Fighting viruses that cause cancer

Contrary to how it may seem, most viruses do not want to kill their hosts. "They want to hang out as long as possible, make more viruses, and infect as many other hosts as they can," says Karl Munger, the Dorothy Todd Bishop Research Professor and chair of developmental, molecular and chemical biology at Tufts University School of Medicine. Unfortunately, that nasty proclivity of viruses to multiply and infect has some unintended consequences.

In the battle between host and invader, cells produce responses to stop viruses from growing, and viruses try and commandeer the cells' defense mechanisms and get them to replicate regardless. "There's a fight between host and virus; because it needs to multiply, it tries to convince a non-dividing cell to divide," Munger says, "which is one of the hallmarks of cancer."

Munger has been studying the connections between viruses and cancer for more than 30 years, starting with his Ph.D. at the University of Zurich, and including stints at the National Institutes of Health (NIH) and Harvard University, before coming to Tufts in 2014. By conservative estimates, viruses are responsible for 15% of cancers.

"It's probably double that if you look at cancers in which viral infections have contributed," says Munger, who focuses his work on human papillomavirus (HPV), the most common sexually transmitted infection. He joined Tufts with the intent of creating a nucleus for basic research into viruses and cancer, a relatively under-recognized and underfunded area of cancer research.

"Studying how viruses contribute to cancer is an opportunity to distinguish Tufts as a center of excellence in cancer research," says Munger, who is also interim vice dean for research at the School of Medicine.

That focus plays to the Tufts' strengths. Brian Schaffhausen, professor emeritus of developmental, molecular and chemical biology, has made seminal discoveries about the growth and suppression of tumors by focusing on murine polyomavirus. John Coffin, American Cancer Society Research Professor and Distinguished Professor in Molecular Biology and Microbiology, has long studied the connections between cancer and retroviruses such as HIV. Katya Heldwein, American Cancer Society, Massachusetts Division, Professor of Molecular Biology, examines how herpesviruses get in and out of cells—and how they might be stopped.

Recently, Tufts hired two new researchers: Rui Guo, assistant professor of molecular biology and microbiology, who focuses on Epstein-Barr virus (EPV) and joined the university last July; and Aaron Mendez, assistant professor of molecular biology and microbiology, who is a specialist on Kaposi's sarcoma-associated herpesvirus (KSHV) and joined Tufts in January.

Munger, who is also affiliated with the Graduate School of Biomedical Sciences, learned the power of collaboration early in his career. As a postdoctoral researcher at the NIH, he focused on two proteins, known as E6 and E7, that are expressed in cervical cancer associated with HPV. At that time, researchers didn't know whether they were drivers of cancer or mere innocent bystanders. In helping to solve that question, Munger was inspired by an annual meeting of researchers working on a specific tumor suppressor protein held in a farmhouse in Western Massachusetts, organized by leaders in the field, including the late David Livingston, who was physician-in-chief at Dana-Farber Cancer Research Institute.

"I learned that even though competition drives scientific progress, research should not be a blood sport, and in general it is more productive to solve problems with help from your friends," Munger wrote in "Viruses and Cancer: An Accidental Journey," an account of his research published in PLOS Pathogens in 2016.

Munger and his colleagues determined that those tiny viral proteins did in fact cause cancer by subverting the cells' usual signaling pathways to create uncontrolled division. "There are around 400 different kinds of HPV, and only a very small number of them are cancer-causing," Munger says. His lab is now looking at ways to target these viral proteins.

Targeting HIV

A class of viruses known as retroviruses, including HIV, infects the body by implanting themselves directly into the chromosomes inside the cell nucleus, joining their DNA to that of the host. Years ago, people thought HIV couldn't cause cancer, explains John Coffin, since HIV usually kills the cells that it infects.

Coffin's lab has long been studying how retroviruses cause cancer, first in animals, and more recently with HIV in human cells. When genetic material is integrated into the wrong gene, it can cause rampant cell division leading to cancer.

"Researchers have identified hundreds of genes like this, where a gene involved in cellular growth is supposed to be turned on and off, but instead it's turned on all the time," says Coffin, who has spent decades studying HIV and other retroviruses. "Then the cell goes out of control and divides all the time, which is basically what cancer is."

That's important, he says, since this process often starts before an individual knows they are infected. HIV patients are also particularly susceptible to side effects of cancer treatments like chemotherapy and radiation, which can stress already weakened immune systems.

Coffin has shown that HIV can cause cancerous changes when integrating into a specific area of the cell's DNA called the STAT3 gene. Identifying the specific cell and viral genes that can cause cancer can help scientists find a targeted treatment to prevent it. "If you can find a small molecule that turns off the expression of the virus, you can kill the cancer even long after it has started."

