Opioid Binding to U51: A Human herpes Virus Protein

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DESCRIPTION: (provided by the applicant) The human herpes virus (HHV)-6 and HHV-7 are viruses that infect the human central nervous system and T lymphocytes. HHV-6, which is closely related to HHV-7 at the genetic level, is frequently associated with disease, particularly in immunocompromised persons and persons with AIDS. Both HHV-6 and HHV-7 express a 7-transmembrane G-protein coupled receptor, U51, which has been identified as an opioid receptor homologue, sharing greater than 50 percent sequence similarity with the Kappa opioid receptor. HHV-6 and -7 U51 share greater sequence similarity with the Kappa, mu and delta opioid receptors than with any other cloned protein. HHV-6 U51 is a chemokine receptor, which binds the chemokine RANTES, and other beta chemokines, such as eotaxin, monocyte chemoattractant protein 1, 3, and 4. While HHV-7 U51 probably binds beta chemokines, this has not been definitely proven and will be addressed in the proposed studies, which will examine the interactions of opioids with both HHV-6 U51 and HHV-7 U51. The overall hypothesis to be tested is that the U51 protein, which binds chemokines and is a homologue of the human Kappa opioid receptor, will bind some opioids, and that these opioids will activate the U51 receptor and regulate the binding and function of RANTES. The following specific aims will be tested: 1) Determine if opioids will inhibit the binding of the chemokine [125I]RANTES to the HHV-6 and HHV-7 U51 protein; 2) Determine if opioids activate the U51 protein, as measured with the [35S]GTPgammaS binding assay; and 3) Determining if opioids modulate RANTES-induced stimulation of [35S]GTPgammaS binding. This proposal qualifies for a Cutting Edge Basic Research Award because if opioids bind to the chemokine receptor U51, this finding would demonstrate a common receptor for both beta chemokines and opioids. In addition, because HHV-6 and -7 infect both T lymphocytes and cells of the human central nervous system, this could result in the expression of a novel opioid receptor that is only present in the human neurons and T lymphocytes.