Tag: herpes simplex

Categories : Diseases, Syndromes and ConditionsTags : Leave a comment

New Antivirals Could Help Prevent HSV-1 by Changing Cell Structures

On By ModernMedia

Lab tests confirm that antiviral class known as Pin1 inhibitors could reduce and stop outbreaks of herpes simplex virus-1

Photo by Cottonbro on Pexels

A class of antivirals called Pin1 inhibitors could reduce or stop outbreaks of herpes simplex virus 1 (HSV-1), the common infection behind oral herpes, according to new research published in Antiviral Research.

HSV-1 causes sores around the mouth, commonly called cold sores or fever blisters. Most people are infected with HSV-1 in childhood, and between 50% and 90% of people worldwide have HSV-1. After the initial infection, HSV-1 remains in the body and can reactivate throughout a person’s life. While HSV-1 infections are usually mild, they can be serious and even deadly for people with suppressed immune systems. Finding new, more effective antivirals for this common illness is essential. 

Pin1 inhibitors suppress HSV-1 replication by inhibiting viral protein synthesis and preventing nucleocapsid egress from the nucleus. (Takemasa Sakaguchi/Hiroshima University)

Researchers focused on an enzyme called peptidyl-prolyl cis-trans isomerase NIMA-interacting 1, or Pin1, that regulates protein stability, function, and cellular structure. When this enzyme is dysregulated, it can play a role in a variety of conditions, including obesity, cancer, heart failure, and more. Viruses, such as cytomegalovirus (CMV) and SARS-CoV-2, are known to affect Pin1, and Pin1 inhibitors have been developed to reduce the impact of these viruses. 

Because HSV-infected cells over-express Pin1, researchers wanted to know if Pin1 inhibitors could also be used to treat HSV-1. “This study revealed that the host factor Pin1 is a crucial therapeutic target for the proliferation of HSV-1. Pin1 inhibitors potently suppress HSV-1 replication at low concentrations,” said Takemasa Sakaguchi, a professor at the Graduate School of Biomedical and Health Sciences at Hiroshima University in Hiroshima, Japan. 

In laboratory tests, the Pin1 inhibitor H-77 and the four newly developed Pin1 inhibitors successfully stopped the replication of HSV-1. VeroE6 cells, derived from the kidney of an African green monkey and commonly used in virology research, were infected with HSV-1 and cultured in the presence of different amounts of a Pin1 inhibitor. As the amount of the inhibitor increased, the effects of HSV-1 on the cells became less pronounced and completely disappeared at 1 μM. They also found that any viral particles released from the treated cells were non-infectious. 

The most important finding is how Pin1 inhibitors affect cell structures to prevent the virus from escaping. They do this by stabilising nuclear membrane structure, physically trapping the virus in the cell nucleus. “The nuclear lamina initially functions as a ‘barrier’ when nucleocapsids of progeny viruses, that replicate within the nucleus, bud from the nuclear membrane. Pin1 overexpressed by the virus removes this barrier. However, through the action of the Pin1 inhibitor H-77, this barrier is rather reinforced, forming a thick and robust lamina layer. This demonstrates that H-77 transforms the nuclear lamina into an ‘impregnable defensive wall,’ physically blocking the escape of viruses from the nucleus of the cell,” said Sakaguchi.

Looking ahead, researchers will continue to evaluate the effectiveness of Pin1 inhibitors to treat HSV-1. They will also research how Pin1 inhibitors could be used to treat other viruses. “The ultimate goal for the future is to aim for the clinical application of Pin1 inhibitors as ‘host-directed therapeutics,’ which are less likely to cause drug resistance. To achieve this, we will first evaluate their efficacy against diverse viruses to clarify the treatable range. Simultaneously, research to optimise the compound structure is essential for creating more potent and selective drugs,” said Sakaguchi. 

Source: University of Hiroshima

Categories : Neurodegenerative DiseasesTags :

The Hidden Connection Between Herpes and Alzheimer’s

On By ModernMedia

A new study has uncovered a surprising link between Alzheimer’s disease and Herpes Simplex Virus-1 (HSV-1).

