P12 protein influences key cell-signaling pathway

New research shows that a protein produced by a cancer-causing virus influences a key signaling pathway in the immune cells that the virus infects. This stimulates the cells to divide, helping the virus spread through the body.

The study, led by researchers at Ohio State University, examined the human T lymphotropic virus type 1 (HTLV-1) and a protein that it produces called p12.

The research is published in the April issue of the journal AIDS Research and Human Retroviruses.

The study found that p12 increases the activity of an important gene in host cells. That gene controls production of a cell protein called p300. The p300 protein, in turn, controls a variety of other genes in many types of cells, including T lymphocytes, the cells that HTLV-1 infects.

The findings might help scientists better understand how HTLV-1 maintains its lifelong infection and how the normal immune cells that “remember” a vaccination or an infection can survive for years or even decades.

“The p300 protein is an important central regulator of gene activity in lymphocytes and many other kinds of cells,” says Michael Lairmore, professor and chair of veterinary biosciences and a member of the OSU Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute. “We were surprised to see p300 show-up among the many genes affected by this viral protein.”

HTLV-1 infects an estimated 15 to 20 million people worldwide. In about five percent of them, the infection will lead to adult T cell leukemia or lymphoma (ATLL). ATLL is an aggressive disease characterized by a long latent period and the proliferation of T lymphocytes. The virus is spread by sexual activity, by contact with infected blood and by infected women to children through breast milk.

HTLV-1, like its cousin HIV, inserts its genetic information permanently into the DNA of a T lymphocyte and remains there for the life of the cell. HTLV-1 infection is also lifelong. A hallmark of HTLV-1 infection is the proliferation of T lymphocytes.

This sets HTLV-1 apart from HIV, Lairmore says. “Unlike HIV, which kills cells and destroys the immune system, HTLV-1 enhances the survival of T cells.”

But scientists don't understand how it prolongs T-cell survival and causes their proliferation.

This study's findings offer some clues. It is the latest in a series of studies led by Lairmore that examine how HTLV-1 affects T lymphocytes and causes cancer.

The p12 gene is called an “accessory gene” because the protein encoded by the gene seemed unnecessary since the virus could still reproduce, or replicate, in cells grown in the laboratory even when p12 was missing.

“But viruses do not keep genes unless they have a purpose,” Lairmore says. In an earlier study, Lairmore and his colleagues tried to infect an animal model with an HTLV-1 that lacked the p12 gene, and it stopped the virus from replicating almost entirely.

“That told us this gene was important,” he says.

Subsequent research led by Lairmore showed that the p12 protein travels to the network of membranes within the cell known as the rough endoplasmic reticulum (RER). Among other things, the RER helps regulate the amount of calcium in the cell. The investigators found that the p12 protein allows calcium to leak out of the RER, thereby causing calcium levels to rise elsewhere in the cell.

“Calcium is exquisitely regulated in cells,” Lairmore says. “When p12 affects that balance, it affects the activity of a variety of genes.”

The current study used a non-infectious form of HIV to transplant the HTLV-1 p12 gene into laboratory-grown T cells. The infected cells then produced a constant level of p12 protein. The researchers then used gene microarray technology to identify which cellular genes out of 33,000 become either more or less active due to the p12 protein.

The researchers found that p12 altered the activity of a variety of genes linked to chemical pathways that control cell signaling, proliferation and death. The p300 gene stood out as one showing increased activity.

Taken overall, the findings suggest that HTLV-1 p12 protein influences the genetic activity of infected T cells to stimulate their proliferation and promote efficient viral infection.

Funding from National Cancer Institute supported this research.