While patients with liver disease are known to have a higher prevalence of glucose intolerance, preliminary studies suggest that hepatitis C virus (HCV) infection may be an additional risk factor for the development of diabetes mellitus. To further study the correlation of HCV infection and diabetes, we performed a retrospective analysis of 1,117 patients with chronic viral hepatitis and analyzed whether age, sex, race, hepatitis B virus (HBV) infection, HCV infection, and cirrhosis were independently associated with diabetes. In addition, a case-control study was conducted to determine the seroprevalence of HCV infection in a cohort of 594 diabetics and 377 clinic patients assessed for thyroid disease. In the former study after the exclusion of patients with conditions predisposing to hyperglycemia, diabetes was observed in 21% of HCV-infected patients compared with 12% of HBV-infected subjects (P ؍ .0004). Multivariate analysis revealed that HCV infection (P ؍ .02) and age (P ؍ .01) were independent predictors of diabetes. In the diabetes cohort, 4.2% of patients were found to be infected with HCV compared with 1.6% of control patients (P ؍ .02). HCV genotype 2a was observed in 29% of HCV-RNA-positive diabetic patients versus 3% of local HCV-infected controls (P F .005). In conclusion, the data suggest a relatively strong association between HCV infection and diabetes, because diabetics have an increased frequency of HCV infection, particularly with genotype 2a. Furthermore, it is possible that HCV infection may serve as an additional risk factor for the development of diabetes, beyond that attributable to chronic liver disease alone. (HEPATOLOGY 1999;29:328-333.)
Since the discovery of the Marburg and Ebola species of filovirus, seemingly random, sporadic fatal outbreaks of disease in humans and nonhuman primates have given impetus to identification of host tropisms and potential reservoirs. Domestic swine in the Philippines, experiencing unusually severe outbreaks of porcine reproductive and respiratory disease syndrome, have now been discovered to host Reston ebolavirus (REBOV). Although REBOV is the only member of Filoviridae that has not been associated with disease in humans, its emergence in the human food chain is of concern. REBOV isolates were found to be more divergent from each other than from the original virus isolated in 1989, indicating polyphyletic origins and that REBOV has been circulating since, and possibly before, the initial discovery of REBOV in monkeys.
Patients with primary biliary cirrhosis develop progressive ductopenia associated with the production of antimitochondrial antibodies that react with a protein aberrantly expressed on biliary epithelial cells and peri-hepatic lymph nodes. Although no specific microbe has been identified, it is thought that an infectious agent triggers this autoimmune liver disease in genetically predisposed individuals. Previous serologic studies have provided evidence to suggest a viral association with primary biliary cirrhosis. Here we describe the identification of viral particles in biliary epithelium by electron microscopy and the cloning of exogenous retroviral nucleotide sequences from patients with primary biliary cirrhosis. The putative agent is referred to as the human betaretrovirus because it shares close homology with the murine mammary tumor virus and a human retrovirus cloned from breast cancer tissue. In vivo, we have found that the majority of patients with primary biliary cirrhosis have both RT-PCR and immunohistochemistry evidence of human betaretrovirus infection in lymph nodes. Moreover, the viral proteins colocalize to cells demonstrating aberrant autoantigen expression. In vitro, we have found that lymph node homogenates from patients with primary biliary cirrhosis can induce autoantigen expression in normal biliary epithelial cells in coculture. Normal biliary epithelial cells also develop the phenotypic manifestation of primary biliary cirrhosis when cocultivated in serial passage with supernatants containing the human betaretrovirus or the murine mammary tumor virus, providing a model to test Koch's postulates in vitro.