Neurons in the brain of an Alzheimer’s patient, with plaques caused by tau proteins. Credit: NIH

A new study led by Dr Or Shemesh at the Hebrew University of Jerusalem has uncovered a surprising connection between Alzheimer’s disease and the Herpes Simplex Virus-1 (HSV-1). The research team used advanced techniques to identify 19 HSV-1-related proteins in the brains of people with Alzheimer’s, across all stages of the disease. This discovery, published in Cell Reports, strengthens the growing evidence that infections like HSV-1 might play a role in the development and progression of Alzheimer’s.

One key finding was the increased activity of a herpesvirus protein called ICP27, which became more prominent as the disease advanced. This protein was found to occupy the same space as tau, a brain protein that becomes harmful when it undergoes changes in Alzheimer’s disease, but it did not appear near amyloid plaques, another hallmark of the illness. This suggests that HSV-1 may directly affect tau and contribute to the changes seen in Alzheimer’s.

The team’s experiments with human brain organoids derived from stem cells revealed that HSV-1 infection can increase tau modifications at specific sites linked to Alzheimer’s disease.

Remarkably, these modifications seem to help protect brain cells early on by reducing the amount of virus and preventing cell death. However, as the disease progresses, these same processes may contribute to the brain damage associated with Alzheimer’s. The study also highlighted the role of Alzheimer’s pathologies as part of the brain’s natural immune system in this process, focusing on a pathway called cGAS-STING, which influences tau changes.

Dr Shemesh explained, “Our research shows how HSV-1 interacts with the brain and influences the pathologies of Alzheimer’s disease. Early on, the changes in tau may protect brain cells by limiting the virus, but as the disease advances, these same changes could lead to more harm and accelerate neurodegeneration.”

This study provides new insights into how infections and the brain’s immune response may be involved in Alzheimer’s disease. It suggests that targeting viral activity or modifying the immune system’s response could offer new treatment possibilities. While more research is needed to fully understand these processes, these findings open the door to innovative ways to slow or stop the progression of this devastating disease.

The research paper titled “Anti-Herpetic Tau Preserves Neurons vis the cGAS-STING-TBK1 Pathway in Alzheimer’s Disease” is now available in Cell Reports and can be accessed at https://www.cell.com/cell-reports/fulltext/S2211-1247(24)01460-8 

Source: The Hebrew University of Jerusalem

Categories : Diseases, Syndromes and ConditionsTags :

Cold Sore Discovery Reveals an Unexpected Trigger for Flare-ups

On By ModernMedia
Photo by Cottonbro on Pexels

Scientists have a new target to prevent cold sores after University of Virginia researchers discovered an unexpected way the herpes virus re-activates in the body. The finding, published in PNAS, could also have important implications for genital herpes caused by the same virus.

The discovery from UVA’s Anna Cliffe, PhD, and colleagues seems to defy common sense. She and her team found that the slumbering herpes virus will make a protein to trigger the body’s immune response as part of its escape from dormancy. You’d think this would be bad for the virus – that activating the body’s antiviral defences would be like poking a bear. But, instead, it’s the opposite: The virus hijacks the antiviral process in infected neurons to make the type of comeback nobody wants.

“Our findings identify the first viral protein required for herpes simplex virus to wake up from dormancy, and, surprisingly, this protein does so by triggering responses that should act against the virus,” said Cliffe of UVA’s Department of Microbiology, Immunology and Cancer Biology. “This is important because it gives us new ways to potentially prevent the virus from waking up and activating immune responses in the nervous system that could have negative consequences in the long term.”

Herpes Simplex Virus-Associated Disease

Cold sores are caused primarily by herpes simplex virus 1 (HSV-1), one of two forms of the herpes virus. HSV-1 is very contagious, and worldwide more than 60% of people under 50 (more than 3.8 billion) have been infected, the World Health Organization estimates.

In addition to causing cold sores, herpes simplex virus 1 can also cause genital herpes, a condition most often associated with HSV-1’s cousin, herpes simplex virus 2. Now, however, there are more new cases of genital herpes in the United States caused by HSV-1 than HSV-2. Notably, the UVA researchers found that herpes simplex virus 2 also makes this same protein and may use a similar mechanism to reactivate. So UVA’s new discovery may also lead to new treatments for genital herpes. 

In addition to cold sores and genital herpes, HSV-1 can also cause viral encephalitis (brain inflammation) and has been linked to the development of Alzheimer’s disease.

