Virus World

Although testing for CMV during pregnancy isn’t routine and there isn’t universal screening for infants, there are steps pregnant people can take to protect themselves and their newborns.

In a recent study published in the Proceedings of the National Academy of Sciences journal, researchers assessed the efficiency of a novel intranasal and injectable therapy in improving life expectancy. The association of increasing age with the decrease in telomere repeat elements found at the end of chromosomes has been well documented. This reinforces the need to develop effective methods of mitigating the effect of aging on human well-being. 

About the study

In the present study, researchers determined the impact of a high-capacity cytomegalovirus vector (CMV) on factors like follistatin (FST) and telomerase reverse transcriptase (TERT) that protect against the influence of aging on human health. The team developed a mouse CMV (MCMV) vector that expressed luciferase as a reporter gene (MCMVLuc) in order to surveil MCMV infection and its replication in culture as well as in a mouse model. Replicated MCMVLuc along with its parental virus was used in this study as a wild-type MCMV virus inoculation (WT) or viral vector control. The team also generated recombinant MCMV vectors that expressed FLAG-tagged genes telomerase reverse transcriptase (TERT) and FST (MCMVTERT and MCMVFST).  Furthermore, the team fused the mouse TERT with the FLAG-tag at the C-terminus using two intermediate amino acids, namely arginine and threonine. The expression kinetics of the target protein and the therapeutic effectiveness of CMV was determined by evaluating the levels of TERT in the blood samples of eight-month-old mice over a span of a month post-treatment. The extension of life after treatment was evaluated by administering seven out of nine groups of aged female mice with mock treatment intraperitoneally (IP), WT-treated intranasally (IN) (WT-IN), WT-IP, MCMVTERT-IN, MCMVTERT-IP, MCMVFST-IN, and MCMVFST-IP, respectively. The treatment was first started in 18-month-old mice. The team sacrificed one mouse in each group at 24 months to perform tissue analysis while the rest of the mice were monitored for changes in their physiology until their natural death. Furthermore, the length of telomeres in kidneys and muscle tissues was determined, and comparisons were drawn between those in different mice groups using quantitative fluorescence in situ hybridization (Q-FISH). The team also estimated the telomere length observed in the skeletal muscles of mice treated with TERT. The telomere length of various organs was also evaluated using real-time quantitative polymerase chain reaction (qPCR).    

Results

The study results showed that the FLAG-tagged genes MCMVTERT and MCMVFST replicated to a degree comparable to that of MCMVLuc (WT) in the fibroblast cells in mice and in vivo. The expression of TERT protein when administered IN or IP was its highest seven days after treatment before gradually reducing to its basal level on day 25. This indicated that the vector was able to deliver proteins in an in vivo environment. Analysis of FST and TERT messenger ribonucleic acids (mRNAs) and proteins in blood and tissue samples obtained from treated animals. Analysis of the impact of treatment on life extension showed that the WT and mock control mice succumbed after a median duration of 26.7, 26.5, and 26.4 months. The median age of death in the MCMVFST-treated and the MCMVTERT-treated mice was 35.1 and 37.5 months, respectively. The team noted that the longest lifespan was observed in MCMVTERT-treated mice at 41.2 months, while that in the MCMVFST-treated mice was 38.0 months. The team remarked that CMV therapy was comparable in effectiveness irrespective of the route of inoculation, which suggested that the expression of genes was not significantly impacted by the interaction of the vector with the immune system. The results of the Q-FISH method showed an increase of 3.1-fold in the length of telomeres in the kidneys of TERT-treated mice in comparison to the untreated mice controls. Moreover, the number of telomeres observed in the kidneys of mice treated with TERT was significantly higher than those in the untreated mice or those treated with WT. Notably, no substantial changes were found in FST-treated or the WT-treated subjects which suggested the efficiency of TERT in the TERT-treated mice. The team also observed that the telomere length in the muscular tissues of the TERT-treated mice increased by almost three times as compared to those in the untreated subjects. In contrast, there was no substantial increase in the telomere length in the FST- or the WT-treated mice. Moreover, qPCR showed no variation in the length of the telomeres in the different tissues of mice treated with TERT. The team noted that the relative telomere length in the brain, heart, lung, liver, and kidney in 24-month-old MCMVTERT-treated mice was almost three times more than that in untreated mice of the same age. 

