Health
What Enables Herpes Simplex Virus To Become Impervious to Drugs?
Research pinpoints key to the cold sore virus’s ability to evade treatment, offering broader clues on antiviral drug resistance
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.”
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.
“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.
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?
Source: Harvard Medical School
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8 Daily Habits to Support Your Heart, Kidney and Metabolic Health
(Feature Impact) When it comes to protecting your heart, supporting your kidney function and improving your metabolic health, you’ll find the advice for each one looks similar. That’s because your body’s systems are deeply interconnected: what affects one will have ripple effects across the others.
Cardiovascular-kidney-metabolic health, or CKM health, is a perfect example. When any one of these systems is compromised, it can lead to problems with the others. Therefore, it’s not uncommon for health problems like heart disease, stroke, diabetes and kidney disease to develop or worsen simultaneously – a condition collectively known as CKM syndrome.
The reverse is also true, so habits that are healthy for your heart will have a positive effect on your kidneys and metabolic system and vice versa. Consider these simple strategies that align with the American Heart Association’s Life’s Essential 8, a list of healthy steps that can improve overall health. Learn more about how these habits and health measures affect your CKM health at Heart.org.
- Choose Healthy Foods – Food is your body’s fuel, so fill your tank wisely. Certain types of foods can help your blood pressure, cholesterol, blood glucose and triglycerides stay within healthy ranges, while poor nutrition can push those numbers into more dangerous territory. Focus on vegetables, fruits, whole grains, plant-based proteins (e.g. beans, legumes and nuts) and lean animal proteins (e.g. seafood, skinless poultry and low-fat dairy). Drink plenty of water throughout the day and limit added sugar and salty or fatty foods.
- Stay Physically Active – Exercise doesn’t have to feel like a chore – in fact, some of your favorite hobbies may already count. The American Heart Association recommends aiming for 150 minutes per week of moderate physical activity like dancing, gardening or walking, moving quickly enough to elevate your heart rate and break a light sweat. Alternatively, choose 75 weekly minutes of vigorous exercise that gets you breathing hard and fast; think running, swimming, playing tennis or riding your bike on hilly terrain.
- Avoid Nicotine – Tobacco and other nicotine products can raise your blood pressure, damage blood vessels and increase your risk of heart attack and stroke, which are all bad news for your CKM health. If you’re currently trying to quit, you aren’t alone, so don’t be afraid to seek out support groups and resources to help.
- Prioritize Healthy Sleep – Sleep gives your body a chance to rest and recover from the day, but it’s often one of the first things people sacrifice when life gets busy. Poor sleep can increase your risk for heart disease, weight gain and other issues. Aim for a solid 7-9 hours a night. Keep your bedroom cool, dark and comfortable, and do your best to limit distractions like late-night smartphone scrolling.
- Watch Your Blood Pressure – When your blood pressure is high, it forces your heart to work harder to pump blood through the body, which can weaken it over time. It can also damage the delicate arteries in and around the kidneys, putting CKM health further at risk. Information is power, so check your blood pressure frequently to know whether further action is needed to keep it under control.
- Manage Your Blood Sugar – High blood sugar can damage the kidneys, eyes, blood vessels and more, thereby increasing your chance of developing harmful CKM conditions. Controlling blood sugar is particularly important for people with diabetes. If you don’t have diabetes and still experience frequent blood sugar spikes and crashes, talk to your doctor.
- Control Your Cholesterol – Cholesterol comes in both “bad” (LDL) and “good” (HDL) forms, requiring a balancing act to keep your levels within a healthy range. If LDL is high and HDL is low, your risk of clogged blood vessels, heart attack and stroke are higher. Healthy levels keep blood flowing to your heart and kidneys, supporting your metabolic health in the process. See your doctor for regular bloodwork so you can monitor cholesterol changes.
- Maintain a Healthy Weight – Since excess body weight puts pressure on the heart, kidneys and other organs, a healthy body weight helps lower your risk of CKM syndrome. Whether you’re hoping to maintain or reduce your weight, regular exercise, healthy eating and quality sleep are all great ways to achieve your goals.
