Research pinpoints key to the cold sore virus’s ability to evade treatment, offering broader clues on antiviral drug resistance
A 3D representation of a herpes simplex virus enzyme involved in viral replication.
« What Enables Herpes Simplex Virus To Become Impervious to Drugs?
Credit: Jonathan Abraham Lab/HMS
Newswise — All organisms — from fungi to mammals — have the capacity to evolve and adapt to their environments. But viruses are master shapeshifters with an ability to mutate greater than any other organism. As a result, they can evade treatments or acquire resistance to once-effective antiviral medications.
Is the Herpes Simplex Virus Becoming Impervious to Drugs?
Working with herpes simplex virus (HSV), a new study led by Harvard Medical School researchers sheds light on one of the ways in which the virus becomes resistant to treatment, a problem that could be particularly challenging among people with compromised immune function, including those receiving immune-suppressive treatment and those born with immune deficiencies.
Using a sophisticated imaging technique called cryogenic electron microscopy (cryo-EM), the researchers found that how parts of a protein responsible for viral replication move into different positions can alter the virus’s susceptibility to medicines.
The findings, published Aug. 27 in Cell, answer long-standing questions about why certain viruses, but not others, are susceptible to antiviral medications and how viruses become impervious to drugs. The results could inform new approaches that impede viruses’ capacity to outpace effective therapies.
Counterintuitive results
Researchers have long known changes that occur on the parts of a virus where antiviral drugs bind to it can render it resistant to therapy. However, the HMS researchers found that, much to their surprise, this was often not the case with HSV.
Instead, the investigators discovered that protein mutations linked to drug resistance often arise far from the drug’s target location. These mutations involve alterations that change the movements of a viral protein, or enzyme, that allows the virus to replicate itself. This raises the possibility that using drugs to block or freeze the conformational changes of these viral proteins could be a successful strategy for overcoming drug resistance.
“Our findings show that we have to think beyond targeting the typical drug-binding sites,” said the study’s senior author, Jonathan Abraham, associate professor of microbiology in the Blavatnik Institute at HMS and infectious disease specialist at Brigham and Women’s Hospital. “This really helps us see drug resistance in a new light.”
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The new findings propel the understanding of how alterations in the conformation of a viral protein — or changes in how the different parts within that protein move when it carries out its function — fuel drug resistance and may be relevant for understanding drug effectiveness and drug resistance in other viruses, the researchers noted.
HSV, estimated to affect billions of people worldwide, is most commonly known as the cause of cold sores and fever blisters, but it can also lead to serious eye infections, brain inflammation, and liver damage in people with compromised immunity. Additionally, HSV can be transmitted from mother to baby via the birth canal during delivery and cause life-threatening neonatal infections.
Clues on resistance rooted in structure and movement
A virus can’t replicate on its own. To do so, viruses must enter a host cell, where they unleash their replication tools — proteins called polymerases — to make copies of themselves.
The current study focused on one such protein — a viral DNA polymerase — crucial for HSV’s ability to reproduce and propagate itself. The ability to carry out its function is rooted in the DNA polymerase’s structure, often likened to a hand with three parts: the palm, the thumb, and the fingers, each carrying out critical functions.
Given their role in enabling replication, these polymerases are critical targets of antiviral drugs, which aim to stop the virus from reproducing itself and halt the spread of infection. The HSV polymerase is the target of acyclovir, the leading antiviral drug for treating HSV infection, and of foscarnet, a second-line drug used for drug-resistant infections. Both drugs work by targeting the viral polymerase but do so in different ways.
Scientists have long struggled to fully understand how alterations in the polymerase render the virus impervious to normal doses of antiviral drugs and, more broadly, why acyclovir and foscarnet are not always effective against the altered forms of the HSV polymerase.
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“Over the years, the structures of many polymerases from various organisms have been determined, but we still don’t fully understand what makes some polymerases, but not others, susceptible to certain drugs,” Abraham said. “Our study reveals that how the different parts of the polymerases move, known as their conformational dynamics, is a critical component of their relative susceptibility to drugs.”
Proteins, including polymerases, are not rigid, motionless objects. Instead, they are flexible and dynamic.Composed of amino acids, they initially fold into a steady, three‐dimensional shape known as the native conformation — their baseline structure. But as a result of various bonding and dispersing forces, the different parts of proteins can move when they come into contact with other cellular components as well as through external influences, such as changes in pH or temperature. For example, the fingers of a polymerase protein can open and close, as would the fingers of a hand.
Conformational dynamics — the ability of different parts of a protein to move — allow them to efficiently administer many essential functions with a limited number of ingredients. A better understanding of polymerase conformational dynamics is the missing link between structures and functions, including whether a protein responds to a drug and whether it could become resistant to it down the road.