Conclusion

Overall, the study findings showed the importance of investigating the impact of CMV TERT and FST vector usage against conditions related to aging, such as chronic inflammatory conditions, sarcopenia, type 2 diabetes, and heart diseases.  

Cited research published in P.N.A.S. (May 10, 2022):

https://doi.org/10.1073/pnas.2121499119 

Tailored T-cells specially designed to combat a half dozen viruses are safe and may be effective in preventing and treating multiple viral infections, according to research led by Children's National Hospital faculty. 

Catherine Bollard, M.B.Ch.B., M.D., director of the Center for Cancer and Immunology Research at Children's National and the study's senior author, presented the teams' findings Nov. 8, 2019, during a second-annual symposium jointly held by Children's National and the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH). Children's National and NIAID formed a research partnership in 2017 to develop and conduct collaborative clinical research studies focused on young children with allergic, immunologic, infectious and inflammatory diseases. Each year, they co-host a symposium to exchange their latest research findings. According to the NIH, more than 200 forms of primary immune deficiency diseases impact about 500,000 people in the U.S. These rare, genetic diseases so impair the person's immune system that they experience repeated and sometimes rare infections that can be life threatening. After a hematopoietic stem cell transplantation, brand new stem cells can rebuild the person's missing or impaired immune system. However, during the window in which the immune system rebuilds, patients can be vulnerable to a host of viral infections.

Because viral infections can be controlled by T-cells, the body's infection-fighting white blood cells, the Children's National first-in-humans Phase 1 dose escalation trial aimed to determine the safety of T-cells with antiviral activity against a half dozen opportunistic viruses: adenovirus, BK virus, cytomegalovirus (CMV), Epstein-Barr virus (EBV), Human Herpesvirus 6 and human parainfluenza-3 (HPIV3). Eight patients received the hexa-valent, virus-specific T-cells after their stem cell transplants:

• Three patients were treated for active CMV, and the T-cells resolved their viremia.
• Two patients treated for active BK virus had complete symptom resolution, while one had hemorrhagic cystitis resolved but had fluctuating viral loads in their blood and urine.
• Of two patients treated prophylactically, one developed EBV viremia that was treated with rituximab.

Two additional patients received the T-cell treatments under expanded access for emergency treatment, one for disseminated adenoviremia and the other for HPIV3 pneumonia. While these critically ill patients had partial clinical improvement, they were being treated with steroids which may have dampened their antiviral responses. 

"These preliminary results show that hexaviral-specific, virus-specific T-cells are safe and may be effective in preventing and treating multiple viral infections. Of note, enzyme-linked immune absorbent spot assays showed evidence of antiviral T-cell activity by three months post infusion in three of four patients who could be evaluated and expansion was detectable in two patients." Michael Keller, M.D., pediatric immunologist at Children's National and the lead study author.

Takeda’s cytomegalovirus (CMV) drug, maribavir, beat Roche’s Valcyte at clearing the virus from patients’ blood in a phase 2 study. The study compared the drugs in patients with CMV infection after receiving an organ transplant or a stem cell transplant. 

Patients who have undergone a transplant are among the most vulnerable to CMV infection because they must take immunosuppressive drugs to ward off organ rejection. CMV doesn’t usually cause symptoms in healthy people, but once someone is infected, the virus stays in their body in a dormant state. However, it can “wake up” in people with weakened immune systems, like transplant patients. 