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Health
3 Steps to Support Mental Health for Rural Youth
Mental Health for Rural Youth Young people face a growing number of pressures, including academic expectations, social responsibilities, complex family situations and uncertainty about their own futures. Mental health support is important for all – but in many rural areas, those pressures are even greater. If the rural mental health crisis affects you or a loved one, consider these ways to help.
3 Steps to Support Mental Health for Rural Youth
(Feature Impact) Young people face a growing number of pressures, including academic expectations, social responsibilities, complex family situations and uncertainty about their own futures. Mental health support is important for all – but in many rural areas, those pressures are even greater.
According to the Centers for Disease Control and Prevention, the suicide rate for rural youth ages 15-19 is 74% higher than their urban counterparts. Barriers like limited insurance coverage, unreliable internet for telehealth, scarce providers, long drive times and lack of public transportation make it harder to get mental healthcare when it’s needed. Plus, asking for help can feel like opening oneself up to judgment and stigmatization.
That’s why Rural Minds, the only nonprofit focused on mental health for rural communities, created the Rural Youth Mental Wellness pilot program supported by Boehringer Ingelheim. It was developed by an advisory committee made up of rural youth to provide their peers with practical, free, accessible mental health resources. Incorporating feedback on the pilot, the updated program sponsored by the Sompo Foundation is now launching its national rollout.
“A young person’s ZIP code should never determine whether they can access meaningful mental health support where and when they need it,” said Jessica L. Schleider, Ph.D., director, Lab for Scalable Mental Health, Northwestern University. “Our lab is thrilled to partner with Rural Minds as they champion evidence-based, anonymous, freely available support tools designed to overcome barriers to help-seeking faced by rural youth across the country.”
If the rural mental health crisis affects you or a loved one, consider these ways to help.
Break the Stigma Surrounding Mental Health
In communities where self-reliance is valued, asking for help can sometimes be viewed as a sign of weakness. Young people who feel unheard and unsupported often struggle with being vulnerable, so they continue carrying their increasingly heavy burdens alone.
Parents, educators, healthcare providers, community leaders and peers can work to change that culture by normalizing mental health conversations. This includes helping teenagers feel seen and accepted by educating them on mental health issues and coping strategies, listening to their experiences without judgment, sharing your own stories and reminding them it’s courageous to seek support.
Consider Single-Session Interventions
The first step is always the hardest when it comes to seeking mental health support, and not every struggling young person is ready or able to see a therapist. With access to free, confidential, self-guided materials to begin building mental wellness skills, the first step may be less scary.
Single-Session Interventions (SSIs) are brief, structured online courses designed to teach youth practical skills for handling stress, low mood, self-image and more. The Rural Youth Mental Wellness Program offers SSIs in partnership with Project YES (Youth Empowerment and Support), a free digital resource developed with Northwestern University’s Lab for Scalable Mental Health at the Feinberg School of Medicine.
Anonymous access to SSIs through the partnership provides strategies for:
- Improving mood
- Rethinking body image
- Reframing negative thoughts
- Knowing your power to change
- Taking steps toward goals
- Protecting LGBTQ+ pride
- Handling self-harm urges
- Staying safe amid dark thoughts
Each SSI typically takes 5-10 minutes. Although SSIs are not a replacement for therapy, they provide a research-backed source of support for young people experiencing bouts of stress or low-to-moderate distress.
Know When to Seek Professional Help
Self-guided resources and supportive conversations are a valuable starting point, but sometimes young people need qualified professional help. Look for symptoms like worsening mood or behavior, substance use, self-harm or difficulty managing everyday tasks, and take teens seriously when they express dark feelings.
Doctors and counselors can provide personalized support for youth in crisis, and the 988 Suicide and Crisis Lifeline offers free, confidential 24/7 support for mental health by dialing 9-8-8.
“I grew up in a small town where mental health was almost taboo,” said committee member Asheton Medlin. “Being part of the committee that built this program let me help make sure rural youth today have the support I didn’t. I’m excited to help bring these resources to them because this generation deserves the chance to grow up and change the world.”
Find more information at RuralMinds.org.