Once HSV-1 makes its way into our bodies, it stays forever. Our immune systems can send it into hiding, allowing infected people to be symptom free. But stress, other infections and even sunburns are known to cause it to flare. UVA’s new discovery adds another, surprising way it can spring back into action.

The researchers found that while the virus can make a protein called UL12.5 to reactivate, the protein was not needed in the presence of another infection. The scientists believe this is because the infections trigger certain “sensing pathways” that act as the home security system for neurons. Detection of a pathogen alone may be sufficient to trigger the herpes virus to begin replicating, the scientists believe, even in instances of “abortive infections” – when the immune system contains the new pathogen before it can replicate.

“We were surprised to find that HSV-1 doesn’t just passively wait for the right conditions to reactivate – it actively senses danger and takes control of the process,” researcher Patryk Krakowiak said. “Our findings suggest that the virus may be using immune signals as a way to detect cellular stress – whether from neuron damage, infections or other threats – as a cue to escape its host and find a new one.” 

With the new understanding of how herpes flares can be triggered, scientists may be able to target the protein to prevent them, the researchers say. 

“We are now following up on this work to investigate how the virus is hijacking this response and testing inhibitors of UL12.5 function,” Cliffe said. “Currently, there are no therapies that can prevent the virus from waking up from dormancy, and this stage was thought to only use host proteins. Developing therapies that specifically act on a viral protein is an attractive approach that will likely have fewer side effects than targeting a host protein.” 

Source: University of Virginia Health System

Categories : Immune System NeurologyTags :

How the Brain Protects Itself Against Herpes Simplex Virus

On By ModernMedia
Source: CC0

More than half of us are carriers of chronic herpesvirus infections. But even though the herpes simplex virus can infect nerve cells, it rarely causes serious infection of the brain. Researchers from Aarhus University have now discovered a key element of the explanation.

The researchers have discovered a previously unknown defence mechanism in the body that is the reason why herpes infection causes a serious and potentially fatal brain inflammation in only one out of 250 000 cases. The study has recently been published in the scientific journal Nature.

“The study has exciting perspectives because it gives us a better understanding of how the brain defends itself against viral infections,” says Professor Søren Riis Paludan from the Department of Biomedicine at Aarhus University. He is the article’s last author, a Lundbeck Foundation Professor and centre director of the Excellence Centre CiViA.

“We’ve discovered how our body prevents herpesvirus from entering into the brain, even though 50–80% of us are chronically infected with this particular virus. The idea behind CiViA is that we want to understand how the body fights infections without harming itself at the same time. The mechanism we’ve found doesn’t cause inflammatory reactions,” he says.

The answer lies in the protective TMEFF1 gene.

The brain uses a novel mechanism to keep the virus out

Many years of experimenting with the genome-wide CRISPR screening technology and development of mice that lacked the critical gene have finally convinced the researchers that TMEFF1 produces a protein that prevents herpesvirus from entering into nerve cells.   

The study in Nature is accompanied by another article describing two patients with brain inflammation caused by herpesvirus infection, called herpes encephalitic. In a collaborative study led by researchers in New York, the research group in Aarhus discovered that two children who developed herpes encephalitis were carrying a genetic defect that disabled the protective TMEFF1 gene.

“The new study is groundbreaking because it updates the basic understanding of immunity against viral infections,” explains Søren Riis Paludan.

 “This is interesting for immunologists because it illustrates that there are still many immunological mechanisms in the brain that we don’t know about. “The study is also relevant for neuroscience because it sheds light on how the brain, so to say, prevents unwanted visitors from intruding without causing harm to the brain itself, i.e. the neuronal cells,” he says.

May provide a better understanding of Alzheimer’s

Søren Riis Paludan hopes that the study is the first step towards revealing a completely new range of brain defence mechanisms. One of the tracks that the researchers will now investigate is what the discovery may mean for the development of dementia.

Research has already demonstrated a correlation between infection with herpesviruses and later development of Alzheimer’s disease.

“Perhaps our discovery of a new antiviral mechanism in the brain can help to clarify whether individual differences in this particular mechanism or similar mechanisms can give the virus access to the brain and accelerate neurodegenerative processes,” says Søren Riis Paludan.

Source: Aarhus University