Báo cáo khoa học: Open Access Occult hepatitis B infection: an evolutionary scenario

Tuyển tập báo cáo các nghiên cứu khoa học quốc tế ngành y học dành cho các bạn tham khảo đề tài: Occult hepatitis B infection: an evolutionary scenario
Nội dung trích xuất từ tài liệu:
Báo cáo khoa học: "Open Access Occult hepatitis B infection: an evolutionary scenario"Virology Journal BioMed Central Open AccessResearchOccult hepatitis B infection: an evolutionary scenarioFormijn J van Hemert*1, Hans L Zaaijer2, Ben Berkhout1 andVladimir V Lukashov1Address: 1Laboratory of Experimental Virology, Department of Medical Microbiology, Center for Infection and Immunity Amsterdam (CINIMA),Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands and 2Laboratory of Clinical Virology, Department of MedicalMicrobiology, Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, theNetherlandsEmail: Formijn J van Hemert* - f.j.vanhemert@amc.uva.nl; Hans L Zaaijer - h.l.zaaijer@amc.uva.nl; Ben Berkhout - b.berkhout@amc.uva.nl;Vladimir V Lukashov - v.lukashov@amc.uva.nl* Corresponding authorPublished: 11 December 2008 Received: 24 November 2008 Accepted: 11 December 2008Virology Journal 2008, 5:146 doi:10.1186/1743-422X-5-146This article is available from: http://www.virologyj.com/content/5/1/146© 2008 van Hemert et al; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: Occult or latent hepatitis B virus (HBV) infection is defined as infection with detectable HBV DNA and undetectable surface antigen (HBsAg) in patients blood. The cause of an overt HBV infection becoming an occult one is unknown. To gain insight into the mechanism of the development of occult infection, we compared the full-length HBV genome from a blood donor carrying an occult infection (d4) with global genotype D genomes. Results: The phylogenetic analysis of polymerase, core and X protein sequences did not distinguish d4 from other genotype D strains. Yet, d4 surface protein formed the evolutionary outgroup relative to all other genotype D strains. Its evolutionary branch was the only one where accumulation of substitutions suggests positive selection (dN/dS = 1.3787). Many of these substitutiions accumulated specifically in regions encoding the core/surface protein interface, as revealed in a 3D-modeled protein complex. We identified a novel RNA splicing event (deleting nucleotides 2986-202) that abolishes surface protein gene expression without affecting polymerase, core and X-protein related functions. Genotype D strains differ in their ability to perform this 2986-202 splicing. Strains prone to 2986-202 splicing constitute a separate clade in a phylogenetic tree of genotype D HBVs. A single substitution (G173T) that is associated with clade membership alters the local RNA secondary structure and is proposed to affect splicing efficiency at the 202 acceptor site. Conclusion: We propose an evolutionary scenario for occult HBV infection, in which 2986-202 splicing generates intracellular virus particles devoid of surface protein, which subsequently accumulates mutations due to relaxation of coding constraints. Such viruses are deficient of autonomous propagation and cannot leave the host cell until it is lysed. encoded by the S gene) in plasma or serum of HBV-BackgroundOccult HBV infections are defined as the presence of HBV infected patients [1]. This infection may persist in individ-DNA and the absence of HBV surface antigen (HBsAg uals for years without emerging symptoms of overt HBV Page 1 of 13 (page number not for citation purposes)Virology Journal 2008, 5:146 http://www.virologyj.com/content/5/1/146infection. Co-infection [2], drug abuse [3] or immuno- polymerase sequences. In this clade, a T-to-G mutation atsuppression [4] can trigger an enhancement of HBV DNA position 173 truncates a splice-promoting polypyrimi-levels without an increase of HBsAg. Transmission of HBV dine tract [23] and also affects the local secondary struc-from individuals with occult HBV infection may occur via ture of the viral RNA [24]. As a result, the splicing activityorgan transplantation or blood transfusion [5]. It is pres- at the neighboring 202 splice acceptor site may be down-ently unclear to what extent occult HBV infection repre- regulated. The splicing possibility (2986-202) based onsents a risk factor for the community other than for the NetGene2 predictions presently awaits further experimen-infected individual [6]. tal support by analysis of liver samples, which are much ...