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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(Family Features) In the U.S., 1 in 3 adults is at risk for a newly recognized syndrome that comes from a combination of heart disease, kidney disease, type 2 diabetes and excess body weight. This cluster of conditions, called cardiovascular-kidney-metabolic (CKM) syndrome, is an example of how problems in one part of your body can affect other parts.
To avoid CKM syndrome, health experts suggest paying close attention to four of the American Heart Association’s Life’s Essential 8 – blood pressure, lipids, body weight and blood sugar level – which are core health factors that impact your metabolic health.
Good metabolic health means your body uses energy well and keeps these factors in a normal range. However, when numbers are off in one area, it can affect others, raising your risk for heart disease, stroke, kidney disease and diabetes.
Consider these tips from the American Heart Association to help keep your core health factors under control.
Blood Pressure
High blood pressure, also known as hypertension, happens when the force of your blood pushing against the walls of your blood vessels is too high. High blood pressure is a leading cause of heart disease, stroke and kidney disease.
Because high blood pressure doesn’t have symptoms, the only way to know you have it is to get your blood pressure checked. Healthy blood pressure is below 120/80. If your blood pressure is 130/80 or higher, talk to your doctor about checking your other core health factors.
Lifestyle changes can help reduce high blood pressure. One example is a Dietary Approaches to Stop Hypertension (DASH) eating pattern that’s low in fat and rich in fruits, vegetables, whole grains and low-fat dairy products. Losing 10 pounds and reducing alcohol consumption can also reduce blood pressure.
Cholesterol
Cholesterol is a waxy substance your liver makes then circulates in the blood where your body uses it to build cells and make vitamins and hormones. You may also get cholesterol from eating animal products. If there’s too much cholesterol circulating, your risk of type 2 diabetes, heart disease and stroke may increase.
For optimal CKM health, your LDL cholesterol should be below 100 and triglycerides below 150. Triglycerides are the most common type of fat in the body. If your triglyceride level is 135 or higher, talk to your doctor about decreasing your risk.
Losing body weight and increasing physical activity decrease triglyceride levels. In addition, DASH and Mediterranean (plant-based, high-fiber, low-fat) eating patterns support healthy LDL and triglyceride levels.
Body Weight
Healthy weight may be determined by body mass index (BMI), a number that represents your weight in relation to your height. Extra body fat can mean a higher risk for many health problems, including heart disease, stroke, high blood pressure, high cholesterol and diabetes.
CKM syndrome starts when BMI is 25 or higher and waist circumference is 88 centimeters or higher for women and 102 centimeters or higher for men. Aim for a BMI between 18.5-25.
To lose weight and keep it off, start by setting realistic goals. Understand how much and why you eat, manage portion sizes, make smart snack substitutions and be physically active.
Blood Sugar
High blood sugar can slowly damage the kidneys. In fact, diabetes is the leading cause of kidney disease, and it increases the risk of heart attack and stroke.
Blood sugar is measured in two ways: a fasting blood glucose test (short term blood sugar) and an A1C test (long term blood sugar control). A normal fasting blood glucose level is 70-99 and a normal A1C level is below 5.7%. Fasting blood glucose above 125 and A1C of 6.5% or higher means you have diabetes.
Habits that help you avoid high blood pressure, weight gain and high cholesterol also keep your blood sugar in check. These are especially important if you have a family history of diabetes.
Learn more about CKM syndrome and how to manage your risk at heart.org/CKMhealth.
Photos courtesy of Shutterstock
SOURCE:
American Heart Association
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(Family Features) Staying up to date on recommended vaccines is important during pregnancy. This is especially true during the winter months when more people tend to get sick from flu, COVID-19 and RSV. These viruses can be especially dangerous for pregnant people and babies.
Vaccines are an important part of routine pregnancy care, both for you and your baby. Getting vaccinated against flu and COVID-19 can cut your risk of hospitalization by about half.
Now is the time to get vaccinated if you haven’t already. Flu vaccines help protect you from getting the flu and getting seriously ill, so it’s a good idea to schedule an appointment now. The latest COVID-19 vaccines are important too because they lower your risk of serious illness. An RSV vaccine may also be recommended for when you are 32-36 weeks pregnant. Be sure to talk to your doctor.
“Right now, we are seeing a concerning increase in cases of respiratory diseases, such as the flu, COVID-19 and RSV,” said Adm. Rachel Levin, MD, assistant secretary for health at the U.S. Department of Health and Human Services. “I encourage all pregnant people to take preventive action to protect their health and the health of their baby. The best and safest way to do this is to get vaccinated. Getting vaccinated is easy and is usually covered by insurance.”
