Scientists at the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health have identified yet another cellular protein to be explored for HIV drug development: CXCL4. The research, authored by Paolo Lusso, MD, PhD, of the institute's Laboratory of Immunoregulation and his colleagues, is published online ahead of print by the Proceedings of the National Academy of Sciences of the United States of America (PNAS).
CXCL4 is derived from platelets, as its other name—platelet factor 4 (PF-4)—implies. It belongs to a family of molecules called chemokines, which help regulate leukocyte trafficking—the movement of immune cells around the body—essential for immune system architecture, development and surveillance.
Chemokines have been eyed for their therapeutic potential against HIV for nearly 20 years. In fact, four chemokines—three of which were identified by Lusso and his colleagues—were found to have anti-HIV activity in the mid-1990s. These four proteins, scientists went on to prove, work by blocking one of two chemokine receptors on CD4 cells, CCR5 or CXCR4, that HIV requires to enter CD4 cells.
While CXCL4 otherwise behaves similarly to the other chemokines, its anti-HIV activity differs considerably. Whereas the other chemokines act directly on chemokine receptors studding CD4 cells, CXCL4 binds directly to the gp120 protein on HIV's outer coat.
The potential advantage of this, Lusso and his colleagues suggest, is that CXCL4 works against HIV strains targeting CCR5 (CCR5-tropic virus) and CXCR4 (CXCR4-tropic virus), not one or the other. This could prove useful as drug developers attempt to mimic CXCL4, considering that available entry inhibitors—Selzentry (maraviroc), for example—are only effective against CCR5-tropic HIV, whereas many people in later stages of the disease have CXCR4-targeted virus.
Using various gp120 antibodies in their studies of CXCL4, Lusso and his colleagues found that the chemokine seems to be targeting an area on the HIV protein that hasn't been previously explored. According to a NIAID news announcement, his team is now working with scientists at the NIAID Vaccine Research Center to define the atomic-level crystal structure of this binding site, which potentially may play a role in the future development of HIV treatments or vaccines. Lusso's group is also pursuing further research to better understand CXCL4's role in HIV disease and to determine whether the chemokine has a protective effect not only in laboratory studies, but also in people.