease
Where is EB virus found?
Where is it produced?
When is it produced?
found in the saliva
probably produced by lymphoid cells in oro-pharynx
virus production may continue for months after the disease is over
Persons latently infected with EB
produce subclinical levels of virus production
oral hairy leucoplakia
one recurrent infection of EB virus

seen when immune response is compromised

common in AIDS patients

characterized by whitish patches on the tongue or buccal mucosa
consequences of latent EB virus in immunocompormised patients
lymphoproliferative disease that occurs when virus-transformed B cells grow uncontrolled and these can develop into tumors

and other EB virus-related malignancies
HUMAN HERPES VIRUS 6
causes a systemic infection with rash (roseola infantum) in infants

most infected infants do not get the rash, but do have a very high fever
HUMAN HERPES VIRUS-7
close relative of HUMAN Herpesvirus-6 and has not been firmly associated with any disease
HUMAN HERPES VIRUS-8
was recently discovered and is a probably cuase of Kaposi's sarcoma
HERPES SIMPLEX TYPE 1
(usual primary infection)
(usual recurrent infection)
Primary: subclinical or stomatitis

Recurrent: cold sore
HERPES SIMPLEX TYPE 2
(usual primary infection)
(usual recurrent infection)
Primary: subclinical or vesicles on genitalia

Recurrent: vesicles on genitalia
VARICELLA-ZOSTER
(usual primary infection)
(usual recurrent infection)
primary: chicken pox

recurrent: zoster (shingles)
CYTOMEGALOVIRUS
(usual primary infection)
(usual recurrent infection)
primary: usually subclinical but causes fetal malformation;

teenagers and older may get heterophile-negative mononucleusis

recurrent: oral hairy leukoplakia or tumors when immune response is compromised
why is selective chemical inhibition of viruses difficult?
they are dependent on their host cells for most biochemical rxns.
why do we have better chemotherapy for herpes viruses than for other virus groups?
viruses with larger genomes have more potential targets for drug therapy
mechanism of antivirals for herpesviruses
only inhibit virus replication, and therefore disease associated with replication

they do NOT eradicate the latent infection, or diseases associated with latency (eg tumors caused by EBV)
Acyclovir
best available durg for systemic infections with:
HERPES SIMPLEX VIRUS
or VARICELLA-ZOSTER

an analogue of deoxyguanosine (a nucleotide that is phosphorylated by herpes viral thymidine kinase, but not host thymidine kinase)

phosphorylated by herpes thymidine kinase and then converted by host cell enzymes to the triphosphate, which is incorporated into DNA and blocks further incorporation of nucleotides
ACYCLOVIR
treats: systemic infections with HERPES SIMPLEX or VARICELLA-ZOSTER viruses

mechanism: analogue of deoxyguanosine, phosphorylated by herpes thymidine kinase, but not host thymidine kinase

converted to chain-terminating triphosphate by host

bc host does not phosphorylate- only terminates DNA synthesis in herpes infected cells
GANCICLOVIR
treats: CMV infections

mechanism: related to acyclovir analog of deoxyguanosine, phosphorylated by herpes thymidine kinase, but not host thymidine kinase

converted to chain-terminating triphosphate by host

bc host does not phosphorylate- only terminates DNA synthesis in herpes infected cells
TRIFLURIDINE
useful for recurrent keratitis (infection of cornea) can be applied LOCALLY to the eye

mechanism: incorporated into DNA, causes lethal replication errors AND inhibits thymidylic acid synthestase of the host cell

cells of the cornea have a very small amount of DNA synthesis and thus are not affected by the drug CANNOT BE USED FOR SYSTEMIC HERPES INFECTIONS (more rapid rates of DNA synthesis and high thymidine kinase activity= sensitive to trifluridine)

recall that herpes simplex infection recurr at site of primary infection

if that site was the eye, recurrent keratitis will result- common cause of blindness
ADENINE ARABINOSIDE
mechanism: an analog of deoxyadenosine, phosphorylated by host cell enzymes to make adenine arbinoside triphosphate, incorporated into viral DNA by viral DNA polymerase, blocks further DNA synthesis (CHAIN TERMINATING ANALOGUE)

useful in HERPEs SIMPLEX ENCEPHALITIS and in some immunosuppressed patients with ZOSTER

largely supplanted by acyclovir
FOSCARNET
treats: (alternative to ganciclovir) for CMV infections

mechanism: analog of pyrophosphate
inhibitor of herpes DNA polymerase, has much less effect on DNA of human cells
AEROSOLIZED RIBAVIRIN
used to treat RSV pneumonia in infants

