A research team has identified a new potential treatment target for diseases related to the human T-cell leukemia virus type 1, which includes a particular form of leukemia and a neuroinflammatory disorder that resembles multiple sclerosis.
Researchers from Penn State College of Medicine have identified a promising new target for addressing conditions associated with human T-cell leukemia virus type 1 (HTLV-1). Their study revealed that inhibiting a group of enzymes known as kinases—which play a vital role in regulating cellular functions—results in cell death through the breakdown of Tax, a vital protein for viral gene expression and the survival of HTLV-1 infected cells. These findings were published in Nature Communications.
HTLV-1 is a type of retrovirus that enters a host cell by integrating its genetic material into the host’s DNA. It affects between 10 to 20 million individuals globally, with the highest prevalence in areas such as southern Japan, central Australia, sub-Saharan Africa, South America, the Caribbean, and the Middle East. Around 10% of those infected go on to develop adult T-cell leukemia/lymphoma (ATLL) or a neuroinflammatory disorder akin to multiple sclerosis known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP).
“HTLV-1 is not extensively researched, and effective treatments for its associated diseases are currently lacking,” stated Edward Harhaj, a professor of microbiology and immunology at Penn State College of Medicine and the senior author of the study. “Our research may pave the way for new clinical strategies to target the Tax protein in patients infected with HTLV-1.”
The research team aimed to pinpoint the kinases necessary for the survival of cells infected by HTLV-1. They performed a short hairpin RNA screen using human cells transformed by the virus, systematically inhibiting the expression of more than 600 kinase-encoding genes. Their findings indicated that only one kinase, KDR (also known as VEGFR2), is crucial for the cell’s survival. To confirm their discovery, the team treated the cells with small-molecule inhibitors aimed at KDR, including one that is already FDA-approved. They found that blocking KDR resulted in cell death.
“KDR was not initially on our radar since it’s typically found in endothelial cells and plays a role in blood vessel formation,” Harhaj remarked. “We were surprised to find it expressed in T cells—white blood cells responsible for immune responses—and specifically in the leukemia we were examining. It’s the first time this kinase has been linked to the survival of these types of cells.”
The research indicated that KDR’s function in preserving HTLV-1-infected cells is related to the viral protein Tax, which is essential for viral gene expression, transmission, and cancer development. When KDR is suppressed, Tax is degraded, disrupting cancer-promoting signaling pathways and leading to cell death. Cells that did not express Tax remained unresponsive to KDR inhibition and survived. The same inhibition effects were observed in blood samples from patients with HAM/TSP.
“We have been examining the Tax protein for a considerable time, yet no one has identified a method to target it. We discovered a potential avenue by focusing on the host kinase KDR,” Harhaj explained. “KDR is typically not present in T cells, but Tax activates its expression and modifies its function, allowing it to maintain stability and resist degradation.”
The results indicate that KDR could serve as a potential drug target for treating ATLL and HAM/TSP. The researchers suggested that repurposing an existing KDR inhibitor or creating a new one might also decrease the viral load of HTLV-1, potentially lowering the likelihood of developing disease.
“From a clinical perspective, KDR inhibitors could have a significant impact, whether by treating patients already affected by the disease or administering it to those with high viral loads to prevent disease onset,” Harhaj noted.
The team intends to pursue further research in this area.
