Which viral enzyme is responsible for activating Acyclovir?
Contributors:Tanner Marshall, MS, Evan Debevec-McKenney, Maria Emfietzoglou, Ursula Florjanczyk, MScBMC
Anti-herpes medications are a group of antiviral agents that treat herpes infections including herpes simplex virus, or HSV, but they can also treat other viral infections like varicella zoster virus, or VZV, and cytomegalovirus, or CMV.
They act by inhibiting viral DNA synthesis and thus, inhibiting viral proliferation.
Alright, now let’s start with HSV, which infects skin and mucosal epithelial cells.
There are two types of HSV, HSV1 and HSV2.
Generally speaking, HSV1 tends to cause infections “above the waist” mostly involving the lips, or labia, which is referred to as herpes labialis, and the mouth and the gingiva, which is called gingivostomatitis.
On the other hand, HSV2 tends to cause infections “below the waist” affecting the genital organs, which is referred to as herpes genitalis.
HSV can also pass from a mother to a baby usually when the baby passes through the infected maternal vaginal secretions and can cause severe neonatal infections.
The typical presentation of a herpes infection is clusters of small, painful, fluid-filled blisters, that ooze and ulcerate. They eventually heal after a few weeks.
However, HSV also infects the nearby sensory neurons, which aren’t destroyed, but instead, they become a permanent home for the herpes virus. This is referred to as the latent phase of the infection and is typically asymptomatic.
From time to time, the herpes virus from the sensory neurons make a few viral copies of itself which can get released and infect the epithelial cells.
Alright, now let’s move on to varicella zoster virus. VZV causes a primary infection called varicella or chickenpox, which is characterized by a rash on the scalp, face, and trunk that contains macules, papules, vesicles, and scabs at the same time.
Now, from the neurons in the skin, VZV travels retrogradely to the nerve ganglia, where it remains dormant.
It can then travel back up through the sensory nerves, anterogradely to the skin and cause an infection in the innervated dermatome - that’s called herpes zoster or shingles.
Now, let’s talk a bit about cytomegalovirus. CMV causes mononucleosis, commonly known as “mono,” which presents with sore throat, fever, lymphadenopathy, malaise, headache, and resolves over a few weeks.
Now, in immunocompromised individuals, CMV can cause more severe infections including pneumonia, esophagitis, and retinitis which can lead to vision loss.
CMV can also pass from a mother to a baby via the placenta causing a potentially life-threatening congenital infection.
Alright, now depending on their mechanism of action, anti-herpes medications can be divided into two categories: the guanosine analogs, and the viral DNA polymerase inhibitors.
Once they’re inside an infected cell, they get phosphorylated to a monophosphate form by a viral enzyme, which is called viral kinase.
For example, acyclovir is converted to the acyclovir monophosphate by the viral thymidine kinase, while ganciclovir is initially phosphorylated by the enzyme UL-97 kinase, which is found in CMV infected cells.
Next, the monophosphate form is phosphorylated twice to the active triphosphate form by cellular enzymes.
This triphosphate form acts as a guanosine analog which means that it’s similar in structure with the normal guanosine nucleotide.
When this analog is inserted into the replicating viral DNA, it causes the growing DNA chain to terminate and DNA synthesis is halted.
Okay, now resistance to these medications can be developed if there is a mutated form of the viral kinase which won’t phosphorylate the medication.
Alright, now let’s move on to indications. Acyclovir is active against HSV and VZV.
When it’s used orally it’s only partially absorbed and so oral acyclovir is used for mild mucocutaneous lesions and genital lesions or for herpes prophylaxis in immunocompromised individuals such as individuals with AIDS.
Now, intravenous acyclovir is the treatment of more severe herpes infections, such as HSV encephalitis.
Acyclovir has no effect on latent forms of HSV and VZV.
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