Healthcare (Commonwealth Union) – A research team from Penn State College of Medicine has identified a new target for treating diseases linked to human T-cell leukemia virus type 1 (HTLV-1). They discovered that inhibiting a group of enzymes known as kinases, which are responsible for regulating cellular functions, results in cell death by degrading Tax, a protein critical for viral gene expression, viral transmission, and the survival of HTLV-1-infected cells. Their findings appeared in Nature Communications.
The research team indicated that HTLV-1 is a retrovirus that infects cells by integrating a copy of its genetic material into the host cell’s DNA. It affects between 10 to 20 million people globally, mainly in southern Japan, central Australia, sub-Saharan Africa, South America, the Caribbean, and the Middle East. About 10 percent of those infected will develop adult T-cell leukemia/lymphoma (ATLL) or a neuroinflammatory disease resembling multiple sclerosis called HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP).
Edward Harhaj, a professor of microbiology and immunology at Penn State College of Medicine and the senior author of the study indicated that HTLV-1 is not well-studied, and there are currently no effective treatments for the diseases it causes. He further pointed out that their research may lead to new clinical methods to target the Tax protein in patients infected with HTLV-1.
The research team aimed to identify the kinases necessary for the survival of HTLV-1-infected cells. With the utilization of human cells transformed by the virus, they conducted a short hairpin RNA screen, a molecular analysis that enabled them to block the expression of more than 600 genes that encode kinases, one by one. The findings revealed that only KDR, a tyrosine kinase also known as VEGFR2, was crucial for the cells’ viability. To confirm their results, the team treated the cells with small-molecule inhibitors targeting KDR, including one that is a Food and Drug Administration (FDA) – approved tyrosine kinase inhibitor. When KDR was inhibited, the cells died.
“KDR wasn’t on our radar because it’s normally expressed in endothelial cells and regulates blood vessel formation,” says Harhaj. “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 for the survival of these particular cells.”
The research demonstrated that KDR’s function in the persistence of HTLV-1-infected cells is linked to the viral protein Tax. Tax plays a vital role in viral gene expression, transmission, and cancer development. Inhibiting KDR results in the breakdown of Tax and interrupts cancer-promoting signaling pathways, ultimately causing cell death. Cells lacking Tax expression were not affected by KDR inhibition and remained viable. The team observed similar outcomes when they blocked KDR in blood samples from patients with HAM/TSP.
“We’ve been studying the Tax protein for a long time, but no one has found a way to target it. We found a potential way by targeting the host kinase KDR,” Harhaj explained. “KDR is not normally expressed in T cells, but Tax turns on its expression and hijacks its function, enabling it to stabilize and protect itself from degradation.”
The findings pointed in the direction of the possibility of a drug target for treating ATLL and HAM/TSP. The researchers noted that repurposing an existing KDR inhibitor or creating a new one might also lower the viral load of HTLV-1, which could potentially decrease the risk of disease development.
Harhaj further pointed out that from a clinical perspective, KDR inhibitors could be highly effective, either in treating patients with the disease or in administering it to individuals with high viral loads to prevent the disease.
The team mentioned that they intend to pursue further research in this area. Many discoveries are made by accident or in the case of this research focusing on a previously neglected area.
