BioWorld International Correspondent

LONDON - New insights into how a virus that infects lymphocytes can sneak from cell to cell could allow pharmacologists to design drugs that inhibit viral enzymes. The researchers who carried out the work, on a virus called human T lymphotropic virus type 1 (HTLV-1) say their findings could be relevant to the search for new drugs to treat HIV, which may well spread between cells in a similar way.

HTLV-1 is estimated to infect between 10 million and 20 million people worldwide. Up to 3 percent of them develop a rapidly fatal form of leukemia, and a further 3 percent develop a chronic inflammatory disease called HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), which causes weakness and paralysis of the legs but is not usually fatal.

An important implication of the study, carried out by Charles Bangham, professor of immunology at Imperial College London, and colleagues, together with collaborators in Oxford, UK, and Japan, is that the diseases caused by HTLV-1 should be amenable to treatment with drugs.

The group has published its findings in a paper in the Feb. 13, 2003, issue of Science titled "Spread of HTLV-1 between lymphocytes by virus-induced polarization of the cytoskeleton."

Bangham and his colleagues set out to challenge the accepted wisdom that HTLV-1, having infected cells in the body, remains latent; that although its genome is incorporated into that of the host, its genes are not expressed.

Bangham told BioWorld International, "We argued against that, because there is a very strong immune response to the virus, and you only get such a response if there is chronic expression of the virus. Nevertheless, it is difficult to find virus particles, which people said you should be able to find if the virus was active."

The group also knew that there had been no documented cases where the infection had been passed from one person to another via body fluids that were free of cells, such as plasma, whereas transfer of body fluids that contained lymphocytes (such as breast milk, semen or transfusion of whole blood) could transfer the infection.

They therefore decided to concentrate on the role of the lymphocytes. Their investigations showed that lymphocytes that recognized HTLV-1 seemed to be preferentially infected with the virus.

"This made us wonder if the lymphocytes get infected during the time when they are recognizing the virus in another cell," Bangham said. "We concluded that cell-cell contact must play an important part in the cells' becoming infected, and decided to examine this further."

Researchers took lymphocytes from people with HAM/TSP and mixed them with lymphocytes from healthy donors for about half an hour. They examined the cells using confocal microscopy, which allowed them to see exactly where the proteins were in the cell.

Lymphocytes, in common with many other types of cell, have a cytoskeleton made of microtubules. In a resting lymphocyte, the focal point of the microtubules - the microtubule organizing center (MTOC) - is located close to the nucleus. But when a lymphocyte detects viral proteins on the surface of an adjacent cell, the MTOC moves to the point at which the two cells are touching. If it is a cytotoxic T cell that recognizes the virus-infected cell, the microtubules form a conduit along which the cytotoxic T cell pours out cytokines in order to kill the other cell.

When Bangham and his colleagues looked at the paired cells that resulted from their experiment, they found that viral proteins accumulated at the point of contact and were then transferred into the uninfected cells. "The virus seems to have subverted the normal function of the microtubules. Viral particles appear to jump onto the tracks' of the microtubules and can then move into the healthy cells," Bangham said.

He added that a similar process may account for cell-cell transfer of virus in HIV infection.

The group is now going to concentrate on identifying the molecules that enable the virus to point the healthy cell's cytoskeleton in the "wrong" direction. They also will investigate why some people infected with HTLV-1 remain healthy while others become ill.

"HTLV-1 is a good system to help answer this question," Bangham said. "The virus reaches a kind of equilibrium in each infected person, and the amount of virus in each person's bloodstream depends on the efficiency of the person's immune response. Furthermore, this knowledge may help us to identify new protease inhibitors, which may be active only at certain stages of the viral life cycle. Only if we can understand which parts of the viral life cycle limit the rate of spread will we be able to identify the weak points to attack with drugs."