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Mark Manzano, Ph.D. (center), with his team (l-r): Andrew Murphy, Thomas Caldarera III, Anthony Carreira and Prasanth Viswanathan, Ph.D.
Image by Bryan Clifton
UAMS Researchers Secure $3.4 Million in NIH Grants after Finding Clues to Stealthy Cancer-Linked Virus
| LITTLE ROCK — New findings at the University of Arkansas for Medical Sciences (UAMS) toward unlocking the secrets of a stealthy virus linked to cancer have led to two grants totaling $3.42 million from the National Institutes of Health (NIH).
Mark Manzano, Ph.D., an assistant professor in the College of Medicine Department of Microbiology and Immunology, is studying how Kaposi sarcoma-associated herpesvirus (KSHV) causes cancer and how it evades the immune system. He received a five-year $3.02 million NIH R01 grant and is co-principal investigator on a two-year $420,335 NIH R21 grant. Craig Forrest, Ph.D., a professor in the same department, shares the co-principal investigator role on the R21 grant. Both Manzano and Forrest are members of the UAMS Winthrop P. Rockefeller Cancer Institute and the Center for Microbial Pathogenesis and Host Inflammatory Responses.
The virus is known for its ability to go into hiding, a dormant state called latency, where it avoids detection while still quietly helping tumors grow. Understanding how the virus stays hidden, and how to shut it down, could one day lead to new treatments or even ways to eliminate it entirely.
“This virus is like a master of disguise,” Manzano said. “It doesn’t need to cause mutations like many cancer-causing agents. It brings its own cancer-causing genes and reprograms the cell.”
KSHV is a member of the herpesvirus family and is most often associated with Kaposi sarcoma, a rare cancer that mostly targets people with weakened immune systems, such as those living with HIV and post-transplant patients. It often first appears in the mouth as painful oral lesions, and it affects the skin, lymph nodes and internal organs. It is also linked to other illnesses such as primary effusion lymphoma and multicentric Castleman disease. Although rare in the U.S., KSHV is widespread in parts of sub-Saharan Africa, where infection rates can exceed 80%.
Manzano is using the gene-targeting tool called CRISPR to study how KSHV behaves inside cells. His work revealed a surprise that became the basis for the NIH R01 grant: a previously unknown RNA molecule produced by the virus in a location typically used during active replication.
“We found this RNA where we didn’t expect it and in an area that’s only supposed to be active when the virus is replicating,” Manzano said. “But this RNA was showing up during latency, when the virus is supposed to be silent.”
The discovery changed his team’s thinking about how the virus stays dormant. Manzano believes this RNA acts like a controller, dictating the viral DNA’s shape to keep it in its cancer-promoting latent state rather than switching to its active, replicating phase, which often kills the cancer cell.
Understanding this control mechanism could lead to new ways to “break” latency, forcing the cancer cells to die.
“If you remove this RNA, everything changes,” he said. “The viral DNA starts to loosen up, and the virus may begin to wake up.”
While most researchers have focused on the virus’s latency genes, which are active while it’s hiding, the more exploratory R21 grant supports the study of lytic, or active, viral genes. Forrest and Manzano suspect the lytic genes could be playing a bigger role in cancer than previously thought.
“Most of the field has ignored these lytic genes because they show up in only 1% to 2% of tumor cells,” Manzano said. “But we think they might be producing signals that help the tumor grow or suppress the immune response.”
Manzano sees the long-term goal of this research as finding a way to either silence the virus permanently or eliminate it from the body altogether. One promising strategy could involve targeting the RNA molecule his lab discovered.
“We might be able to develop an antisense therapy, something that binds to the RNA and triggers the cell to destroy it,” he said. “That technology already exists; the question is whether we can adapt it to target this virus.”
Manzano believes a vaccine may be more feasible in connection with the proteins produced during viral reactivation, which is the focus of Forrest’s work and a potential angle for future prevention efforts.
Forrest also received an NIH R01 totaling $2.9 million that was announced in January and focuses on a key viral protein called LANA (latency-associated nuclear antigen), which helps KSHV evade the immune system and maintain latency.
Although the research centers on KSHV, Manzano said the findings could extend to other herpesviruses, including another cancer-causing virus Epstein-Barr virus (EBV) and herpes simplex virus. Like KSHV, those viruses use latency to persist in the body, usually for life.
The R01 grant was awarded by the NIH National Institute of Dental & Craniofacial Research under Award Number R01DE035025. The R21 grant was awarded by the NIH National Institute of Allergy and Infectious Diseases under Award Number R21AI189385.
The content of this news release is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Leading up to the R01 and R21 awards, Manzano and Forrest received support from the UAMS Center for Microbial Pathogenesis and Host Inflammatory Responses, a Center of Biomedical Research Excellence funded by the NIH National Institute of General Medical Sciences.
UAMS is the state’s only health sciences university, with colleges of Medicine, Nursing, Pharmacy, Health Professions and Public Health; a graduate school; a hospital; a main campus in Little Rock; a Northwest Arkansas regional campus in Fayetteville; a statewide network of regional campuses; and eight institutes: the Winthrop P. Rockefeller Cancer Institute, Jackson T. Stephens Spine & Neurosciences Institute, Harvey & Bernice Jones Eye Institute, Psychiatric Research Institute, Donald W. Reynolds Institute on Aging, Translational Research Institute, Institute for Digital Health & Innovation and the Institute for Community Health Innovation. UAMS includes UAMS Health, a statewide health system that encompasses all of UAMS’ clinical enterprise. UAMS is the only adult Level 1 trauma center in the state. UAMS has 3,553 students and 902 medical residents and fellows. It is the state’s largest public employer with about 12,000 employees, including 1,200 physicians who provide care to patients at UAMS, its regional campuses, Arkansas Children’s, the VA Medical Center and Baptist Health. Visit www.uams.edu or uamshealth.com. Find us on Facebook, X (formerly Twitter), YouTube or Instagram.###