The clearance of the hepatitis B surface antigen (HBsAg) from serum usually indicates a resolution of biochemical and histological hepatitis in patients with chronic hepatitis B. 1 However, there are clearly documented cases of reactivation of latent viral infection following chemotherapy and immunosuppressive treatment, as well as de novo infection in patients receiving organs from HBsAg-negative donors with serological evidence of previous hepatitis B virus (HBV) infection. [2][3][4][5][6][7] In this setting, the reactivated infection is not entirely unexpected, because most patients who have cleared HBsAg from the serum still have detectable HBV DNA in the liver using the polymerase chain reaction (PCR) methodology. [8][9][10][11][12][13][14] In fact, HBV DNA can also be found in bodily secretions and peripheral blood mononuclear cells from patients with acute and chronic HBV infection after sustained loss of serum HBsAg. [15][16][17] Taken together, these studies suggest that following the loss of HBsAg from serum, HBV persists in a state of low-level replication or in a replication-competent state that can be reactivated to form infectious particles.The natural biology of the latent virus may be further investigated by assessing the transcriptional activity and the molecular form of the persistent HBV DNA. Using in situ hybridization, we were unable to detect hepatic HBV RNA in patients who had cleared serum HBsAg, and other investigators had little success using reverse-transcription (RT) PCR studies because of the inability to completely eradicate tissue HBV DNA. 11 Furthermore, the molecular form of the persistent HBV DNA has proved difficult to define because of the minute quantities of virus found in patients with resolved hepatitis.During chronic infection, HBV DNA can be detected in four predominant molecular forms. Following infection by the intact Dane particle, the partially double-stranded HBV-DNA genome becomes a covalently closed circular (CCC) DNA molecule that acts as a template for transcription of mRNA and the RNA pregenome. The reverse transcription of the RNA pregenome and second-strand HBV DNA synthesis results in low-molecular-weight replicative intermediates, whereas the HBV DNA that integrates into the host' s genome can be detected as high-molecular-weight species on Southern blot. 18,19 Similar to retroviral integration at the site of the long terminal repeats, HBV DNA generally inserts into DNA flanked by the direct repeat regions, which share sequence homology with the U5 region of murine leukemia virus long terminal repeats. [20][21][22] The genomic organization of the HBV direct repeat region provides a potential strategy for the detection of replicating virus when only minute quantities of HBV DNA are present (Fig. 1). Using PCR primers flanking the direct repeat region, the CCC HBV DNA can be amplified using PCR. In contrast, the HBV DNA within the Dane particle is incomplete, and integrated HBV DNA is usually, but not always, disrupted in the direct repeat region (Fig. 1). Th...
Patients with primary biliary cirrhosis (PBC) have both serologic and tissue evidence of infection. A recently identified human betaretrovirus was originally cloned from the biliary epithelium cDNA library of a patient with PBC. By conducting a BLASTN search, the initial partial pol gene fragment was found to have 95% to 97% nucleotide homology with mouse mammary tumor virus (MMTV) and with retrovirus sequences derived from human breast cancer samples. Using an anti-p27 CA MMTV antibody, viral proteins were detected in the perihepatic lymph nodes but not in liver tissue samples from patients with PBC, suggesting a higher viral burden in lymphoid tissue. Therefore, in the current study, we used lymph node DNA to clone the proviral genome of the human betaretrovirus from two patients with PBC using a polymerase chain reaction (PCR) walking methodology with conserved primers complementary to MMTV. The human betaretrovirus genome contains five potential open reading frames (ORF) for Gag, protease (Pro), polymerase (Pol), envelope (Env), and superantigen (Sag) proteins that are collinear with their counterparts in MMTV. Alignment studies performed with characterized MMTV and human breast cancer betaretrovirus amino acid sequences revealed a 93% to 99% identity with the p27 capsid proteins, a 93% to 97% identity with the betaretrovirus envelope proteins, and a 76% to 85% identity with the more variable superantigen proteins. Phylogenetic analysis of known betaretrovirus superantigen proteins showed that the human and murine sequences did not cluster as two distinct species. In conclusion, human betaretrovirus nucleic acid sequences have been cloned from patients with PBC. They share marked homology with MMTV and human breast cancer-derived retrovirus sequences. (HEPATOLOGY 2004;39:151-156.)
Histological and biochemical endpoints were achieved in the Combivir pilot study suggesting a larger placebo-controlled trial is required as a proof of principle to assess whether antiviral therapy impacts the PBC disease process.
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