Virus World

With a new method for examining virus samples researchers from the University of Copenhagen have solved an old riddle about how Hepatitis C virus avoids the human body's immune defenses. The result may have an impact on how we track and treat viral diseases in general. An estimated 50 million people worldwide are infected with with chronic hepatitis C. The hepatitis C virus can cause inflammation and scarring of the liver, and in the worst case, liver cancer. Hepatitis C was discovered in 1989 and is one of the most studied viruses on the planet. Yet for decades, how it manages to evade the human immune system and spread through the body has been a riddle—one that Danish researchers have become the first to solve.

A new method for examining virus samples has led researchers at the University of Copenhagen and Hvidovre Hospital to the answer, which is: the virus just puts on a 'mask'. By donning a mask, the virus can remain hidden while making copies of itself to infect new cells. The mask cloaks the virus in the form of a molecule already in our cells. Disguised by the molecule, our immune systems confuse the virus with something harmless that needn't be reacted to. "How the Hepatitis C virus manages to hide in our liver cells without being detected by the immune system has always been a bit of a mystery. Our revelation of the virus' masking strategy is important, as it could pave the way for new ways of treating viral infections. And it is likely that other types of viruses use the same trick," says Associate Professor Jeppe Vinther of the Department of Biology, who together with associate professor Troels Scheel and professor Jens Bukh from Copenhagen Hepatitis C Program headed the research. The study has just been published in Nature.

Camouflage for a malicious virus

The mask used by the hepatitis virus to hide in our cells is called FAD, a molecule composed of Vitamin B2 and the energy carrying molecule ATP. FAD is vital for our cells to convert energy. The FAD molecule's importance and familiarity to our cells makes it ideal camouflage for a malicious virus. For several years, the research team had a good idea that FAD was helping the virus hide in infected cells, but they lacked a clear way to prove it. To solve the challenge, they turned to Arabidopsis, a well-known experimental plant among researchers. "We were getting desperate to find a way to prove our hypothesis, which is when we purified an enzyme from the Arabidopsis plant that can split the FAD molecule in two," explains Anna Sherwood from Department of Biology, who together with Lizandro Rene Rivera Rangel are first authors of the study. Using the enzyme, the researchers were able to split the FAD and prove that the hepatitis C virus used it as a mask.

Other viruses probably use the same trick

Like both the coronavirus and influenza virus, Hepatitis C is an RNA virus. Its genetic material consists of RNA that must be copied once the virus enters its host organism. New RNA copies are used to take over new cells, and one end of the RNA's genetic material is masked by the FAD. According to Jeppe Vinther, it is very realistic that other RNA viruses use similar masking techniques to spread without being detected by cellular control systems. In fact, researchers have already found another virus that uses the same strategy. And there are likely more. "All RNA viruses have the same need to hide from the immune system and there is a good chance that this is just the beginning. Now that we're attuned to this trick, it opens up the possibility of developing new and perhaps improved methods of tracking and treating viral infections in the future," concludes Jeppe Vinther.

Research published in Nature (July 5, 2023):

https://doi.org/10.1038/s41586-023-06301-3 

Reuse of needles and syringes, unscreened blood transfusions, and sharing of surgical instruments driving increase in new cases. Pakistan is now home to the world’s largest population of hepatitis C patients, with nearly 10 million people infected by the virus amid rampant use of unclean needles and unhygienic health services. Around half a million new infections were detected in Pakistan between 2015 and 2021, according to the US Centre for Disease Analysis (CDA). The findings are the result of a two-year research and analysis conducted jointly by the CDA and Pakistan’s provincial health departments, health officials said on Friday. “Pakistan is now home to the world’s largest population of patients living with hepatitis C, surpassing even China, India and Nigeria,” Dr Homie Razavi, an epidemiologist, told reporters. The growing burden of the virus, which transmits through blood-to-blood contract and can cause severe liver complications if untreated, is expected to further strain a public health system identified by the World Health Organization as one of the globe’s worst. Health experts say the reuse of needles and syringes, unscreened blood transfusions, and sharing of razors by barbers and surgical instruments by dentists are the main reasons for the spread of hepatitis C in Pakistan. The country also has one of the highest rates for therapeutic injections per capita in the world. “Unfortunately, we have poor infection prevention control,” said Dr Amna Subhan of Aga Khan University Hospital. “Also, pregnant women are not vaccinated for hepatitis B, resulting in transmission of the virus from mother to child.”

