In addition to infectious viral particles, hepatitis B virus-replicating cells secrete large amounts of subviral particles assembled by the surface proteins, but lacking any capsid and genome. Subviral particles form spheres (22-nm particles) and filaments. Filaments contain a much larger amount of the large surface protein (LHBs) compared to spheres. Spheres are released via the constitutive secretory pathway, while viral particles are ESCRT-dependently released via multivesicular bodies (MVBs). The interaction of virions with the ESCRT machinery is mediated by ␣-taxilin that connects the viral surface protein LHBs with the ESCRT component tsg101. Since filaments in contrast to spheres contain a significant amount of LHBs, it is unclear whether filaments are released like spheres or like virions. To study the release of subviral particles in the absence of virion formation, a core-deficient HBV mutant was generated. Confocal microscopy, immune electron microscopy of ultrathin sections and isolation of MVBs revealed that filaments enter MVBs. Inhibition of MVB biogenesis by the small-molecule inhibitor U18666A or inhibition of ESCRT functionality by coexpression of transdominant negative mutants (Vps4A, Vps4B, and CHMP3) abolishes the release of filaments while the secretion of spheres is not affected. These data indicate that in contrast to spheres which are secreted via the secretory pathway, filaments are released via ESCRT/MVB pathway like infectious viral particles. IMPORTANCEThis study revises the current model describing the release of subviral particles by showing that in contrast to spheres, which are secreted via the secretory pathway, filaments are released via the ESCRT/MVB pathway like infectious viral particles. These data significantly contribute to a better understanding of the viral morphogenesis and might be helpful for the design of novel antiviral strategies.T he human hepatitis B virus (HBV) is a spherical particle, 42 nm in diameter, consisting of an outer envelope and an inner icosahedral nucleocapsid. The nucleocapsid is formed by the core protein and harbors the viral genomic DNA. The HBV genome encodes at least four different open reading frames, coding for the viral polymerase, the core and the e antigen (HBcAg and HBeAg), the regulatory X protein (HBx), and the three different surface proteins (HBsAg): the large HBV surface protein (LHBs), the middle surface protein (MHBs) and the small surface protein (SHBs) (1). LHBs encompasses the PreS1 domain, the PreS2 domain, and the S domain, MHBs consists of the PreS2 and the S domain, and SHBs contains the S domain. These surface proteins are not only constitutive components of the envelope of viral particles but also assemble to capsid-free subviral particles lacking any viral genome having the shape of spheres and filaments (2) that are secreted in 1,000-to 100,000-fold excess relative to infectious viral particles. SHBs, the predominant part of these subviral particles, can assemble to 22-nm spherical particles. The incorporation ...

We investigate MIMO eigenmode transmission using statistical channel state information at the transmitter. We consider a general jointly-correlated MIMO channel model, which does not require separable spatial correlations at the transmitter and receiver. For this model, we first derive a closed-form tight upper bound for the ergodic capacity, which reveals a simple and interesting relationship in terms of the matrix permanent of the eigenmode channel coupling matrix and embraces many existing results in the literature as special cases. Based on this closed-form and tractable upper bound expression, we then employ convex optimization techniques to develop low-complexity power allocation solutions involving only the channel statistics. Necessary and sufficient optimality conditions are derived, from which we develop an iterative water-filling algorithm with guaranteed convergence. Simulations demonstrate the tightness of the capacity upper bound and the near-optimal performance of the proposed lowcomplexity transmitter optimization approach.

In this paper, we propose a new channel estimation prototype for the amplify-and-forward (AF) two-way relay network (TWRN). By allowing the relay to first estimate the channel parameters and then allocate the powers for these parameters, the final data detection at the source terminals could be optimized. Specifically, we consider the classical three-node TWRN where two source terminals exchange their information via a single relay node in between and adopt the maximum likelihood (ML) channel estimation at the relay node. Two different power allocation schemes to the training signals are then proposed to maximize the average effective signal-to-noise ratio (AESNR) of the data detection and minimize the meansquare-error (MSE) of the channel estimation, respectively. The optimal/sub-optimal training designs for both schemes are found as well. Simulation results corroborate the advantages of the proposed technique over the existing ones.Index Terms-Channel estimation, amplify-and-forward, twoway relay networks, power allocation, training design.