These therapies are becoming even more important for HIV patients, who can now live much longer than they used to due to new antiretroviral treatments that can extend life.

"Prior to the 1990s, patients were dying at a much younger age, and didn't have a chance to develop these problems," says Jose Caro, an attending physician at Tufts Medical Center and the Dr. Jane Murphy Gaughan Professor and assistant professor of medicine at the School of Medicine. In the late 1990s, physicians noticed many more HIV patients developing anal cancer, which is associated with HPV. While female patients are often screened for cervical cancer, he says, precursors to anal cancer were often left undetected until it was much farther along.

"Because HIV has an effect on the immune system, it is more likely that somebody would acquire another virus—or if they previously acquired the virus, that it would progress and replicate," says Caro. While 80% of sexually active people acquire HPV, it may persist in tissues of HIV patients longer than it does in others, he says—and the longer it persists, the higher likelihood of causing cancer.

Anal cancer, he adds, is a very difficult cancer to treat, especially in HIV patients with weakened immune systems. "Chemo and radiation come with their set of difficulties and side effects, at the same time, there are also the emotional and psychological side effects of having a genital cancer that can affect someone's sex life," Caro says. Lately, there has been hope for the condition, with a landmark study last year that identified a precursor to anal cancer that can help doctors catch it early.

Battling herpes

Another class of viruses that can cause cancer are herpesviruses—however, not the oral or genital herpes that usually come to mind. "There are nine different types of herpesviruses that infect humans, and only two cause cancer," says Katya Heldwein. Those are EBV, better known for causing infectious mononucleosis or "mono," and KSHV, which can cause a rare cancer affecting bone and soft tissue. Heldwein's research focuses on how these viruses get inside and out of these cells.

"If they can't get inside the cell, then the cell doesn't get infected," she says. Just as importantly, once viral material is inside the nucleus, "they still have to assemble all of the viral components, so the complete viral particle comes out to infect more cells. If you understand how this happens, you can identify weak points and target them."

Heldwein says viruses—including HIV and influenza—fuse with the cell membrane by using a single protein to unlock the membrane and spill its contents inside. Herpesviruses, however, distribute that unlocking function across three or four different proteins, Heldwein says.

"Instead of one person using a key, it's like one person picks up the key, another sticks it in the lock, another turns it, and another pushes open the door." It's a mystery why these viruses have evolved such a complicated method, she says, but it makes it much more difficult to target them with a vaccine. "You could raise antibodies against one protein, but in isolation, it might not look to the immune system the same way it does to its friends," she says. She and other biologists are just beginning to understand how all these parts work together.

While Heldwein doesn't focus specifically on the connection between herpesviruses and cancers, she is thrilled about the recruitment of Guo and Mendez, who work on cancer and EBV and KSHV respectively, to the School of Medicine.

Guo's research focuses on how EBV transforms normal human cells into cancerous ones, particularly in immunocompromised individuals. "Some 95 percent of people have this virus, but in most people, their immune system can suppress it, pushing it into the direction of latency," he says. In addition to mononucleosis, EBV can also cause certain types of cancer, such as Burkitt's lymphoma, which hides within white blood cells and can cause abnormalities within those cells that lead to cancer development.

As a postdoctoral researcher at Brigham and Women's Hospital and Harvard Medical School, Guo was interested in discovering how EBV manages such metabolic processes, performing genetic screens to see whether those genetic chances can be stopped. He and colleagues focused on how the virus uses certain nutrients, including a particular amino acid called methionine. In a paper published last year, they showed that in mice infected with Burkitt's lymphoma, a diet low in methionine changed the makeup of tumor cells, causing EBV to become visible to the immune system—and therefore potentially subject to attack.

"Just by changing the diet, we could see the EBV gene got repressed in those mice, and the tumor stopped growing within two weeks," Guo says. While treatment in humans is still a way off, the findings provide hope that a similar strategy could be followed as an alternative to more invasive chemo and radiation therapies, perhaps combined with T-cells that can target tumor cells in the blood.

While all these researchers are pursuing different viruses, exploring different pathways towards intervention, there are enough commonalities in their approach to make collaboration fruitful, says Munger. Each is examining the mechanism in which these viruses manipulate the body's genetic processes and cause cells to become cancerous—and each is searching for a way to stop that malfunction with treatments that could potentially be a less invasive alternative to current cancer treatments.

While such research can be slow, and frustrating at times, the payoff could be huge, says Munger, who is often reminded of something his mentor Livingston, who passed away in 2021, used to say, "Even if you have bad days where your grants get rejected and your research doesn't work, a cancer patient never has a good day." That idea has always stuck with Munger and continues to motivate him to create a powerful center of excellence devoted to viruses and cancer. "There are a lot of commonalities between what these viruses do and the pathways they target," he says. "This is definitely something we can examine together."

Provided by Tufts University