Disease is a ‘ticking bomb’

The recent floods have exacerbated the situation by damaging nearly 900 health facilities across the country and exposing 75,000 pregnant women to infection, officials said. Many pregnant women were forced to give birth in partially flooded and unhygienic homes, in cramped refugee camps or in makeshift tents – often without a midwife or doctor. Even as the government has committed to eliminating all hepatitis viruses by 2030, the growing prevalence of the disease shows that Pakistan is sitting on a “ticking bomb”, one health official told The Telegraph. Experts attribute the persistent rise in hepatitis C cases to the absence of a comprehensive, population-wide screening programme that can identify the “missing millions of people who require treatment”. “There are several challenges that hinder the elimination of HCV from Pakistan including the lack of patient awareness about the causes and transmission of disease, lack of affordability for investigations and drug treatment and lack of experienced healthcare professionals,” said Dr Yasir Waheed, a leading Pakistani virologist. The lack of effective drugs and robust epidemiological data are also major contributors to the growing prevalence of the disease, he added. In Pakistan, the control of hepatitis has so far remained a low political priority, with poor implementation of health-related policies and government-sponsored treatment programmes by the devolved provincial health ministries. However, the establishment of the National Blood Transfusion Authority in Pakistan has been a major development that addresses one of the biggest sources of infection in the country: contaminated blood units. But Dr Waheed believes the elimination of hepatitis from Pakistan by 2030 will be impossible under current initiatives. “It will be a significant development if the country succeeded in reducing the annual hepatitis deaths from 200,000 to less than 25,000. The control of hepatitis epidemics requires political will, financial investment and support from pharmaceutical, medical and civil societies around the globe,” he said. Razavi said Pakistan gets half a million new infections every year and if it continued the gap between the country and other nations would widen. Pakistan needs to scale up testing and treatment to reach the WHO target by 2030, he said.

“To achieve the WHO elimination targets, Pakistan needs to screen 9.4 to 22.6 million people annually, treat 491000 to 1.2 million people and reduce new infections,” he said.

The SARS coronavirus 2 (SARS-CoV-2) has caused an ongoing global pandemic with currently 29 million confirmed cases and close to a million deaths. At this time, there are no FDA-approved vaccines or therapeutics for COVID-19, but Emergency Use Authorization has been granted for remdesivir, a broad-spectrum antiviral nucleoside analog. However, remdesivir is only moderately efficacious against SARS-CoV-2 in the clinic, and improved treatment strategies are urgently needed. To accomplish this goal, we devised a strategy to identify compounds that act synergistically with remdesivir in preventing SARS-CoV-2 replication.

We conducted combinatorial high-throughput screening in the presence of submaximal remdesivir concentrations, using a human lung epithelial cell line infected with a clinical isolate of SARS-CoV-2. We identified 20 approved drugs that act synergistically with remdesivir, many with favorable pharmacokinetic and safety profiles. Strongest effects were observed with established antivirals, Hepatitis C virus nonstructural protein 5 A (HCV NS5A) inhibitors velpatasvir and elbasvir. Combination with their partner drugs sofosbuvir and grazoprevir further increased efficacy, increasing remdesivir's apparent potency 25-fold. We therefore suggest that the FDA-approved Hepatitis C therapeutics Epclusa (velpatasvir/sofosbuvir) and Zepatier (elbasvir/grazoprevir) should be fast-tracked for clinical evaluation in combination with remdesivir to improve treatment of acute SARS-CoV-2 infections.