The phase 2, open-label study tested three doses of maribavir in 159 adults, comparing it to Valcyte (valganciclovir). After three weeks of treatment, 62% of patients taking maribavir had no signs of CMV in their blood plasma, compared to 56% of those on Valcyte. After six weeks, 79% of maribavir patients had cleared the virus, compared to 67% of Valcyte patients. The findings appear in the New England Journal of Medicine.  “The Phase 2 study showed that maribavir has demonstrated antiviral activity as a potential treatment of CMV infection and demonstrated a reduction of actively multiplying CMV in the blood, following hematopoietic cell transplant or solid organ transplant,” Takeda said in a statement. 

Takeda is already enrolling two phase 3 studies for maribavir. One will test the drug in stem cell transplant patients with their first CMV infection and the other will test it in patients who have received a stem cell or solid organ transplant and have a resistant or refractory CMBV infection. The second study will pit maribavir against treatments chosen by the study investigators, including Valcyte and a trio of antivirals that were approved in the 1980s and 1990s.  

Maribavir’s safety profile may pose a challenge—67% of patients taking maribavir had a treatment-related side effect, compared to 22% of those on Valcyte. Serious side effects, such as acute graft-versus-host disease, diarrhea and renal failure, affected 10% of maribavir patients versus 2% of Valcyte patients. But the lack of treatments for patients with stubborn CMV infections may outweigh these issues. Maribavir has orphan drug status in the U.S. and EU. “There is a significant unmet need for additional treatment for post-transplant patients with CMV infection especially those with a CMV infection that is resistant to currently available antiviral therapies,” said principal investigator Johan Maertens, M.D., Ph.D. of Universitaire Ziekenhuizen Leuven in Leuven, in a statement. “These results are encouraging and warrant further investigation of maribavir as a potentially effective and tolerated treatment for CMV in transplant patients.”  Maribavir, also called TAK-620, has had a checkered past. ViroPharma abandoned a phase 3 CMV trial in 2009 after the drug failed to beat placebo in reducing the rate of CMV in patients who had undergone a bone marrow transplant. Maribavir, along with the hereditary angioedema drug Cinryze in ended up at Shire through its $4.2 billion ViroPharma buyout in 2013, and eventually landed at Takeda following its $62 billion megamerger with Shire.

Study published on Sept. 19, 2019 in New England Journal of Medicine:

https://doi.org/10.1056/NEJMoa1714656

A promising vaccine that clears an HIV-like virus from monkeys is closer to human testing after a new, weakened version of the vaccine has been shown to provide similar protection as its original version.

The vaccine uses a form of the common herpes virus cytomegalovirus, or CMV—was live-attenuated, or weakened so CMV couldn't spread as easily. The new version still managed to eliminate SIV, the monkey version of HIV, in 59 percent of vaccinated rhesus macaques. That result is similar to earlier findings involving the vaccine's original, non-attenuated version. The immunity generated by the attenuated vaccine was also long-lasting, as nine of 12 vaccinated monkeys could still fight off SIV infection three years later.

"These papers are important because they recapitulate the previously reported unique CMV vector efficacy with a genetically modified vector that is highly attenuated and therefore potentially safer for clinical  use" said Louis Picker, M.D., a corresponding author on both papers. "In addition, this new work demonstrates most vaccinated rhesus monkeys that are protected against SIV can also be protected against a second challenge years after initial vaccination. This is a level of durability that would be very important for a human HIV vaccine". The CMV vaccine platform has been licensed by Vir Biotechnology, Inc., of San Francisco, which plans to lead a clinical trial with a human version of the CMV-based HIV vaccine. 

The studies were published on July 17 on Science Translational Medicine:

