Study shows MARCH8 protein protects against infection through antiviral mechanisms

According to a new study published in the eLife journal, a protein known as MARCH8 protects humans from infection by tagging the vesicular stomatitis virus (VSV) for destruction, while simply holding the HIV hostage.

These discoveries demonstrate how numerous strategies are used by an individual protein to protect cells against viral infections. The study could also enhance one’s interpretation of how HIV tricks the human immune defense.

Earlier studies have demonstrated that MARCH8 targets the viral proteins to prevent VSV and HIV from penetrating the human cells. These viral proteins are crucial for these viruses to penetrate cells. However, it is not clear how the MARCH8 protein does this.

Japanese researchers suspected that MARCH8 targets a specific amino acid, known as lysine, to potentially flag a crucial VSV envelope protein for destruction.

The VSV G-glycoprotein (VSV-G) has a short tail containing five lysines, making it an ideal target. The HIV envelope glycoprotein (Env), by contrast, has a very long tail with only two lysines, making it harder for MARCH8 to flag it for destruction.”

Kenzo Tokunaga, Study Senior Author and Principal Investigator, Department of Pathology, National Institute of Infectious Diseases

Tokunaga and his research group, including the study’s co-first authors and Postdoctoral Fellows Yanzhao Zhang and Takuya Tada, tested the concept by substituting the five lysines on the VSV-G tail with a total of five arginines—which constitute another type of amino acids.

The team also substituted the two lysines on the HIV Env tail with a couple of arginines. The substitution enabled the VSV-G to evade MARCH8, but not the HIV Env. This indicates that MARCH8 protein uses two different mechanisms to target VSV-G and HIV Env.

Rather than labeling the HIV Env for destruction, the researchers observed that MARCH8 protein holds it hostage, suppressing its potential to make infectious copies of itself (replicate) and proliferate to other kinds of cells.

When the researchers developed a mutant version of MARCH8 lacking a particular pattern of the amino acid called tyrosine, they discovered that HIV Env escaped successfully, enabling the virus to make copies of itself. This indicates that the tyrosine pattern seen in MARCH8 is crucial to its HIV defense strategy.

Our work may help explain why humans don’t develop symptoms when infected with VSV, even though it can make some animals, mostly cows, horses and pigs, very ill. The findings might also explain, at least in part, why HIV is able to hide from the human immune system, causing persistent infections that are difficult to treat.”

Kenzo Tokunaga, Study Senior Author and Principal Investigator, Department of Pathology, National Institute of Infectious Diseases