Transcript Zovirax

What is the difference
between HSV-1 and HSV-2?
• Both types infect the body’s mucosal surfaces,
usually mouth or genitals, and then establish latency
in the nervous system.
• For both types, at least two-thirds of the infected
people have no symptoms, or symptoms too mild to
notice.
• However, both types can recur and spread, even
after a period in which there were no symptoms.
The differences
• HSV-1 usually establishes latency in the
trigeminal ganglion, a collection of nerve
cells near the ear. Then it tends to
recur on the lower lip or face.
• HSV-2 usually establishes latency in
sacral ganglion at the base of the spine.
From there, it recurs in the genital area.
HSV-1
• However, one can have HSV-1 both genitally and
orally.
• HSV-1 is usually mild, especially when it infects the
lips, face, or genitals.
• However, HSV-1 can recur in the eye, causing ocular
herpes, which can lead to blindness, and can even
spread spontaneously to the brain, causing herpes
encephalitis, which can lead to death.
HSV-2
• 22% of adult Americans have HSV-2
• Like HSV-1, HSV-2 symptoms are usually
mild, so mild, in fact, that two-thirds of
infected people don’t know they have it.
• HSV-2 rarely causes complications or
spreads to other parts of the body.
• Oral HSV-2 infections are rare. But even
when an infection does occur, recurrent oral
outbreaks are uncommon.
Transmission of HSV-2
• In the first year of HSV-2 infection, people shed the
virus from the genital area about 6 to 10% of those
days when they are asymptomatic. This decreases
over time and can also be further lessened by the
use of oral medication. Sex should be avoided in the
presence of symptomatic lesions.
• Having a previous HSV-1 infection seems to provide
some immunity to an HSV-2 infection. This is
probably the reason that oral HSV-2 infections are
rare, given the studies which show that a significant
proportion of the population practices oral sex.
How severe an infection?
• HSV is a lifelong illness
• But HSV-2 usually produces only mild symptoms or
signs or no symptoms at all. However, HSV-2 can cause
recurrent painful genital sores in many adults, and HSV2 infection can be severe in people with suppressed
immune systems.
• Another factor is how long a person has had the
infection. It seems to decrease in severity over time,
for reasons which are unclear.
Symptoms
• If signs and symptoms occur during the
first episode, they can be quite
pronounced. The first episode usually
occurs within two weeks after the virus
is transmitted, and the sores typically
heal within two to four weeks.
• Other signs and symptoms during the
primary episode may include a second
crop of sores, or flu-like symptoms,
including fever and swollen glands.
Is there a cure?
• There is no treatment that can
cure herpes, but antiviral
medications can shorten and
prevent outbreaks during the
period of time the person takes the
medication.
Vaccines?
• NIH is now in the midst of Phase III
clinical trial of an HSV-2 vaccine. This
vaccine appears to be about 50%
effective.
• If approved, it would be available in
2008.
Antiviral Chemotherapy for HSV
• There are several prescription antiviral
medications for controlling herpes outbreaks,
include acyclovir (Zovirax), valacyclovir
(Valtrex), famcyclovir (Famvir), and
pencyclovir.
• Acyclovir was the original and prototypical
member of this class
• Valacyclovir and famcyclovir are prodrugs of
acyclovir and pencyclovir respectively, with
improved oral bioavailability.
Chemotherapy for HSV
O
O
HN
N
N
H2N
N
N
H2N
N
HN
N
H2N
HO
O
O
O
O
Acyclovir (Zovirax)
Valacyclovir (Valtrex),
O
N
HN
H2N
O
N
HN
N
N
HO
H2N
N
N
AcO
OH
OAc
pencyclovir
Famcyclovir (Famvir),
Mechanism of Action of
Antivirals to treat HSV
• Both acyclovir and pencyclovir work by
interfering with viral replication, effectively
slowing the replication rate of the virus, and
providing a greater opportunity for the
immune response to intervene.
• All drugs in this class depend on the activity
of the viral thymidine kinase to convert the
drug to a monophosphate form and
subsequently interfere with viral DNA
replication.
DNA Virus
• Recall that HSV is a DNA virus (influenza was an
RNA virus)
• In general, more drugs are available to treat DNA
viruses than for RNA viruses (excluding those used to
treat HIV).
• Most of the drugs available for treatment of DNA
viruses have been developed against herpesviruses.
• Diseases include cold sores, genital herpes,
chickenpox, shingles, mononucleosis, etc.
Acyclovir (ZOVIRAX)
• Discovered by random compound
screening and introduced into the
market in 1981.
• It was the first non-toxic herpes drug to
be used systemically.
• It is used for the treatment of infections
due to both HSV-1 and HSV-2.
http://www.cat.cc.md.us/biotut
orials/dna/dnareppr.html
• http://www.dnalc.org/ddnalc/resources/s
angerseq.html
• Aciclovir interferes with DNA synthesis, but must first become activated.
•To become activated, Aciclovir must be phosphorylated (3x)
• However, Aciclovir itself is not a good substrate for mammalian kinases,
thus it relies on the viral thymidine kinase to become phosphorylated the
first time.
• This is good, since the drug cannot interfere with DNA synthesis in cells
that are not infected with the virus, thus reducing the toxicity of the drug.
• The second and third phosphorylations, however, are performed by the
cellular thymidylate kinase.
•Aciclovir triphosphate is mistaken for
deoxyguanosine triphosphate.
• However, since it lacks the 3’-OH
group, it cannot be linked to the
adjacent residue in the ‘usual’
fashion.