Photos courtesy of Shutterstock
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recipes
Build Heart-Healthy Habits That Last with 4 Simple, Everyday Steps
Build Heart Healthy Habits: Small, consistent lifestyle changes and healthy habits, including staying active and making smart food choices, can help support cardiovascular health. This Warm Lentil, California Grape and Arugula Salad includes a quick homemade rosemary lemon vinaigrette to pack in the flavor and complement black lentils and sweet grapes.
(Feature Impact) Your heart works around the clock, making heart health one of the most important parts of your overall well-being. The good news is improving heart health doesn’t require an overnight transformation. Small, consistent lifestyle changes and healthy habits, including staying active and making smart food choices, can help support cardiovascular health.
Sit Less Throughout the Day
If you work in an office setting, spending long periods sitting may be the norm. Even if you exercise regularly, those long-seated hours may affect heart health. Look for opportunities to move more by taking short walking breaks, standing while on the phone, stretching between meetings or taking the stairs instead of an elevator.
Prioritize Foods That Support Heart Health
A heart-healthy eating pattern can begin with foods that are low in saturated fat and sodium, and provide beneficial vitamins and plant compounds, like fresh, juicy grapes. They contain 7% of the daily recommended intake of potassium per serving, are a good source of vitamin K and deliver beneficial antioxidants and other polyphenols, including flavonoids, that can help relax blood vessels and promote healthy circulation.
Some studies also suggest grapes have a beneficial impact on blood lipids and more. In fact, one study found women who consumed 1 1/4 cups of grapes every day benefited from reduced blood triglyceride levels, LDL cholesterol levels, inflammatory proteins and other markers of heart disease.
Whether enjoyed as a snack, added to salads or blended into smoothies, Grapes from California make it easy to add more heart-smart nutrition throughout the day. For example, this Warm Lentil, California Grape and Arugula Salad includes a quick homemade rosemary lemon vinaigrette to pack in the flavor and complement black lentils and sweet grapes.
Cut Back on Added Sodium
Adding heart-healthy foods like grapes to your menu is a good place to start, but caring for your cardiovascular system is also about what you’re not eating. Many packaged and restaurant foods contain more sodium than some people realize, making it important to read nutrition labels, prepare more meals at home and flavor foods with herbs, spices, citrus or vinegar instead of extra salt to support healthy blood pressure.
Make Good Sleep a Priority
Quality sleep affects many aspects of health, including cardiovascular. Adults should aim for 7-9 hours of sleep each night in a cool, comfortable environment. To get a good night’s rest, try limiting screen time before bed, blocking out light and avoiding alcohol or caffeine in the evenings.
To learn more about the heart-health benefits of grapes and find additional health-supporting recipes, visit GrapesFromCalifornia.com.
Warm Lentil, California Grape and Arugula Salad
Servings: 6
- 1 pouch (8 ounces) precooked black lentils
- 1 1/2 cups Grapes from California, halved
- 1 cup radicchio, torn
- 1 cup arugula
- chopped toasted walnuts
Rosemary Lemon Vinaigrette:
- 1/4 cup extra-virgin olive oil
- 3 tablespoons lemon juice
- 2 tablespoons fresh rosemary leaves
- 2 teaspoons honey
- 1/2 teaspoon sea salt
- 1 clove garlic
- freshly ground pepper, to taste
- To make rosemary lemon vinaigrette: In small blender or food processor, process olive oil, lemon juice, rosemary, honey, salt, garlic and pepper, to taste, until rosemary is finely chopped; set aside until ready to use. May be made 2 days in advance and refrigerated in covered container until ready to serve. Bring to room temperature before using.
- In large glass bowl, microwave lentils 45 seconds, or until warm. Add grapes, radicchio, arugula and dressing to bowl and toss lightly to coat. Sprinkle with walnuts.
Nutritional information per serving: 160 calories; 4 g protein; 18 g carbohydrates; 9 g fat (51% calories from fat); 1.5 g saturated fat (8% calories from saturated fat); 0 mg cholesterol; 200 mg sodium; 4 g fiber.
SOURCE:
California Table Grape Commission
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