Researchers Identify Protein That Helps HIV Penetrate Cells

A discovery reported in the March 16, 2003, Journal of Virology, ultimately could lead to new therapies that researchers hope might block the entry of HIV into some white blood cells, thus slowing the reproduction of the virus.

Led by Professor William A. O'Brien, UTMB researchers Jana J. von Lindern, Daniel Rojo, Cheng Deng, Georges Herbein, Monique Ferguson and Todd C. Pappas implicated a protein known as CD63 in the intricate dance of biochemical reactions that enables HIV to slip through the protective cell membranes of macrophages, one of the two most important types of white blood cells targeted by the virus.

"The study demonstrated that antibody to CD63 -- a membrane-associated protein whose function is not yet fully understood -- blocks entry and infection by a diverse group of HIV strains," O'Brien said. "It is most effective in blocking virus strains that use the chemokine receptor CCR5, termed R5 strains, which includes almost all the viruses commonly seen in patients with HIV infection."

O'Brien's team discovered the involvement of CD63 after testing a large "library" of antibodies that blocked the action of different proteins on the surfaces of macrophages. They were looking for a protein whose deactivation would prevent HIV from entering the cells. When an antibody for CD63--a so-called "transmembrane" protein that lies partly inside and partly outside the cell membrane--prevented HIV from getting in, they knew that CD63 was a necessary part of the process by which HIV entered macrophages.

The scientists found that CD63 antibody did not keep HIV out of the other major type of cells the virus infects, T-helper lymphocytes, despite the presence of CD63 on the surface of those cells. Still, the ability to prevent infection of macrophages would be a significant advance for HIV therapy, since the cells are an important reservoir for HIV and may be directly involved in illnesses specifically caused by HIV, such as AIDS-related dementia.

"We need to understand what CD63 does, because understanding its mechanism may lead to targets that would be suitable for therapies to block HIV entry," O'Brien said. His team is now investigating how that mechanism works, which he thinks might involve the way in which the virus initially attaches itself to the macrophage. A compound able to block that process could be part of a battery of "entry inhibitor" drugs aimed at fighting HIV at the cell membrane. Current therapies target the virus only after it enters cells.