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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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.
SAN DIEGO, CA, USA /EINPresswire.com/ — Missing teeth can have obvious consequences for your smile, but many people are not aware of how tooth loss affects their oral health, general well-being, and even their facial shape. Once a tooth is detached from the gums, there is no tooth root to stimulate the underlying jawbone; unfortunately, this often causes the bone structure to recede and lose volume. Bone loss can raise a number of aesthetic and functional concerns — particularly when a tooth has been without a replacement for a significant amount of time — including the shifting of surrounding teeth, an increased risk of gum disease, and changes in your jaw structure. In general, greater bone loss is experienced the longer an absent space remains unfilled. While jawbone recession can be debilitating, San Diego cosmetic dentist Landon Libby, DDS discusses potential solutions for bone loss to prevent further damage and regenerate additional bone density.
According to Dr. Libby, implant dentistry can offer a myriad of benefits for individuals with missing teeth, including the ability to maintain bone volume and preserve the full integrity of the jawbone after tooth loss. Using dental implants, implant dentistry aims to replace a missing tooth with an artificial tooth root and a custom-made restoration indistinguishable from a patient’s natural teeth. A titanium post is implanted into the jawbone during treatment, which serves as the “replacement” tooth root. Unlike other tooth replacement options that are not surgically affixed to the underlying bone, dental implants and implant-supported restorations promote new bone regeneration. Not only can this enhance a patient’s oral health and strengthen their jawbone, but implant restorations are also considered to look and feel the most similar to natural teeth. Best of all, implants can be used to replace a single tooth, multiple teeth in a row, or even a full dental arch.
It’s important to understand that every patient may not be a good candidate for dental implants, and bone grafting may be necessary prior to treatment to provide more support for implant placement. As a multi-stage process involving oral surgery, Dr. Libby stresses the importance of selecting an experienced, compassionate, and qualified dental team to place implants and provide a seamless patient experience.
About Landon Libby, DDS Dr. Landon Libby is a Mission Valley-based cosmetic dentist who provides cosmetic, restorative, and family dentistry treatments for patients in and around San Diego. As a DOCS-certified dentist with training in sedation dentistry, Dr. Libby strives to enhance patient comfort during every stage of treatment and redefine what it means to “go to the dentist.” After receiving his Doctor of Dental Surgery (DDS) from the Loma Linda University School of Dentistry, Dr. Libby went into private practice and has been serving the dental needs of the San Diego community for years. Dr. Landon Libby is available for interview upon request.
PUNE, MAHARASHTRA, INDIA /EINPresswire.com/ — Healthcare Education Market Perspective
The Global Healthcare Education Market size was worth USD 103.64 billion in 2022 and is estimated to grow to USD 202.75 billion by 2030, with a compound annual growth rate (CAGR) of approximately 8.75% over the forecast period. The report analyzes the healthcare education market’s drivers, restraints/challenges, and their effect on the demands during the projection period. In addition, the report explores emerging opportunities in the healthcare education market.
Medical professionals watching webinar on online platform. People having virtual class flat vector illustration. Online education, medicine concept for banner, website design or landing web page
Healthcare Education Market Developments
• In 2023, HealthStream (US) purchased Electronic Education Documentation System, LLC (US). This acquisition will broaden Healthstream’s ecosystem by bringing a cutting-edge, cloud-based continuing education management system for healthcare organizations and delivering cutting-edge solutions in the form of Software-as-a-Service (SaaS).
• In 2022, To promote access for surgeons and benefit more patients across the US, GE Healthcare (US) and DePuy Synthes (US) worked together to make GE Healthcare’s OEC 3D Imaging System and DePuy Synthes’ extensive product line more widely available.
