Jan. 20, 2004 The HIV protein Nef sparked intensive research after observations that patients with a rare strain of HIV lacking Nef took a very long time to develop AIDS symptoms. Nef has been linked to molecules involved in cell signaling pathways and may use them for its own ends. But how Nef does this has not been clear. Now Jacek Skowronski and his colleagues at Cold Spring Harbor Laboratory in New York have identified a mechanism involving Nef, by which HIV-infected T cells are kept from traveling to sites within lymphatic tissues where they can become activated.
Skowronski's lab found that Nef associates with two proteins, DOCK2 and ELMO1. DOCK2 regulates enzymes (Rac1 and Rac2) that are required for normal lymphocyte migration and antigen-specific responses. ELMO1 has also been shown to help DOCK2 activate Rac. Because DOCK2 activates Rac as part of two different signaling pathways--one activated by the T cell receptor, which mediates T cell activation, and one by a chemokine receptor, which controls T cell migration--the researchers investigated whether Nef could affect these important pathways by modulating Rac activity. They found that Nef in fact activates Rac by binding to the DOCK2ELMO1 complex. And they went on to show that HIV uses these components of the chemokine receptor pathway to disrupt T cell migration. To generate an effective immune response, it is crucial that T cells travel to sites within lymphatic tissues where they interact with other lymphocytes. By inhibiting T cell migration, the researchers propose, Nef prevents these critical interactions, thereby providing a mechanism for stifling the immune response.
These results, the authors argue, provide the biochemical evidence that Nef targets a protein "switch" that can interfere with important aspects of T cell function. In this way, Nef subverts the immune response pathways controlled by receptors on the surface of T cells to effectively disarm the immune system and turn T cells into viral replication factories. Understanding how Nef interacts with these proteins to spread infection could lay the foundation for valuable new therapies aimed at inhibiting and arresting HIV infection by blocking Nef-mediated effects.
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