Preprint available at bioRxiv (Sept. 18, 2020):

https://doi.org/10.1101/2020.09.18.302398

More than 1,000 incarcerated people died from hepatitis C-related complications between 2014 and 2019, even though a simple cure is available, according to a new STAT investigation.

He knew he had hepatitis C. And he knew, too, about the simple, once-daily pills that could fully cure him of the potentially deadly viral infection in about 12 weeks. But Ritchie was serving a 20-year sentence for armed robbery, and the Missouri Department of Corrections refused to treat him. Ritchie begged repeatedly for the medicine. He went through all the formal steps to request medical care. The prison system knew he was getting sicker and sicker — it documented his deteriorating condition in his health records. The prison’s doctors wrote frequently he would benefit from hepatitis C treatment. But officials still denied him, in the same way a STAT investigation documented prisons around the country are still denying thousands of others the cure. So the virus infecting Ritchie’s blood continued to replicate, scarring his liver until it was so damaged that it could hardly function. Eventually he was diagnosed with liver cancer, a common complication of untreated hepatitis C. Now, the prison argued, he was too sick for the drugs to work. They refused him again. “I don’t have the energy to do nothing anymore,” Ritchie told a court in 2019. “I try to talk too long, I can’t breathe … I get out and get a little fresh air, but I can’t do a lot of walking, and I can’t get in the sun.” He died in June 2021 at the age of 64, nearly five years after his first request for medication.

STAT’s investigation found that 1,013 people died of hepatitis C-related complications in states’ custody in the six years after the first cure, a Gilead antiviral drug called Sovaldi, hit the market in late 2013. This tally, based on an analysis of 27,674 highly restricted death records, has never before been reported. Many of those 1,013 people were not serving life sentences; they would likely have had the chance to return home, reapply for jobs, and reconnect with parents, spouses, and children — or, in Ritchie’s case, his one grandchild, Gabe. Many should not have died. In fact, the treatment for hepatitis C is a modern medical marvel. The scientists who paved the way for its discovery won a Nobel Prize. Public health experts say it’s possible to cut hepatitis C deaths to virtually zero, and effectively eliminate the virus as we’ve done with smallpox or polio. Francis Collins, the White House science adviser and former longtime director of the National Institutes of Health, called STAT’s findings “unacceptable.” “You have to wonder if this individual [Ritchie] had received [treatment] at the first opportunity, would he still be alive today?” Collins said. Told of STAT’s findings, Chelsea Clinton, a global health advocate and vice chair of the Clinton Foundation, said the rationing of hepatitis C care by prisons and people dying as a result is “incredibly infuriating.” “It certainly is a gross injustice that we are continuing to punish people who are already incarcerated as a punishment,” she said. “That sometimes there’s a death sentence attached if there’s untreated hepatitis C — that to me is morally indefensible.....

Harvey Alter, Michael Houghton and Charles Rice share the award for research on a virus that causes hundreds of thousands of deaths a year. A trio of scientists who identified and characterized the virus responsible for many cases of hepatitis and liver disease — hepatitis C — are the recipients of the 2020 Nobel Prize in Physiology or Medicine. The winners are Harvey Alter at the US National Institutes of Health in Bethesda, Maryland; Michael Houghton, now at the University of Alberta in Canada; and Charles Rice, now at Rockefeller University in New York City. Their work on the hepatitis C virus paved the way for effective treatments against the infection that are now available. The World Health Organization (WHO) estimates that 71 million people worldwide are chronically infected with hepatitis C, which causes nearly 400,000 deaths per year, mostly from cirrhosis and liver cancer. The prize is well deserved, says Ellie Barnes, who studies liver medicine and immunology at the University of Oxford, UK. “It stands out as an emblem of great science,” she says. “We’ve got to a point where we can cure most people who are infected.” The prizewinners will share an award of 10 million kronor (US$1.1 million).