Increasing need for skilled healthcare workers to drive market growth
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The market for healthcare education is expanding significantly due to the increasing need for skilled healthcare workers. The market for healthcare education is being significantly shaped by the growing demand for qualified healthcare workers. The demand for skilled physicians, nurses, allied health workers, and administrators who can deliver high-quality healthcare services is rising as the world’s population continues to expand and get older. The rising incidence of chronic illnesses and complicated medical disorders that need specialized care has increased this demand. Additionally, the need for healthcare professionals is growing outside conventional clinical responsibilities. The demand for non-clinical positions such as healthcare administrators, informatics experts, and others is also growing. As a result, healthcare education incorporates a variety of academic fields to produce a workforce that is well-rounded and able to meet the many demands of the healthcare sector.
Healthcare Education Market: Regional Landscape
Asia Pacific dominated the Healthcare Education market in 2022
There is a sizable and constantly expanding population in the Asia Pacific region, which generates a sizable demand for healthcare services. The demand for qualified and trained healthcare personnel grows proportionally as healthcare systems enlarge to meet this demand. Additionally, greater investments in healthcare infrastructure, including educational institutions, have been made as a result of the Asia Pacific region’s economic expansion. Governments and commercial organizations are becoming more aware of how crucial a strong healthcare education system is to the development of healthcare services.
Healthcare Education Market Top Players: Stryker (US), SAP (Germany), Adobe (US), Infor (US), Oracle (US), HealthStream (US), Symplr (US), Elsevier (Netherlands), Articulate (US), PeopleFluent (US), Fujifilm Corporation (Japan), GE Healthcare (US), Trivantis Corporation (US), Koninklijke Phillips (Netherlands), Siemens Healthineers (Germany), Coursera (US), and IBM (US).
Healthcare Education Market: Segmentation
The global healthcare education market has been segmented into provider, delivery mode, application, and end-user.
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Based on universities, educational platforms, and medical simulation are segments of the global healthcare education market. The university segment to improve the business and department workers, the requirement for continuous learning in a field that is rapidly evolving, partnerships with healthcare organizations, and the emphasis on patient-centered care and interprofessional collaboration are all factors driving the growth of universities and academic institutions in the market for healthcare education solutions. The aforementioned elements help healthcare education programs grow and evolve to satisfy industry demands.
Based on delivery mode, the market is classified into classroom-based, and e-learning. In 2022, the e-learning processing category dominated the global market. Due to a variety of online learning platforms, students have access to educational resources like lectures, videos, quizzes, and other resources in a digital setting. Students can learn at their own pace and convenience in e-learning environments, which usually offer flexibility. Coursera, Blackboard, and Moodle are a few popular e-learning platforms. Because of the COVID-19 pandemic, e-learning platforms have proliferated as a medium of delivery, and this trend is anticipated to continue during the projected period. The overall revenue for Coursera in 2022 was US$523.8 million, a 26% increase over 2021, while the gross profit was US$249.5 million, a 33% increase over 2021.
Based on application, the market is classified into neurology, cardiology, and pediatrics. In 2022, the cardiology category dominated the global market. It is anticipated that factors including the increased prevalence of cardiovascular diseases (CVD), technological improvements, and online courses will raise demand for educational solutions. According to the WHO’s 2021 update, CVDs encompass illnesses like coronary heart disease, cerebrovascular disease, rheumatic heart disease, and others.
Based on end-users, the market is classified into students and physicians. In 2022, the student category dominated the global market. Student prospects have increased as a result of the growing accessibility and availability of healthcare education alternatives, notably online and remote learning options. Students can learn at their own pace, from any location, at any time, and with the help of digital tools and online platforms. This accessibility makes it easier for people from different backgrounds to enter the healthcare industry by allowing students to pursue healthcare education while juggling other responsibilities.
nForming Solutions also provides customization options to tailor the reports as per client requirements. This report can be personalized to cater to your research needs. Feel free to contact our sales team, who will ensure that you get a report per your needs. Thanks for reading this article; you can also get individual chapter-wise sections or region-wise report versions like North America, Europe, or Asia.
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Ron Barrett, Professor of Anthropology, Macalester College
This article is republished from The Conversation under a Creative Commons license. Read the original article.
