Virus World

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

When scientists discovered that the Zika virus can survive in semen for up to 6 months, people exposed to the disease—especially those hoping to have children—were horrified. It’s now known that the virus can be sexually transmitted up to 41 days. Now, a new meta-analysis has found that 26 other viruses can also live in human semen and go on to infect the bloodstream. Those include the viruses that cause Ebola, HIV, hepatitis B, and herpes. After reviewing more than 3800 scientific publications, the authors also found evidence that at least 11 viruses can live in the testes, including those that cause influenza, dengue, and severe acute respiratory syndrome. 

These viruses could potentially be found in semen, too, the authors say. Though not all 27 viruses are capable of person-to-person transmission, they can have other serious consequences, like reducing fertility or increasing the risk of acquiring a sexually transmitted disease. Some of these viruses can even cause mutations in the DNA of sperm, which could then fertilize an egg and pass along the virus-induced mutations to future generations. 

The findings, published last week in the Centers for Disease Control and Prevention’s Emerging Infectious Diseasesjournal, suggest that more viruses can live in semen than previously thought.  But the authors warn that far more research is needed to understand how and whether the viruses can be sexually transmitted and exactly which viruses remain viable in semen, for how long, and at what concentrations. 

Original findings published in the journal Emerging Infectious Diseases:

https://doi.org/10.3201/eid2311.171049

Table of viruses found in semen available at:

https://wwwnc.cdc.gov/eid/article/23/11/17-1049-t1

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