https://doi.org/10.1126/scitranslmed.aaw2607

https://doi.org/10.1126/scitranslmed.aaw2603 

Aging, or senescent cells, which stop dividing but don’t die, can accumulate in the body over the years and fuel chronic inflammation that contributes to conditions such as cancer and degenerative disorders. In mice, eliminating senescent cells from aging tissues can restore tissue balance and lead to an increased healthy lifespan. Now a team led by investigators at Massachusetts General Hospital (MGH), a founding member of Mass General Brigham (MGB), has found that the immune response to a virus that is ubiquitously present in human tissues can detect and eliminate senescent cells in the skin. For the study, which is published in Cell, the scientists analyzed young and old human skin samples to learn more about the clearance of senescent cells in human tissue. The researchers found more senescent cells in the old skin compared with young skin samples. However, in the samples from old individuals, the number of senescent cells did not increase as individuals got progressively older, suggesting that some type of mechanism kicks in to keep them in check. Experiments suggested that once a person becomes elderly, certain immune cells called killer CD4+ T cells are responsible for keeping senescent cells from increasing. Indeed, higher numbers of killer CD4+ T cells in tissue samples were associated with reduced numbers of senescent cells in old skin. When they assessed how killer CD4+ T cells keep senescent cells in check, the researchers found that aging skin cells express a protein, or antigen, produced by human cytomegalovirus, a pervasive herpesvirus that establishes lifelong latent infection in most humans without any symptoms. By expressing this protein, senescent cells become targets for attack by killer CD4+ T cells.

“Our study has revealed that immune responses to human cytomegalovirus contribute to maintaining the balance of aging organs,” says senior author Shawn Demehri, MD, PhD, director of the High Risk Skin Cancer Clinic at MGH and an associate professor of Dermatology at Harvard Medical School. “Most of us are infected with human cytomegalovirus, and our immune system has evolved to eliminate cells, including senescent cells, that upregulate the expression of cytomegalovirus antigens.” These findings, which highlight a beneficial function of viruses living in our body, could have a variety of clinical applications. “Our research enables a new therapeutic approach to eliminate aging cells by boosting the anti-viral immune response,” says Demehri. “We are interested in utilizing the immune response to cytomegalovirus as a therapy to eliminate senescent cells in diseases like cancer, fibrosis and degenerative diseases.” Demehri notes that the work may also lead to advances in cosmetic dermatology, for example in the development of new treatments to make skin look younger.

Co-authors include Tatsuya Hasegawa, Tomonori Oka, Heehwa G. Son, Valeria S. Oliver-García, Marjan Azin, Thomas M. Eisenhaure, David J. Lieb, and Nir Hacohen. This study was supported by the Burroughs Wellcome Fund and Shiseido Co. Ltd.

Study Published in Cell (March 30, 2023):

https://doi.org/10.1016/j.cell.2023.02.033

Takeda has scored the first-ever FDA approval of a treatment for refractory cytomegalovirus (CMV) infections in organ transplant patients, which can lead to an increased risk of complications and even death. Livtencity (maribavir) has been cleared for use in transplant patients aged 12 or over with CMV infections that do not respond to first-line treatment with current antiviral drugs for CMV, such as ganciclovir, valganciclovir, foscarnet and cidofovir. The FDA followed its advisory committee’s advice and backed Livtencity for use regardless of whether patients are infected with CMV strains that have resistance mutations, as checking for these could delay treatment. Maribavir works by blocking the activity of a CMV enzyme called pUL97 that is essential for replication of the virus, and also avoids some of the serious haematological side effects that are associated with the older antivirals. It was one of the drugs acquired by Takeda when it merged with Shire in 2019. The approval marks the culmination of a lengthy development for a drug that failed a phase 3 trial more than a decade ago for CMV prevention in hematopoietic stem cell transplant (HSCT) recipients.

Originally developed by GlaxoSmithKline, it was licensed to ViroPharma, which was subsequently bought put by Shire. The approval is based on the phase 3 SOLSTICE trial. which showed Livtencity was superior to conventional antiviral therapies in refractory CMV. More than 55% of transplant recipients with refractory infections achieved confirmed viral clearance with Takeda’s drug, compared to around 24% of those on the older drugs. CMV is one of the most common and serious post-transplant infections with an estimated incidence rate of between 16% and 56% in solid organ transplants, and 30% to 70% in HSCT procedures. Livtencity is one of Takeda’s ‘Wave1’ of new therapies that the company said a couple of years ago could collectively add more than $10 billion in aggregate peak sales, and the drugmaker has previously predicted sales revenues from the drug could top $700 million a year at peak. There’s no word yet on pricing, but Takeda said it would launch the drug “in the coming days.”

