Herpes linked to Alzheimer's: Antivirals may help

A new commentary by scientists at the Universities of Manchester and Edinburgh on a study by Taiwanese epidemiologists supports the viability of a potential way to reduce the risk of Alzheimer's disease.

When the Taiwanese authors looked at subjects who suffered severe herpes infection and who were treated aggressively with antiviral drugs, the relative risk of dementia was reduced by a factor of 10.

Manchester's Professor Ruth Itzhaki and Edinburgh's Professor Richard Lathe say the paper, by Tzeng et al. and published in Neurotherapeutics in February 2018, also shows that herpes simplex virus type 1 (HSV1) leads to an increased risk of developing the disease.

"This article and two others by different research groups in Taiwan provide the first population evidence for a causal link between herpes virus infection and Alzheimer's disease, a hugely important finding," said Professor Itzhaki.

They publish a commentary in the Journal of Alzheimer's Disease on the three articles, arguing that they provide the strongest evidence yet for a causal link between herpes infection and Alzheimer's disease, backing 30 years of research by Professor Itzhaki.

Professor Itzhaki said: "I believe we are the first to realise the implications of these striking data on this devastating condition which principally affects the elderly. No effective treatments are yet available.

"Almost 30 million people worldwide suffer from it and sadly, this figure will rise as longevity increases.

"But we believe that these safe and easily available antivirals may have a strong part to play in combating the disease in these patients.

"It also raises the future possibility of preventing the disease by vaccination against the virus in infancy.

"Successful treatment by a specific drug, or successful vaccination against the putative microbe, are the only ways to prove that a microbe is the cause of a non- infectious human disease."

Most Alzheimer's disease researchers investigate its main characteristics -- amyloid plaques and neurofibrillary tangles; however, despite the vast amount of research, the causes of their formation are unknown.

HSV1 infects most humans in youth or later and remains lifelong in the body in dormant form within the peripheral nervous system.

From time to time the virus becomes activated and, in some people, it then causes visible damage in the form of cold sores.

The Taiwanese study identified 8,362 subjects aged 50 or more during the period January to December 2000 who were newly diagnosed with severe HSV infection.

The study group was compared to a control group of 25,086 people with no evidence of HSV infection.

The authors then monitored the development of dementia in these individuals over a follow-up period of 10 years between 2001 and 2010.

The risk of developing dementia in the HSV group was increased by a factor of 2.542. But, when the authors compared those among the HSV cohort who were treated with antiviral therapy versus those who did not receive it, there was a dramatic tenfold reduction in the later incidence of dementia over 10 years.

Professor Richard Lathe added: "Not only is the magnitude of the antiviral effect remarkable, but also the fact that -- despite the relatively brief duration and the timing of treatment -- in most patients severely affected by HSV1 it appeared to prevent the long-term damage in brain that results in Alzheimer's.

Professor Itzhaki said: "It was as long ago as 1991 when we discovered that, in many elderly people infected with HSV1, the virus is present also in the brain, and then in 1997 that it confers a strong risk of Alzheimer's disease in the brain of people who have a specific genetic factor.

"In 2009, we went on to show that HSV DNA is inside amyloid plaques in Alzheimer's patients' brains.

"We suggested that the virus in brain is reactivated by certain events such as stress, immunosuppression, and infection/inflammation elsewhere.

"So we believe the cycle of HSV1 reactivation in the brain eventually causes Alzheimer's in at least some patients."

Source: https://www.sciencedaily.com/releases/2018/07/180712100515.htm

A new class of drug to treat herpes simplex virus infection

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.

Source: https://www.sciencedaily.com/releases/2018/02/180215110339.htm