Blocking the tyrosine kinase KDR could lead to cell death caused by the degradation of the TAX viral protein, thereby treating diseases associated with human T-cell leukemia virus type 1 (HTLV-1), according to a recent study published by Mohanty et al in Nature Communications.
Background
HTLV-1 is a retrovirus that infects about 10 to 20 million individuals across the world—primarily in southern Japan, central Australia, sub-Saharan Africa, South America, the Caribbean, and the Middle East. Approximately 10% of those infected develop adult T-cell leukemia/lymphoma (ATLL) or HTLV-1–associated myelopathy/tropical spastic paraparesis (HAM/TSP), a neuroinflammatory disease similar to multiple sclerosis. KDR is also known as VEGFR2. The TAX protein is essential for viral gene expression, viral transmission, and the survival of cells infected by HTLV-1.
“HTLV-1 is understudied and there is currently a lack of effective treatments for the diseases it causes,” stressed senior study author Edward Harhaj, PhD, Professor of Microbiology and Immunology at the Penn State College of Medicine. “Our study could lead to possible new clinical approaches to target the TAX protein in patients infected by HTLV-1,” he added.
Study Methods and Results
In the recent study, the researchers used human cells transformed by the HTLV-1 virus to perform a short hairpin RNA screen, allowing them to inhibit the expression of over 600 genes encoding kinases one at a time—with the goal of identifying kinases potentially necessary for the survival of HTLV-1–infected cells. They showed that only KDR was essential for the viability of the cells.
To validate their findings, the researchers then treated the cells with small-molecule inhibitors targeting KDR, including one U.S. Food and Drug Administration–approved tyrosine kinase inhibitor. When KDR was blocked, the cells died.
“KDR wasn’t on our radar because it’s normally expressed in endothelial cells and regulates blood vessel formation. We were surprised that it was expressed in T cells … and this particular leukemia we were studying. No one has ever implicated it before for the survival of these particular cells,” Dr. Harhaj emphasized.
Further, the researchers demonstrated that KDR’s role in the survival of HTLV-1–infected cells may be connected to the TAX protein—which is crucial for the development of cancer. Suppression of KDR led to the degradation of the TAX protein and disrupted cancer-causing signaling pathways, leading to cell death. The cells that didn’t express TAX weren’t sensitive to KDR inhibition and didn’t die. The researchers observed the same results when they inhibited KDR in blood samples from patients with HTLV-1–associated myelopathy/tropical spastic paraparesis.
“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. 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,” detailed Dr. Harhaj.
Conclusions
The findings represent the potential of the novel drug target for the treatment of ATLL and HTLV-1–associated myelopathy/tropical spastic paraparesis. The researchers proposed that repurposing an existing KDR inhibitor or developing a new drug may also reduce the viral load of HTLV-1, possibly minimizing the risk of developing disease.
“Clinically, KDR inhibitors could be very impactful, either by treating patients with disease or giving it to [patients] with high viral loads to prevent disease,” Dr. Harhaj underscored.
The researchers plan to continue their line of research to better understand their findings.
Disclosure: The research in this study was funded by the National Institute of Allergy and Infectious Diseases. For full disclosures of the study authors, visit nature.com.