Dengue infection (DI) is the most important arboviral infection in the world. The majority of immunocompetent patients will have asymptomatic or mild infections, but the degree of dengue severity in kidney transplant recipients (KTx) is unknown. In recent decades, the growing number of organ transplant recipients in developing countries, living in or traveling to an endemic area of dengue, is at risk of developing this infection. Additionally, in kidney transplant recipients (KTx), DI may be associated with other viral infections, such as cytomegalovirus (CMV), increasing the risk for the recipients after renal transplantation (Tx). Because CMV remains one of the most important viruses affecting KTx, it is not clear whether the CMV coinfection may modify the outcome of DI as it usually does in other viral coinfections

In this study, we report the clinical profile and outcomes of 39 dengue cases in KTx. From a total of 1,186 KTx outpatients in follow-up we reviewed clinical and laboratory records of 60 (5%) patients admitted with suspected DI initially screened by NS-1, IgM, and when possible, multiplex nested PCR. The prevalence of DI in KTx was 3% (39/1,118), with symptoms leading to hospital admission being fever, myalgia, malaise, and headache.

Laboratory tests showed leucopenia, thrombocytopenia, and liver enzyme elevation. DI was confirmed by positivity of NS-1 (33%), IgM (69%), and/or RT-PCR (59%). Twenty-three patients (59%) had dengue with warning signs, and 15% had severe dengue, 2 of them with a fatal course. Acute graft dysfunction occurred in 59% (mean nadir serum creatinine: 2.9 ± 2.6mg/dL), 4 of them requiring dialysis. CMV coinfection diagnosed in 19% of the cases and patients was associated with worse clinical presentation.

Our results suggest that KTx with DI presented initial physical and laboratorial profile similar to the general population. However, DI in KTx seems to have a higher risk for graft dysfunction, severe dengue, and death. Because CMV coinfection aggravates the DI clinical presentation and recovery, it must be evaluated in all cases.

Published in PLOS One (October 30, 2019):

https://doi.org/10.1371/journal.pone.0219117

Latent herpes virus reactivation has been documented in more than half of astronauts during space shuttle and International Space Station missions, and according to a recent study funded by NASA, the cause is stress.“Herpes virus is a broad category of viruses, beyond the small subset that cause sexually transmitted diseases.Most humans become infected early in life with one or more, and never fully clear these viruses,” Satish Mehta, PhD, senior scientist in the immunology/virology lab at the Johnson Space Center in Houston, told Infectious Disease News.

Results showed that 47 out of 89 (53%) astronauts on short space shuttle flights, and 14 out of 23 (61%) on longer space station missions shed herpes viruses in their saliva or urine samples. According to the study, astronauts shed four of the eight major human herpes viruses: Epstein-Barr, varicella-zoster and herpes simplex-1 in saliva and cytomegalovirus in urine. The researchers said most astronauts were asymptomatic, with only six developing symptoms.

“Larger quantities and increased frequencies for these viruses were found during spaceflight as compared to before or after flight samples and their matched healthy controls,” Mehta and colleagues wrote.  Mehta explained why: “[The] short answer is stress. In people with reduced immunity, such as the elderly or stressed individuals, these viruses can awaken and cause disease,” he said.

“Although NASA believes there is no clinical risk to astronauts during orbital spaceflight, there is concern that during deep space exploration missions, there may be clinical risks related to viral shedding. Although we do not have a serious clinical problem related to herpes viruses, their reactivation is an excellent ‘flag,’ or biomarker, for stress and reduced immunity.”

In the study, Mehta and colleagues noted that continued viral shedding after a flight can pose a potential risk for crew who may encounter infants, seronegative adults or immunocompromised people, so protocols have been put in place. 

The study was published in February 2019  in Frontiers in Microbiology - Virology:

https://doi.org/10.3389/fmicb.2019.00016