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Biotech / Medical : Indications -- Hepatitis -- Ignore unavailable to you. Want to Upgrade?

To: scaram(o)uche who wrote (49)	8/24/2003 2:12:08 AM
From: russet	Respond to of 312

The internet is the only way doctors can be brought up to speed with the leading edge of medicine,...what is being done to drag the ignorant 98% up to where they stop doing harm?

To: scaram(o)uche who wrote (49)	9/22/2003 8:08:52 PM
From: tuck	Respond to of 312

>>Published online before print September 22, 2003 Proc. Natl. Acad. Sci. USA, 10.1073/pnas.1834545100 Medical Sciences The p7 polypeptide of hepatitis C virus is critical for infectivity and contains functionally important genotype-specific sequences Akito Sakai , Marisa St. Claire , Kristina Faulk , Sugantha Govindarajan , Suzanne U. Emerson , Robert H. Purcell , and Jens Bukh * *Hepatitis Viruses and Molecular Hepatitis Sections, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; Bioqual, Inc., Rockville, MD 20850; and Liver Research Laboratory, Rancho Los Amigos Medical Center, Downey, CA 90242 Contributed by Robert H. Purcell, July 18, 2003 The role of the hepatitis C virus (HCV) p7 protein in the virus life cycle is not known. Previous in vitro data indicated that this 63-aa polypeptide is located in the endoplasmic reticulum and has two transmembrane domains (TMDs) connected by a cytoplasmic loop; the amino- and carboxyl-terminal tails are oriented toward the endoplasmic reticulum lumen. Furthermore, recent in vitro studies suggested that HCV p7 could function as a virus-encoded ion channel. It might therefore be a relevant target for future drug development. We studied the role of HCV p7 in vivo. Because HCV does not replicate efficiently in cell culture, we mutagenized p7 of an infectious genotype 1a cDNA clone and tested RNA transcripts of each mutant for infectivity in chimpanzees by intrahepatic transfection. Appropriate processing of mutant polypeptides was confirmed by studies in transfected mammalian cells. Mutants with deletions of all or part of p7 and a mutant with substitutions of two conserved residues in the cytoplasmic loop were not viable. Thus, p7 is essential for infectivity of HCV. A chimera in which the p7 of the 1a clone was replaced with p7 from an infectious genotype 2a clone also was not viable. This finding suggests a genotype-specific interaction between p7 and other genomic regions. To define which portions of p7 played the most significant role for this interaction, we tested three chimeras with the 1a backbone in which only specific domains of p7 had the 2a sequence. A p7 chimera with 2a tails and TMDs and the 1a cytoplasmic loop was not viable. A mutant with 2a tails and cytoplasmic loop and 1a TMDs also was not viable. However, a p7 chimera with 2a TMDs and cytoplasmic loop and 1a tails was viable. The transfected chimpanzee became viremic at week 2, and recovered viruses had the chimeric sequence. These data indicate that the amino- and/or carboxyl-terminal intraluminal tails of p7 contain sequences with genotype-specific function.<< Cheers, Tuck