Unraveling the mystery
Many structural studies have captured DNA polymerases in various distinct conformations. However, a detailed understanding of the impact of polymerase conformational dynamics on drug resistance is lacking. To solve the puzzle, the researchers carried out a series of experiments, focusing on two common polymerase conformations — an open one and a closed one — to determine how each affects drug susceptibility.
First, using cryo-EM, they conducted structural analysis to get high-resolution visualizations of the atomic structures of HSV polymerase in multiple conformations, as well as when bound to the antiviral drugs acyclovir and foscarnet. The drug-bound structures revealed how the two drugs selectively bind polymerases that more readily adopt one conformation versus another. One of the drugs, foscarnet, works by trapping the fingers of the DNA polymerase so that they are stuck in a so-called closed configuration.
Further, structural analysis paired with computational simulations suggested that several mutations that are distant from the sites of drug binding confer antiviral resistance by altering the position of the polymerase fingers responsible for closing onto the drug to halt DNA replication.
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The finding was an unexpected twist. Up until now, scientists have believed that polymerases closed partially only when they attached to DNA and closed fully only when they added a DNA building block, a deoxynucleotide. It turns out, however, that HSV polymerase can fully close just by being near DNA. This makes it easier for acyclovir and foscarnet to latch on and stop the polymerase from working, thus halting viral replication.
“I’ve worked on HSV polymerase and acyclovir resistance for 45 years. Back then I thought that resistance mutations would help us understand how the polymerase recognizes features of the natural molecules that the drugs mimic,” said study co-author Donald Coen, professor of biological chemistry and molecular pharmacology at HMS. “I’m delighted that this work shows that I was wrong and finally gives us at least one clear reason why HSV polymerase is selectively inhibited by the drug.”
Authorship, funding, disclosures
Additional authors included Sundaresh Shankar, Junhua Pan, Pan Yang, Yuemin Bian, Gábor Oroszlán, Zishuo Yu, Purba Mukherjee, David J. Filman, James M. Hogle, Mrinal Shekhar.
This work was supported by the National Institutes of Health (awards R21 AI141940 and R01 AI19838), with additional funding from a Centers for Integrated Solutions in Infectious Diseases grant.
What Enables Herpes Simplex Virus To Become Impervious to Drugs?
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(Family Features) Many people don’t think much about whether their blood is clotting properly. However, when you have a bleeding disorder, a condition that affects the way your body controls clots, it’s no small matter.
According to the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health, abnormal clotting can lead to a host of problems, including excessive bleeding after an injury or during surgery.
About 3 million people in the U.S. have bleeding disorders. Some types, such as hemophilia, are inherited, meaning a person who has it is born with it. Inherited bleeding disorders are caused by certain genes passed down from parents to children. These genes contain instructions for how to make proteins in the blood called clotting factors, which help blood clot. If there is a problem with one of these genes, such as a mutation – a change in the gene’s instructions – the body may make a clotting factor incorrectly or not make it at all.
You can also have what’s called an acquired bleeding disorder, meaning you develop it during your lifetime. Acquired bleeding disorders can be caused by medical conditions, medicines or something unknown. Your risk of developing a bleeding disorder depends on your age, family history, genes, sex, or other medical conditions. If bleeding disorders run in your family, you may have a higher risk of developing or inheriting one.
Symptoms of a bleeding disorder may appear soon after birth or develop later in life and can include:
Excessive bleeding or bruising, such as frequent or long nose bleeds (longer than 15 minutes) or frequent or long menstrual periods
Petechiae, which are tiny purple, red, or brown spots caused by bleeding under the skin
Redness, swelling, stiffness, or pain from bleeding into muscles or joints
Blood in urine or stool
Excessive umbilical stump bleeding
Excessive bleeding during surgery or after trauma
If you believe you, or someone you care for, may have a bleeding disorder, talk to a health care provider. Your provider may make a diagnosis based on symptoms, risk factors, family history, a physical exam, and diagnostic tests. Health care providers typically screen for bleeding disorders only if you have known risk factors or before certain surgeries.
How your bleeding disorder is treated depends on its type. If your disorder causes few or no symptoms, you may not need treatment. If you have symptoms, you may need daily treatment to prevent bleeding episodes, or you may need it only on certain occasions, such as when you have an accident or before a planned surgery.
If you have been diagnosed with a bleeding disorder, it’s important to be proactive about your health and follow your treatment plan. To lower your risk of complications:
A Story of Bravery, Balance, and a Bleeding Disorder
There are lots of things that make Mikey White Jr. special. He’s a dedicated athlete. He’s determined, disciplined, and optimistic. He’s also living with hemophilia, a type of bleeding disorder.
