Structure, dynamics, and function of the viroporins Vpu from HIV and p7 from HCV

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DESCRIPTION (provided by applicant): Infections with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) are among the most significant causes of human morbidity and mortality. Worldwide, there are more than 40 million (HIV) and 170 million (HCV) people infected with these viruses. In the United States, 0.6% (HIV) and 1.7% (HCV) of the population is infected. More than 25% of those infected with HIV are co-infected with HCV (up to 90% of i.v. drug users). Despite the success of highly active anti-retroviral therapy, there is an urgent need to develop entirely new classes of anti-HIV drugs targeted to novel receptors in order to ensure different susceptibilities to the development of resistance. Current therapies for HCV are grossly inadequate, and multiple first-generation anti- HCV drugs are needed. Both HIV-1 and HCV have a viroporin, a small membrane protein with ion channel activity and a potential drug target. The proposed research builds upon recent results, and represents a substantial expansion of our structural studies of membrane proteins. Determining the structures of Vpu (Virus protein "u") from HIV-1 and the p7 protein from HCV are essential in order to understand the molecular mechanisms of their biological activities and to nucleate the discovery of drugs that interfere with these activities. Our NMR methods are particularly well suited for determining the structures of these proteins in their native environment of phospholipid bilayers. And since our approach is unaffected by the molecular mass of the polypeptides, studies of isotopically labeled Vpu bound to unlabeled cellular partners are no more difficult than for Vpu alone. We will explore the application of SAR (structure activity relationships) by NMR to Vpu and p7 as examples of membrane-bound receptors and to identify potential binding sites for drugs. PUBLIC HEALTH RELEVANCE: Infections with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) are among the most significant causes of human morbidity and mortality. Worldwide, there are more than 40 million (HIV) and 170 million (HCV) people infected with these viruses. In the United States, 0.6% (HIV) and 1.7% (HCV) of the population is infected. More than 25% of those infected with HIV are co-infected with HCV (up to 90% of i.v. drug users). HIV is a lentivirus in the Retroviridae family. It causes the acquired immunodeficiency syndrome (AIDS) by infecting CD4+ T and other cells of the immune system; the resulting decline of immune functions means that opportunistic infections, such as tuberculosis and Kaposi's sarcoma, and co-infections, such as HCV, have devastating effects on human health. HAART (highly active antiretroviral therapy) is effective in many patients; however, the genetic variability of HIV means that drugs against additional molecular targets are needed to combat resistance that inevitably develops in the course of treating a disease in which the genome of the causative agent is integrated into the host DNA. The proposed studies will provide structural information about Vpu, a key protein in the viral lifecycle that has the potential to be a new target for the development of drugs to treat AIDS. HCV is a member of the Flaviviridae family of enveloped single-stranded RNA viruses that mainly infects hepatocyte. Most HCV infections are persistent and lead to liver diseases, including hepatitis, cirrhosis, and hepatocellular carcinoma. Consequently, HCV is the leading indicator for liver transplantation in the Nation. Current therapy for HCV infections consists of the administration of pegylated interferon and ribivirin and has many limitations; not only is it lengthy, expensive and poorly tolerated, but also it works in only a fraction of cases. The development of effective anti-HCV drugs is a high priority, especially because of the difficulties encountered in treating patients co-infected with HIV and HCV. The proposed studies will provide structural information about p7, a key protein in the viral lifecycle that has the potential to be a new target for the development of drugs to treat hepatitis C.