A team of researchers from Penn State College of Medicine has found a new target for treating diseases associated with human T-cell leukemia virus type 1 (HTLV-1). They determined that blocking a class of enzymes called kinases, which regulate cellular functions, leads to cell death caused by the degradation of Tax, a protein essential for viral gene expression, viral transmission, and the survival of infected cells. are infected with HTLV-1. The team published the findings in Nature communications.
HTLV-1 is a retrovirus -? a type of virus that tricks a cell by inserting a copy of its genetic material into the host cells’ DNA – and infects 10 to 20 million people worldwide, mostly in southern Japan, central Australia, sub-Saharan Africa, South America, the Caribbean and the Middle East. About 10% of those infected will develop adult T-cell leukemia/lymphoma (ATLL) or a neuroinflammatory disease similar to multiple sclerosis called HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP).
HTLV-1 has not been well studied and there is currently a lack of effective treatments for the diseases it causes. Our study could lead to potential new clinical approaches to target the Tax protein in HTLV-1-infected patients.”
Edward Harhaj, professor of microbiology and immunology at Penn State College of Medicine and senior author of the study
The research team set out to identify the kinases that cells infected with HTLV-1 need to survive. Using human cells transformed by the virus, the researchers performed what is called a short hairpin RNA screen -. a molecular analysis that allowed the team to inhibit the expression of over 600 genes encoding kinases, one by one. The results showed that only KDR, a tyrosine kinase also known as VEGFR2, was necessary for cell viability. To validate their findings, the team then treated the cells with small-molecule inhibitors that target KDR, including one that is a Food and Drug Administration-approved tyrosine kinase inhibitor. When KDR was blocked, the cells died.
“KDR was not on our radar because it is normally expressed in endothelial cells and regulates blood vessel formation,” Harhaj said. “We were surprised that it was expressed in T cells—a type of white blood cell that protects against infection—and this particular leukemia we were studying. No one has ever implicated it before in the survival of these particular cells.”
The study showed that KDR’s role in the survival of HTLV-1-infected cells is linked to the viral protein called Tax. Tax is critical for viral gene expression, viral transmission, and cancer development. Suppression of KDR leads to Tax degradation and disrupts cancer-causing signaling pathways, leading to cell death. Cells not expressing Tax were insensitive to KDR inhibition and did not die. The team saw the same results when they inhibited KDR in blood samples from HAM/TSP patients.
“We have been studying the Tax protein for a long time, but no one has found a way to target it. We found a possible way by targeting the host kinase KDR,” Harhaj said. “KDR is not normally expressed on T cells, but Tax activates its expression and disrupts its function, allowing it to be stabilized and protected from degradation.”
The findings indicate a potential drug target for the treatment of ATLL and HAM/TSP. The researchers said that repurposing an existing KDR inhibitor or developing a new one could also potentially reduce the viral load of HTLV-1, potentially reducing the risk of disease development.
“Clinically, KDR inhibitors could be very effective, either treating patients with disease or giving them to people with high viral loads to prevent disease,” Harhaj said.
The team said it plans to continue this line of research.
Suchitra Mohanty, a postdoctoral fellow in microbiology and immunology at Penn State College of Medicine was the paper’s first author. Other authors of the paper include Sujit Suklabaidya, a postdoctoral fellow in microbiology and immunology at Penn State College of Medicine. Jun-ichi Fujisawa, professor, and Takaharu Ueno, assistant professor, from Kansai Medical University in Osaka, Japan. Nyater Ngouth and Steven Jacobson of the National Institute of Neurological Disorders and Stroke. and Alfonso Lavorgna, former postdoctoral fellow at Johns Hopkins School of Medicine and currently at Millipore-Sigma.
Funding from the National Institute of Allergy and Infectious Diseases supported this work.
Source:
Journal Reference:
Mohanty, S., et al. (2024). The tyrosine kinase KDR is essential for the survival of HTLV-1-infected T cells by stabilizing the Tax oncoprotein. Nature communications. doi.org/10.1038/s41467-024-49737-5.