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White was diagnosed with hemophilia at age 3 after experiencing several severe bleeding episodes. He had to give up baseball and basketball, his passions, because of the high risk of injuries, but he found competitive swimming – and he’s been breaking records ever since.
“Competitive swimming is a noncontact sport, so it complements my hemophilia while still being an intense and rigorous sport,” White said.
Being an athlete with hemophilia requires support, White admits. He works with his healthcare team and coaching staff to make sure he safely manages his condition and balances it with his training. He hopes his story encourages others living with bleeding disorders to accept and appreciate their bodies the way they are.
(Family Features) Most people don’t want to think about death – let alone talk about it. When the time comes, families often find themselves overwhelmed, not only by grief but by the many decisions that need to be made quickly.
Funeral directors witness this every day. They see the stress and confusion that can come when there is no plan in place and the peace of mind that comes with thoughtful preparation.
After consulting funeral directors nationwide, the National Funeral Directors Association (NFDA) uncovered five things they wish families knew before a death occurs.
It’s Never Too Early to Start Planning
While everyone knows death and taxes are inevitable, conversations about death are often avoided.
Simply documenting your wishes and discussing your preferences with your family can alleviate the difficult decisions your loved ones will have to make in the future. Speak with a funeral director to explore the many options for planning a meaningful funeral.
Legal and Financial Details Can Cause Unexpected Issues
Families often don’t realize power of attorney ends at death, meaning a designated person can no longer make decisions or access bank accounts once an individual dies.
To avoid complications, consider adding a trusted loved one to your bank account and ensure life insurance beneficiaries are up to date. Too often, deceased individuals leave minor children, deceased spouses or former partners as beneficiaries, leading to legal and financial challenges.
Final Wishes Shouldn’t Be In Your Will
Many people believe the best place to document their final wishes is in their will. However, wills are often not read until after funeral services take place, making them an unreliable way to communicate last requests. Instead, discuss and document your wishes with family members or a trusted funeral professional who can keep your wishes on file until there is a need.
There Are a Variety of Memorialization Options
End-of-life planning offers more choices than many realize. While burial remains a common preference, cremation is an increasingly popular choice and can even include a viewing and funeral service. Additionally, eco-friendly options, such as alkaline hydrolysis, natural burial and natural organic reduction are becoming more widely available for those seeking green memorialization. In fact, according to NFDA’s 2024 Consumer Awareness and Preferences Study, 68% of respondents expressed interest in green funeral options.
Exploring these possibilities with a funeral professional can help ensure your final arrangements reflect your values, traditions and personal wishes.
Funeral Directors Don’t Just Manage Funerals – They’re Trusted Guides In Honoring Life
Funeral directors play a vital role in helping families create meaningful services that reflect their loved one’s life, values and traditions. Whether planning ahead or facing a recent loss, funeral professionals provide expertise, compassionate care and personalized guidance during one of life’s most difficult moments.
Choosing the right funeral director is an important decision and finding someone who understands your needs can make all the difference in honoring your loved one in a personal and meaningful way.
Start the conversation today by talking about end-of-life planning. It isn’t easy, but it’s one of the most important conversations you can have with your loved ones. A little planning today can make a world of difference tomorrow.
Use comprehensive resources like RememberingALife.com, which is designed to guide families through every stage of the journey, including planning, funeral options and grief resources. The site offers valuable tools and support, such as the “Find a Funeral Home” tool to connect families with compassionate, local funeral directors and much more.
Photo courtesy of Shutterstock
SOURCE:National Funeral Directors Association
Workers who are in frequent contact with potentially sick animals are at high risk of bird flu infection.
Costfoto/NurPhoto via Getty ImagesRon Barrett, Macalester College
Disease forecasts are like weather forecasts: We cannot predict the finer details of a particular outbreak or a particular storm, but we can often identify when these threats are emerging and prepare accordingly.
The viruses that cause avian influenza are potential threats to global health. Recent animal outbreaks from a subtype called H5N1 have been especially troubling to scientists. Although human infections from H5N1 have been relatively rare, there have been a little more than 900 known cases globally since 2003 – nearly 50% of these cases have been fatal – a mortality rate about 20 times higher than that of the 1918 flu pandemic. If the worst of these rare infections ever became common among people, the results could be devastating.
Approaching potential disease threats from an anthropological perspective, my colleagues and I recently published a book called “Emerging Infections: Three Epidemiological Transitions from Prehistory to the Present” to examine the ways human behaviors have shaped the evolution of infectious diseases, beginning with their first major emergence in the Neolithic period and continuing for 10,000 years to the present day.
Viewed from this deep time perspective, it becomes evident that H5N1 is displaying a common pattern of stepwise invasion from animal to human populations. Like many emerging viruses, H5N1 is making incremental evolutionary changes that could allow it to transmit between people. The periods between these evolutionary steps present opportunities to slow this process and possibly avert a global disaster.