Help Protect Your Baby
When you get flu, COVID-19 and RSV vaccines, you’re helping protect your baby by passing your immunity on to them. Getting vaccinated against flu, COVID-19 and RSV during pregnancy can protect your baby during the first 6 months of life. These viruses can be very harmful to newborns. In fact, RSV is the leading cause of hospitalization in infants
Talk to Your Doctor About Timing
Millions of people in the U.S. have already gotten vaccinated against flu, COVID-19 and RSV this season. If you haven’t gotten your vaccines yet, be sure to talk with your doctor. They can help you choose the right vaccines and determine the best timing to help protect you and your baby.
Get the Facts
Getting vaccinated can give you peace of mind, ensuring you have done everything you can to protect yourself and your baby from serious respiratory illness. Information can give you power and comfort, especially when you’re pregnant.
Go to cdc.gov/RiskLessDoMore to learn more about flu, COVID-19 and RSV vaccines, or go to vaccines.gov to get started today.
Photo courtesy of Shutterstock
SOURCE:
U.S. Department of Health and Human Services
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Lifestyle
Here’s to a Healthy New Year: What your family needs to know about vaccines
Vaccines for flu, COVID-19, and RSV are vital for family health, especially as respiratory viruses increase during colder months. Stay updated to reduce serious illness and hospitalizations.
(Family Features) This year, make a plan to keep your family healthy by helping them get vaccinated for respiratory infections like flu, COVID-19 and RSV. These respiratory illnesses are more likely to become serious for people who are not up to date on their vaccines.
In colder months, respiratory viruses tend to surge, and people spend more time indoors where they are more likely to be exposed. These respiratory infections can cause serious illness and hospitalization. This season’s flu and COVID-19 vaccines, as well as the RSV vaccine, are the best way to help your family risk less serious illness and do more of what they enjoy.
What should your family know?
Vaccines can keep you and your family from getting very sick from respiratory illnesses. The Centers for Disease Control and Prevention (CDC) recommends everyone ages 6 months and older get this season’s flu and COVID-19 vaccines.
In addition, all adults ages 75 and older – and those ages 60 and older with certain health conditions or who live in a nursing home – should get one dose of an RSV vaccine if they haven’t before. Pregnant people should also talk to their doctor about getting an RSV vaccine to protect their baby during their first 6 months of life.
Is your family at high risk?
It’s important to know the risks of getting very sick from flu, COVID-19 or RSV. According to the CDC, some people have a higher risk than others, including:
- People not up to date on their vaccines: Vaccines cut your risk of needing hospital care for flu or COVID-19 by about half, according to the CDC. In 2023, 90% of adults admitted to the hospital for COVID-19 were not up to date on their COVID-19 vaccine. People who skipped their flu shot were twice as likely to need to see a doctor for the flu.
- Older adults: Most flu, COVID-19 and RSV deaths are in people ages 65 and older. If you help care for an older family member or friend, let them know vaccines are their best protection from getting very sick.
- People with underlying health conditions: Heart and lung disease, diabetes, kidney disease and other chronic conditions can cause complications and more severe illness from flu, COVID-19 and RSV.
- Those who live in long-term care: Respiratory viruses can be a greater threat to older people in long-term care, who often have health issues that raise their risk of severe flu, COVID-19 or RSV.
- Pregnant people: Pregnancy raises the risk of severe illness from flu and COVID-19. Getting vaccinated during pregnancy helps protects the pregnant person and baby. An RSV vaccine during pregnancy protects the baby from severe RSV in their first 6 months of life.
Get your family vaccinated now for a healthy new year
Join the millions of people who’ve already gotten vaccinated this season. Take your family to get vaccinated now to risk less severe illness and do more of what you enjoy. It’s safe to get flu and COVID-19 vaccines (and an RSV vaccine, if eligible) at the same time.
Visit cdc.gov/RiskLessDoMore to learn more about flu, COVID-19 and RSV vaccines. Talk with your doctor about which vaccines are right for you or go to vaccines.gov to find a nearby pharmacy. You can order free COVID-19 test kits (up to four per household) at COVIDTests.gov.
Know Your Risk
In the United States, there are additional groups of people who are at higher risk from these respiratory illnesses.
- People in rural parts of the country: Vaccines matter even more in rural areas where there may be fewer doctors or clinics to help people who get very sick. Yet in these regions, less than half of adults got a flu vaccine last year. Fewer than 1 in 5 got an updated COVID-19 vaccine.
- Black and Hispanic people: At last year’s respiratory virus peak, Black people were more likely than white and Hispanic people to be in the hospital for flu, COVID-19 or RSV. By the end of last year’s virus season, Hispanic people were more likely than non-Hispanic white people to have been in the hospital for flu.
Photos courtesy of Shutterstock
SOURCE:
U.S. Department of Health and Human Services
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