(efficacy uncertain)
ALPHA INTERFERON (for months)

Alpha interveron + Ribavirin
drug used to treat chronic hepatitis caused by HCV
ALPHA INTERFERON LAMUVINDINE
used to treat chronic heptatitis caused by HBV
AMANTIDINE [RIMANTIDINE]
used to treat INFLUENZA A (only A)
OSELTAMIVIR [zanamivir]
used to treat all influenza (A, B and C)
ACYCLOVIR
used to treat all severe primary infections with herpes simplex virus

also used prophlactically to reduce the incidence of recurrent herpes simplex infection, espeically genital and corneal (keratitis) lesions
TRIFLURIDINE or ACYCLOVIR
used to treat recurrent herpes simplex keratitis (non retinitis- note the anatomical difference)
why do we have better chemotherapy for herpes viruses than for other virus groups?
viruses with larger genomes have more potential targets for drug therapy
mechanism of antivirals for herpesviruses
only inhibit virus replication, and therefore disease associated with replication

they do NOT eradicate the latent infection, or diseases associated with latency (eg tumors caused by EBV)
Acyclovir
best available durg for systemic infections with:
HERPES SIMPLEX VIRUS
or VARICELLA-ZOSTER

an analogue of deoxyguanosine (a nucleotide that is phosphorylated by herpes viral thymidine kinase, but not host thymidine kinase)

phosphorylated by herpes thymidine kinase and then converted by host cell enzymes to the triphosphate, which is incorporated into DNA and blocks further incorporation of nucleotides
ACYCLOVIR
treats: systemic infections with HERPES SIMPLEX or VARICELLA-ZOSTER viruses

mechanism: analogue of deoxyguanosine, phosphorylated by herpes thymidine kinase, but not host thymidine kinase

converted to chain-terminating triphosphate by host

bc host does not phosphorylate- only terminates DNA synthesis in herpes infected cells
GANCICLOVIR
treats: CMV infections

mechanism: related to acyclovir analog of deoxyguanosine, phosphorylated by herpes thymidine kinase, but not host thymidine kinase

converted to chain-terminating triphosphate by host

bc host does not phosphorylate- only terminates DNA synthesis in herpes infected cells
TRIFLURIDINE
useful for recurrent keratitis (infection of cornea) can be applied LOCALLY to the eye

mechanism: incorporated into DNA, causes lethal replication errors AND inhibits thymidylic acid synthestase of the host cell

cells of the cornea have a very small amount of DNA synthesis and thus are not affected by the drug CANNOT BE USED FOR SYSTEMIC HERPES INFECTIONS (more rapid rates of DNA synthesis and high thymidine kinase activity= sensitive to trifluridine)

recall that herpes simplex infection recurr at site of primary infection

if that site was the eye, recurrent keratitis will result- common cause of blindness
ADENINE ARABINOSIDE
mechanism: an analog of deoxyadenosine, phosphorylated by host cell enzymes to make adenine arbinoside triphosphate, incorporated into viral DNA by viral DNA polymerase, blocks further DNA synthesis (CHAIN TERMINATING ANALOGUE)

useful in HERPEs SIMPLEX ENCEPHALITIS and in some immunosuppressed patients with ZOSTER

largely supplanted by acyclovir
FOSCARNET
treats: (alternative to ganciclovir) for CMV infections

mechanism: analog of pyrophosphate
inhibitor of herpes DNA polymerase, has much less effect on DNA of human cells
AEROSOLIZED RIBAVIRIN
used to treat RSV pneumonia in infants

(efficacy uncertain)
ALPHA INTERFERON (for months)

Alpha interveron + Ribavirin
drug used to treat chronic hepatitis caused by HCV
ALPHA INTERFERON LAMUVINDINE
used to treat chronic heptatitis caused by HBV
AMANTIDINE [RIMANTIDINE]
used to treat INFLUENZA A (only A)
OSELTAMIVIR [zanamivir]
used to treat all influenza (A, B and C)
ACYCLOVIR
used to treat all severe primary infections with herpes simplex virus

also used prophlactically to reduce the incidence of recurrent herpes simplex infection, espeically genital and corneal (keratitis) lesions
TRIFLURIDINE or ACYCLOVIR
used to treat recurrent herpes simplex keratitis (non retinitis- note the anatomical difference)
all severe varicella-zoster virus infections can be treated with
acyclovir
all severe CMV infecetions (mostly in immunosuppressed patients) can be treated with
ganciclovir or goscarnet
acyclovir-resisitant herpes simple or varicella-zoster virus infections can be treated with
foscarnet