Physicians have a responsibility to recognize caregiver burden. Caregiver assessment and intervention should be tailored to the individual circumstances and contexts in which caregiver burden occurs.

No abstract

H epatitis B virus (HBV) infection is a major health problem.There are more than 350 million chronic carriers worldwide, and they are at high risk of developing liver cirrhosis and hepatocellular carcinoma (1). Chronic HBV infection is the result of impaired HBV-specific immune responses such that the infected hepatocytes cannot be eliminated or cured efficiently, but many of the associated issues remain unclear (2, 3).Due to the paucity of in vitro and in vivo models for HBV infection, HBV-transgenic mice are the most widely used model. These mice have the viral genome integrated into the chromosome and produce infectious HBV particles or viral antigens in the liver; however, the main limitation of HBV-transgenic mouse models is that they are immunologically tolerant to viral antigens (4, 5). Various routes have been exploited to introduce the HBV genome into the hepatocytes of adult mice. One is to introduce a replication-competent HBV genome into the mouse liver by hydrodynamic injection (HDI) through the tail vein (6); although HBV replicates in the mouse liver, the virus is rapidly cleared by immune responses against HBV proteins (7). Recently, Huang and colleagues used HDI to create a nontransgenic model of persistent HBV replication (8). The virus persisted in 40% of mice or was eliminated according to the genetic background. These mice rapidly develop anti-hepatitis B virus core (HBc) antibody, which is the first serological marker of acute HBV infection in humans. An alternative method uses adenoviral vectors to transfer 1.3 copies of the HBV genome into immunocompetent mice (9, 10), and acute or chronic HBV infection was obtained depending on the dose of adenoviral vector injected.Here, we describe an alternative murine model for the study of HBV persistence based on the liver-targeted transduction of adeno-associated virus serotype 2/8 (AAV2/8). We produced an AAV2/8 construct carrying a replication-competent HBV DNA genome and by intravenous injection established a model of HBV persistence in humanized HLA-A2/DR1 immunocompetent mice. Hepatitis B virus surface antigen (HBsAg), hepatitis B virus e antigen (HBeAg), and HBV DNA persisted for at least 1 year in sera of all AAV2/8-injected mice, and viral replication intermediates and transcripts were detected in their livers. HBcAg was expressed in 60% of hepatocytes without significant inflammation in the liver. The persistence of infection was associated with the presence of regulatory T cells (Tregs) in the liver. This mouse model of HBV persistence recapitulates viral and histological characteristics of human chronic HBV infection in the immunetolerant stage of the disease (11,12).In HLA-A2/DR1 mice, cellular immune responses were completely restricted to HLA molecules. Antibody, T-helper, and cytotoxic-T-lymphocyte responses to vaccination with recombinant HBsAg or HBsAg-expressing DNA were similar to those in vaccinated humans (13,14) or in HBV-infected individuals (15). Therefore, this AAV2/8-HBV-transduced HLA-A2/DR1 murine model may be useful fo...

The hepatitis B virus X protein (HBx) is essential for virus replication and has been implicated in the development of liver cancer. HBx is recruited to viral and cellular promoters and activates transcription by interacting with transcription factors and coactivators. Here, we purified HBx-associated factors in nuclear extracts from HepG2 hepatoma cells and identified protein arginine methyltransferase 1 (PRMT1) as a novel HBx-interacting protein. We showed that PRMT1 overexpression reduced the transcription of hepatitis B virus (HBV), and this inhibition was dependent on the methyltransferase function of PRMT1. Conversely, depletion of PRMT1 correlated with increased HBV transcription. Using a quantitative chromatin immunoprecipitation assay, we found that PRMT1 is recruited to HBV DNA, suggesting a direct effect of PRMT1 on the regulation of HBV transcription. Finally, we showed that HBx expression inhibited PRMT1-mediated protein methylation. Downregulation of PRMT1 activity was further observed in HBV-replicating cells in an in vivo animal model. Altogether, our results support the notion that the binding of HBx to PRMT1 might benefit viral replication by relieving the inhibitory activity of PRMT1 on HBV transcription.