The human hepatitis B virus (HBV), that is causative for more than 240 million cases of chronic liver inflammation (hepatitis), is an enveloped virus with a partially double-stranded DNA genome. After virion uptake by receptor-mediated endocytosis, the viral nucleocapsid is transported towards the nuclear pore complex. In the nuclear basket, the nucleocapsid disassembles. The viral genome that is covalently linked to the viral polymerase, which harbors a bipartite NLS, is imported into the nucleus. Here, the partially double-stranded DNA genome is converted in a minichromosome-like structure, the covalently closed circular DNA (cccDNA). The DNA virus HBV replicates via a pregenomic RNA (pgRNA)-intermediate that is reverse transcribed into DNA. HBV-infected cells release apart from the infectious viral parrticle two forms of non-infectious subviral particles (spheres and filaments), which are assembled by the surface proteins but lack any capsid and nucleic acid. In addition, naked capsids are released by HBV replicating cells. Infectious viral particles and filaments are released via multivesicular bodies; spheres are secreted by the classic constitutive secretory pathway. The release of naked capsids is still not fully understood, autophagosomal processes are discussed. This review describes intracellular trafficking pathways involved in virus entry, morphogenesis and release of (sub)viral particles.

Differences in composition of SVPs may result in genotype-specific immunogenicity and pathogenesis. In the patients with preS-mutations, secreted HBsAg and released viral genomes cannot be derived from the same genetic source. As viral genomes are derived from covalently closed circular DNA (cccDNA), HBsAg is presumably derived from integrated DNA. This important HBsAg source should be considered for novel antiviral strategies in HBeAg-negative chronic HBV-infected patients.

qHBsAg serum levels depend on the HBV genotype and together with HBV DNA levels on frequent mutations in PC, BCP and preS in HBeAg-negative patients. qHBsAg cut-offs when used as prognostic markers require genotype-dependent validation.

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1Seventy million people worldwide are chronically infected with hepatitis C virus (HCV). Chronic HCV infection is associated with an elevated risk of developing liver cirrhosis and hepatocellular carcinoma (1). HCV is a single-stranded, positivesense RNA virus that belongs to the Flaviviridae family. The viral RNA encodes a single polyprotein of about 3,100 amino acids, which is cleaved co-and posttranslationally by cellular and viral proteases into 10 viral proteins: the structural proteins (core, E1, E2), which build up the viral particles; the p7 polypeptide, which forms an ion channel; and the nonstructural (NS) proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B), which support viral replication and assembly processes (2-5).NS5A is known to act as a regulator of intracellular signal transduction cascades. The kinase c-Raf was identified to bind to the C-terminal domain of NS5A. Thereby, c-Raf is located at the HCV replication complex (6, 7). The interaction of NS5A with c-Raf leads to the activation of c-Raf in association with the phosphorylation of c-Raf at serine 338 (6, 7). Moreover, it was found that inhibition of c-Raf blocks HCV replication (6,8). However, due to the delocalization of c-Raf to the replicon complex/endoplasmic reticulum (ER) membrane, c-Raf in HCV-replicating cells is withdrawn from the classic MEK/extracellular signal-regulated kinase (ERK) signaling pathway (6). Therefore, although c-Raf is activated in HCV-replicating cells, signal transduction to the MEK/ERK pathway is impaired.The HCV infection cycle is tightly associated with lipid metabolism. HCV replication occurs on the cytoplasmic face of the ER in the replication complexes (RCs) formed by nonstructural proteins. HCV replication and morphogenesis take place at specialized rearranged intracellular ER membranes, the socalled membranous web, that are enriched in proteins involved