Spillover and viral chatter
When a disease-causing pathogen such as a flu virus is already adapted to infect a particular animal species, it may eventually evolve the ability to infect a new species, such as humans, through a process called spillover.
Spillover is a tricky enterprise. To be successful, the pathogen must have the right set of molecular “keys” compatible with the host’s molecular “locks” so it can break in and out of host cells and hijack their replication machinery. Because these locks often vary between species, the pathogen may have to try many different keys before it can infect an entirely new host species. For instance, the keys a virus successfully uses to infect chickens and ducks may not work on cattle and humans. And because new keys can be made only through random mutation, the odds of obtaining all the right ones are very slim.
Given these evolutionary challenges, it is not surprising that pathogens often get stuck partway into the spillover process. A new variant of the pathogen might be transmissible from an animal only to a person who is either more susceptible due to preexisting illness or more likely to be infected because of extended exposure to the pathogen.
Even then, the pathogen might not be able to break out of its human host and transmit to another person. This is the current situation with H5N1. For the past year, there have been many animal outbreaks in a variety of wild and domestic animals, especially among birds and cattle. But there have also been a small number of human cases, most of which have occurred among poultry and dairy workers who worked closely with large numbers of infected animals.
Pathogen transmission can be modeled in three stages. In Stage 1, the pathogen can be transmitted only between nonhuman animals. In stage 2, the pathogen can also be transmitted to humans, but it is not yet adapted for human-to-human transmission. In Stage 3, the pathogen is fully capable of human-to-human transmission.Ron Barrett, CC BY-SA
Epidemiologists call this situation viral chatter: when human infections occur only in small, sporadic outbreaks that appear like the chattering signals of coded radio communications – tiny bursts of unclear information that may add up to a very ominous message. In the case of viral chatter, the message would be a human pandemic.
Sporadic, individual cases of H5N1 among people suggest that human-to-human transmission may likely occur at some point. But even so, no one knows how long or how many steps it would take for this to happen.
Influenza viruses evolve rapidly. This is partly because two or more flu varieties can infect the same host simultaneously, allowing them to reshuffle their genetic material with one another to produce entirely new varieties.
Genetic reshuffling – aka antigenic shift – between a highly pathogenic strain of avian influenza and a strain of human influenza could create a new strain that’s even more infectious among people.Eunsun Yoo/Biomolecules & Therapeutics, CC BY-NC
These reshuffling events are more likely to occur when there is a diverse range of host species. So it is particularly concerning that H5N1 is known to have infected at least 450 different animal species. It may not be long before the viral chatter gives way to larger human epidemics.
Reshaping the trajectory
The good news is that people can take basic measures to slow down the evolution of H5N1 and potentially reduce the lethality of avian influenza should it ever become a common human infection. But governments and businesses will need to act.
People can start by taking better care of food animals. The total weight of the world’s poultry is greater than all wild bird species combined. So it is not surprising that the geography of most H5N1 outbreaks track more closely with large-scale housing and international transfers of live poultry than with the nesting and migration patterns of wild aquatic birds. Reducing these agricultural practices could help curb the evolution and spread of H5N1.
Large-scale commercial transport of domesticated animals is associated with the evolution and spread of new influenza varieties.ben/Flickr, CC BY-SA
People can also take better care of themselves. At the individual level, most people can vaccinate against the common, seasonal influenza viruses that circulate every year. At first glance this practice may not seem connected to the emergence of avian influenza. But in addition to preventing seasonal illness, vaccination against common human varieties of the virus will reduce the odds of it mixing with avian varieties and giving them the traits they need for human-to-human transmission.
At the population level, societies can work together to improve nutrition and sanitation in the world’s poorest populations. History has shown that better nutrition increases overall resistance to new infections, and better sanitation reduces how much and how often people are exposed to new pathogens. And in today’s interconnected world, the disease problems of any society will eventually spread to every society.
For more than 10,000 years, human behaviors have shaped the evolutionary trajectories of infectious diseases. Knowing this, people can reshape these trajectories for the better.Ron Barrett, Professor of Anthropology, Macalester College
This article is republished from The Conversation under a Creative Commons license. Read the original article.
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(Family Features) Most people don’t want to think about death – let alone talk about it. When the time comes, families often find themselves overwhelmed, not only by grief but by the many decisions that need to be made quickly.
Funeral directors witness this every day. They see the stress and confusion that can come when there is no plan in place and the peace of mind that comes with thoughtful preparation.
After consulting funeral directors nationwide, the National Funeral Directors Association (NFDA) uncovered five things they wish families knew before a death occurs.
Ron Barrett, Professor of Anthropology, Macalester College
This article is republished from The Conversation under a Creative Commons license. Read the original article.
