Scientists have discovered a key molecule that the AIDS virus uses to hijack a special type of cell in the body's outermost tissues, providing vital information into how the virus is first transmitted in the body. The molecule transports the virus to immune system tissues, and actually facilitates infection.
The findings, by scientists at New York University School of Medicine and University Hospital Nijemgen in the Netherlands, provide a new explanation as to how the virus gets into the body and makes its way to tissues where immune system cells reside. The AIDS virus then infects immune cells and eventually overwhelms the body's ability to fight infection.
This research shines a spotlight on the first encounter between HIV and cells in the body. It offers fresh avenues of research for developing innovative treatments for AIDS, and may lead to vaccines that could prevent the virus from gaining access to the body's immune cells. It is far too early, however, to determine whether the current finding will lead to new treatments.
In a study published in the March 3 issue of the journal Cell, researchers report that when HIV is deposited in the mucosal tissue lining the rectum and vagina, the first sites exposed to sexually transmitted infection, it binds specifically to a specialized type of cell, called a dendritic cell, by way of a molecule on the surface of this cell. The virus, which is now bound to this molecule, is then ferried to areas of the body rich in T-lymphocytes, the cells that are ultimately infected by the bound HIV. The molecule has been named DC-SIGN.
The research teams were led by Dan R. Littman, M.D., Ph.D., Helen L. and Martin S. Kimmel Professor of Molecular Immunology and Professor of Pathology at NYU School of Medicine, and a Howard Hughes Medical Institute Investigator, and by Dr. Yvette van Kooyk at University Hospital Nijmegen in the Netherlands.
Scientists had previously suspected that the AIDS virus interacted with dendritic cells. The current findings show how the interaction occurs. A protein (gp120) on the surface of HIV latches onto DC-SIGN, a receptor on the surface of dendritic cells. Receptors are like locks; only certain keys will fit into them. In the case of DC-SIGN, however, the key doesn't open the lock. Instead, once the virus is bound to DC-SIGN, it is transported to lymph nodes, where the dendritic-cell complex presents the virus to immune cells, particularly T-lymphocytes. T-cells have a different receptor system to which the virus binds, and this system allows the virus to infect T-cells.
"We feel these findings are very exciting and are likely to provide us with vital information into how the virus is first transmitted and amplified in the body," says Dr. Littman. "We have identified the key molecule that HIV uses to hijack dendritic cells. The virus subverts the normal function of these cells, which is to protect the body from infection."
In the current study, the scientists report that the dendritic cells bearing the cell-surface receptor DC-SIGN are especially abundant at mucosal sites in the rectum, uterus, and cervix, and they show that the AIDS virus is remarkably durable when bound to the receptor. HIV is a rather brittle virus, but once bound to the receptor, it becomes far more long lived. The scientists speculate that DC-SIGN protects the virus from decay.
In the study, the scientists also generated antibodies in the laboratory that were directed against DC-SIGN. The antibodies blocked the cells' ability to bind to HIV, potentially providing an avenue to develop therapies or a vaccine that could thwart HIV infection in the body.
Dendritic cells are a subset of immune cells that present foreign proteins or antigens to another group of cells called T-lymphocytes, the foot soldiers of the body's immune system and the ones targeted by HIV. Once the antigen is presented, T-cells go into action, marshalling recruits to battle a foreign foe with special messenger molecules called cytokines and chemokines. Previously, Dr. Littman and colleagues discovered that HIV must bind to chemokine receptors on the surface of T-cells in order to enter the cell. Now, with the new discovery, he and his colleagues have found an even earlier event in HIV's battle plan.
"Our data suggest that after HIV has been ferried by dendritic cells to the lymph nodes, the bound virus particle is presented to the chemokine-receptor complex on T-cells, greatly enhancing the entry of viral particles into these cells," says Dr. Littman.
The current studies were performed with cultured cells in the laboratory, and scientists now need to validate their findings in people infected with HIV. Dr. Littman says he would like to learn whether there are variations in DC-SIGN that make dendritic cells resistant to the AIDS virus. People who have these variations would potentially be naturally resistant to HIV infection, despite being exposed many times to the virus.
This information potentially could be used to design vaccines that will elicit antibody responses that block the interaction of HIV with dendritic cells and to develop ne therapies that will interfere with the amplification of the HIV replication process by dendritic cells, says Dr. Littman.
Journal
Cell