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.

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-1

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 HSV- 2 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 Acyclovir (Zovirax) Valacyclovir (Valtrex), pencyclovirFamcyclovir (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 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.

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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.