For patients with
the herpes simplex-1 virus (HSV-1),
there are just a handful of drugs available to treat the painful condition that
can affect the eyes, mouth and genitals.If patients develop resistance to these drugs, there are
even fewer choices left to treat the infection, which lasts for life.
Researchers at the University of Illinois at Chicago have
now identified a small drug molecule that can clear the HSV-1
infection in the cells of the cornea -- the clear outer layer of the eyeball --
and works completely differently than the currently-available drugs, making it
a promising potential option for patients who have developed resistance.
The researchers believe the drug could be equally
effective in treating HSV-1 in the
mouth and HSV-2 -- which primarily affects the genitals -- and possibly even
other viral infections like HIV. The findings are reported in the journal Science
Translational Medicine.
HSV-1 is one
of the most common human pathogens, affecting between 50 percent and 90 percent
of people worldwide. HSV-1 primarily infects the mouth and eyes, although
genital cases of HSV-1 infection are on the rise. The virus is transmitted
through bodily fluids. It establishes a lifelong infection that leads to sores
in affected tissues when active and hides in nerve cells during its latent
phase. The infection can be temporarily eliminated in the eye using oral and
topical antiviral drugs, but inflammation of the cornea can persist
indefinitely, requiring ongoing treatment with steroid-based eye drops. HSV-1
infection is a leading cause of infectious blindness in the U.S.
Currently available drugs to treat HSV-1
infection work by preventing the virus from producing the proteins it needs to
replicate and are known as nucleoside analogs. Resistance is a significant
problem with the ongoing use of nucleoside analogs, which when applied
topically to the eye can cause serious side effects including glaucoma.
"We have needed alternative drugs that work on new
targets for a very long time because patients who develop resistance to
nucleoside analogs have very few good options for treating their
infection," said Deepak Shukla, the Marion Schenk Professor of
Ophthalmology and professor of microbiology and immunology in the UIC College
of Medicine, and corresponding author on the paper. "We have found a
molecule that works in a totally novel fashion. Instead of working on the
virus, it works in the host cells and helps them to clear the virus."
Shukla and colleagues discovered that a small drug
molecule called BX795, which is sold to labs for use in experiments, helped
clear HSV-1
infection in cultured human corneal cells, in donated human corneas, and in the
corneas of mice infected with HSV-1.
The researchers were quite surprised by their finding
because BX795 is known as an inhibitor of TBK1, an enzyme involved in innate
immunity and neuroinflammation. When TBK1 is suppressed in cells, infection
is actually promoted. But when the researchers added higher concentrations of
BX795 to cultured human corneal cells infected with HSV-1, the infection was
quickly cleared. They had the same result in intact human corneas, and in mice
whose eyes had been infected with HSV-1.
"This isn't what we expected," said Tejabhiram
Yadavalli, a postdoctoral fellow studying herpes virus at UIC and a co-author
of the paper. "Instead of promoting infection, at higher concentrations,
BX795 actually helped cells clear the infection."
Additionally, the concentration of BX795 needed to clear HSV-1
infection is quite low.
"We saw clearance of the virus at concentrations of
BX795 that were five times lower than concentrations of antiviral compounds in
available nucleoside analogs," Shukla said.
The researchers also found that BX795 only worked in
cells infected with the HSV-1
virus.
"There was no discernible toxicity or negative side
effects at therapeutic concentrations in cells that are not infected with the
virus," Shukla said.
"Because BX795 targets a common pathway that many
viruses use to replicate inside the cell, it could be a new kind of
broad-spectrum antiviral that might be used to treat other viral infections,
including HSV-2,
which primarily affects the genitals, and HIV, although we have not yet tested
it on viruses other than HSV-1."
"It will be very exciting to see if the study can
move to a clinical trial soon," said Alex Agelidis, a graduate student at
UIC and co-author on the paper. "Because of BX795's low toxicity, it has a
great potential for systemic use as well as topical application."
Dinesh Jaishankar, Abraam Yakoub, Alex Agelidis, Neel
Thakkar, Satvik Hadigal and Joshua Ames, from the University of Illinois at
Chicago, are co-authors on the paper.
This work was supported by grant R01 EY024710 from the
National Eye Institute.
