When attacked by bacteria and viruses, the body’s “army” – the immune system – is called into action to fight off and destroy the harmful invaders and thus prevent disease and infection. But viruses, among them HIV, have evolved numerous and varied strategies to evade the immune response and infect cells. Weizmann Institute scientists have recently uncovered a new “weapon” in HIV’s arsenal that specifically targets the activity of the immune system’s “elite force” – certain white blood cells called T cells. These findings have enabled the scientists to imitate the virus’s way of manipulating the immune system – one that has the potential to reduce the severity of such autoimmune diseases as multiple sclerosis, which arise from the “friendly fire” of T cells when they mistakenly attack healthy cells in the body.
The first step in HIV infection is to enter the T cells. To do this, the virus joins its outer membrane to that of a T cell. This is achieved with the help of a short molecular sequence found on a certain protein located within the HIV membrane. The point at which the two membranes fuse is found in the vicinity of T cell receptors (TCRs) – molecules on the surface of T cells that are usually responsible for recognizing harmful invaders and helping the T cells mount an effective response. Such a response includes T cell proliferation and the release of pro-inflammatory substances that kill the intruders.
Prof. Yechiel Shai, former research student Avraham Ashkenazi and Omri Faingold of the Biological Chemistry Department found that the fusing sequence is conserved in this protein throughout different HIV strains, leading them to believe it must have additional, biologically important roles. Together with Prof. Avraham Ben-Nun and his research associate Dr. Nathali Kaushansky in the Immunology Department, they discovered, as reported in Blood, that this molecular pattern does indeed provide the virus with an added function: The sequence interacts directly with the TCRs, interfering with the TCR complex assembly. As a result, the activation of T cells is inhibited, preventing them from mounting an immune response.
Because multiple sclerosis is a T cell-mediated autoimmune disease, the scientists thought this action might prevent the harmful immune response in the disease. They worked with mouse models of this disease to gauge whether an isolated version of the sequence in the form of a peptide – a small piece of a protein sequence – would have the same inhibitory effect on T cells. They found that upon administration of the peptide, T cell activation was indeed suppressed and the severity of the disease was reduced. “As to the inhibitory effects on T cells, the peptide can do what the virus does, but without the virus,” says Ben-Nun.
In a follow-up study, reported in the Journal of Biological Chemistry, the scientists engineered a more stable form of the peptide based on the original HIV sequence. Not only has this allowed them to further understand the unique molecular mechanisms of HIV infection, but it turns out that this so-called killer may also help save lives: The engineered peptide, which is based on the virus’s sequence, could potentially be used as a tool to manipulate the immune system and shut down T cell activation, thereby suppressing the development of various T cell-mediated autoimmune diseases.
“And because it specifically targets T cells, unlike existing immunosuppressive drugs that affect all types of white blood cells, it is likely to mount a more effective response with fewer unwanted side effects,” says Shai.
Prof. Avraham Ben-Nun’s research is supported by the Jeanne and Joseph Nissim Foundation for Life Sciences Research; the Croscill Home Fashions Charitable Trust; Ellie Adiel, New York, NY; Maria Halphen, France; and the estate of Fannie Sherr. Prof. Ben-Nun is the incumbent of the Eugene and Marcia Applebaum Professorial Chair.
Prof. Yechiel Shai’s research is supported by the Nella and Leon Benoziyo Center for Neurological Diseases; the Yeda-Sela Center for Basic Research; the Carolito Stiftung; the Helmsley Charitable Trust; and Mario Fleck, Brazil. Prof. Shai is the incumbent of the Harold S. and Harriet B. Brady Professorial Chair in Cancer Research.