Leukemia is a terrible form of cancer in which the cancerous white blood cells travel throughout the bloodstream or lymphatic systems, and thus have access throughout the body to initiate tumors. Adult T cell leukemia is a particularly aggressive form of leukemia associated with Human T cell lymphotropic virus 1 (HTLV1) infection. After this retrovirus infects CD4+ helper T cells, it inserts randomly into the genome, where it produces the HTLV1 Tax protein. This protein is thought to initiate cell transformation via growth stimulation and repressing tumor suppressor genes. Researchers have been trying to identify specific targets of these transformed T cells.
What kind of tool can be used to target these transformed T cells? Some scientists think the answer is another virus. The Vesicular Somatitis Virus (VSV) is often used as a molecular tool – it is a well-characterized virus with a robust genetic system that can express genes from other viruses for characterization purposes, such as envelope-related genes. In a new article from the Journal of Virology, Dillon Betancourt and Dr. Glen Barber propose an engineered VSV may be more than a tool - it could be a means to infect and lyse HTLV1-infected T cells.
How to target VSV, which normally attaches to an LDL receptor, to T cells? The researchers used the gp160 gene from another T cell-targeting virus, HIV, to give the VSV a T-cell tropism (see schematic). This gene was cloned in place of the VSV-G gene, replacing its endogenous receptor. The researchers showed the new virus replicated only in CD4+ T cells using both cell culture and animal model systems – unlike the control VSV-XN2, there was no neurotoxicity of the VSV-gp160G in immunocompromised mice.
Proof-of-principle came from a mouse model of leukemia. Mice with tumors from a patient-derived luciferase-expressing tumor cell line were treated with VSV-gp160G or PBS. The VSV-gp160G group survived longer and had fewer metastatic lesions than PBS-treated mice.
How do the cancerous cells die? The researchers observed syncytia formation in the VSV-gp160G-infected T cells. Syncytia are the fusion of many cells to form giant cells with many nuclei. These abnormal cells alert the immune system, both by their presence and by their formation of exosomes carrying tumor-associated antigens. These syncytia cells help the immune system recognize and fight the tumors.
There are clearly many questions about this means of tumor attack that need to be addressed before application in the clinic. How will scientists prevent syncytia from forming uncontrolled, or incorporated noncancerous cells? Could the engineered VSV cause neurotoxicity associated with VSV-XN2? Will the VSV-gp160G attack healthy T cells? The engineered VSV used in this study forms a strong platform that scientists can use to ask these questions. And given that patients diagnosed with acute ATL can succumb in as short as 6-9 months, adding to the available tools to fight this disease will have a direct impact on many people’s lives.
-- Julie Wolf