Blood-borne pathogen

In the 1970s, Alter studied the transmission of hepatitis, or liver inflammation, as a result of blood transfusions. Earlier work had identified hepatitis A and B viruses, but Alter showed that a third, blood-borne viral pathogen could transmit the disease to chimpanzees. Houghton, then working at Chiron Corporation in Emeryville, California, and his colleagues identified the virus on the basis of genetic material from infected chimpanzees, showing that it was a new kind of RNA virus that belonged to the Flavivirus family. They named it hepatitis C virus. 

A team led by Rice, then based at Washington University in St. Louis, Missouri, used genetic-engineering techniques to characterize a portion of the hepatitis C genome responsible for viral replication, demonstrating its role in causing liver disease. Some researchers had considered virologist Ralf Bartenschlager at the University of Heidelberg a candidate for a Nobel prize for hepatitis C, for his research into ways to propagate the pathogen in the laboratory. But Bartenschlagerhe says that the Nobel committee made a reasonable choice. “It’s a really difficult decision,” he says. “I think the way they have approached it is fairly well understandable.” In the past, Houghton has been vocal critic of scientific prizes that limit the number of recipients; the maximum number of awardees for a single Nobel prize is three. In 2013, he declined a prestigious Canada Gairdner Award — which came with a $100,000 prize — because the award did not recognize his collaborators Qui-Lim Choo and George Kuo at Chiron. “He always wants to see his discovery as a team approach,” says Thomas Baumert, a virologist and hepatologist at the University of Strasbourg in France.

Vaccine difficulties

The result of research by the prizewinners and others has led to significant improvements in hepatitis testing and treatment. In the past decade, harsh and poorly effective treatments for the infection have been replaced by drugs that directly block the virus. These medicines have the potential to cure the vast majority of hepatitis C infections, but their high cost has limited access in many low- and middle-income countries. Treatment requires following a drug regimen for 8–12 weeks, says Barnes. “Many of the people living with hepatitis C remain in vulnerable settings or are i.v. drug users, where it’s actually quite hard to get the drugs to the people affected.”  Bartenschlager says that he hopes that the Nobel will bring attention to the “silent epidemic” of hepatitis C around the world. The WHO has set a goal of eradicating the hepatitis C virus by 2030, which Barnes says could be achievable. But to do so, she adds, might require a vaccine.

People infected with hepatitis C may be able to donate their kidney without the risk of infection spreading, a study has suggested. 

Hepatitis C is spreads through the bloodstream, therefore those infected are not allowed to donate blood or organs. 

Currently, hepatitis C kidneys can only be transferred to patients already infected with the virus. But American scientists now say the process is safe after successfully transplanting 53 infected kidneys into healthy recipients, none of whom contracted the virus.  American scientists say transplanting kidneys from patients with hepatitis C is safe after successfully transplanting 53 infected kidneys into healthy recipients. 

Hepatitis C is a viral infection that inflames the liver and is usually acquired from infected blood. If left untreated, the infection can cirrhosis - or scarring of the liver.  Over time, this can cause the liver to stop working properly. In severe cases, life-threatening problems such as liver failure or liver cancer can eventually develop. The virus killed 1.34million people in 2016 alone - 140,000 more than tuberculosis, 340,000 more than HIV and 621,00 more than malaria. Worldwide, it affects 71million people, and a great number of those infected will develop liver cancer or cirrhosis in the future. 

The study was carried out by the University of Tennessee Health Science Centre in Memphis.  All kidneys were successfully transplanted and participants received a 12-week-long antiviral therapy.  None of the patients showed any signs of hepatitis C following the procedures but they did contract other viral infections. Three developed the BK virus, which is common after transplantation and is treatable. Symptoms can feel like a common cold. The BK virus is a latent infection that lives in the kidneys in about 90 per cent of healthy people who show no sign of infection. Reactivation can occur after an organ transplant as the the immune system is put under heightened stress. But by the end of the 12-week study, all participants were infection-free.  

Results of the trial were published in July 15, 2019 in American Journal of Transplantation: