In this prospective study, viral load is associated with increased mortality from HCC and CLD in HBV-infected subjects. Viral load may be a useful prognostic tool in HBV infection, and interventions aimed at its reduction should be explored.
BackgroundFor most classes of drugs, rapid development of therapeutics to treat emerging infections is challenged by the timelines needed to identify compounds with the desired efficacy, safety, and pharmacokinetic profiles. Fully human monoclonal antibodies (mAbs) provide an attractive method to overcome many of these hurdles to rapidly produce therapeutics for emerging diseases.MethodsIn this study, we deployed a platform to generate, test, and develop fully human antibodies to Zaire ebolavirus. We obtained specific anti-Ebola virus (EBOV) antibodies by immunizing VelocImmune mice that use human immunoglobulin variable regions in their humoral responses.ResultsOf the antibody clones isolated, 3 were selected as best at neutralizing EBOV and triggering FcγRIIIa. Binding studies and negative-stain electron microscopy revealed that the 3 selected antibodies bind to non-overlapping epitopes, including a potentially new protective epitope not targeted by other antibody-based treatments. When combined, a single dose of a cocktail of the 3 antibodies protected nonhuman primates (NHPs) from EBOV disease even after disease symptoms were apparent.ConclusionsThis antibody cocktail provides complementary mechanisms of actions, incorporates novel specificities, and demonstrates high-level postexposure protection from lethal EBOV disease in NHPs. It is now undergoing testing in normal healthy volunteers in preparation for potential use in future Ebola epidemics.
Superantigens are microbial proteins that strongly stimulate T cells. We described previously that the Epstein-Barr virus (EBV) transactivates a superantigen encoded by the human endogenous retrovirus, HERV-K18. We now report that the transactivation is dependent upon the EBV latent cycle proteins. Moreover, LMP-2A is sufficient for induction of HERV-K18 superantigen activity.Superantigens are pathogen-derived proteins that elicit a strong primary T-cell response from the host (reviewed in references 25 and 27). Superantigens are presented to T cells by major histocompatibility complex (MHC) class II molecules on antigen-presenting cells. They differ from conventional peptide antigens by binding solely to the V portion of the T-cell receptor (TCRBV) outside of the peptide-binding groove, thus forming a bridge between the T cell and the antigen-presenting cell (29). This bridging transduces a signal to the T cell, causing it to secrete cytokines that can further activate surrounding T cells. The hallmark of a superantigen response is the rapid and strong primary T-cell activation, which is MHC class II dependent and TCRBV restricted. In addition, antigen processing into peptides is not required. Both bacteria and viruses encode superantigens. The bacterial superantigens are mainly enterotoxins, which are secreted and bind externally to MHC class II molecules for presentation (34). In contrast, viral superantigens are glycosylated proteins that are endogenously produced in the infected cells.There are three families of viruses that are associated with superantigen or superantigen-like activity: Retroviridae, Rhabdoviridae, and Herpesviridae. Retroviral superantigens were first depicted in the B-type virus group in mouse mammary tumor viruses and are found in both infectious mouse mammary tumor viruses and endogenous proviruses (14,18,39,63). It has been previously shown that the env gene of HERV-K18, a defective human endogenous provirus located on chromosome 1, encodes a superantigen activity (51, 52). The HERV-K family is closely related to the B-type retroviruses based on amino acid similarity in the reverse transcriptase gene (48). HERV-K18 is a relatively recent integrant in the genome, as it is found in Old World primates but not in New World primates, indicating that it was acquired subsequent to the evolutionary divergence of these species (28). A few years ago, it was reported that Epstein-Barr virus (EBV) is associated with TCRBV13-specific superantigen activity, which is MHC class II dependent and not due to a recall antigen response (53). More recently, it was demonstrated that the superantigen activity is due to EBV transactivation of HERV-K18 env (52). We show here that this activity is dependent upon the major EBV latent gene transactivator EBNA-2, which upregulates most of the other EBV latent genes, all of which have the ability to transactivate host cell genes. In accordance with this finding, we show that the EBV latent membrane protein LMP-2A is sufficient for transactivation of HERV-K18 env.E...
Chronic hepatitis B virus (HBV) carriers with high-titer viremia (>10(5) virions/ml) are at increased risk for hepatocellular carcinoma (HCC). The aim of this study was to determine the relationship between clearance of high-titer viremia and subsequent risk of HCC. The study population was a prospective cohort of 114 adults from Haimen City, China, all HBV DNA(+) at study entry and followed for 797.8 person-years in total. During follow-up, 54 (47.4%) subjects spontaneously cleared high-titer viremia at least once. Of these, 27 were considered to have undergone stable seroconversion, 16 were considered unstable (12 reversions to HBV DNA positivity and 4 multiple clearances), and 11 did not have sufficient follow-up to determine stability. Of the 114 persons, 26 (22.8%) died during follow-up, 21 (18.4%) from HCC. Using Cox proportional hazards models, the RR of HCC death associated with seroconversion was 2.8 (95% CI = 1.1-7.4), controlling for age, sex, family HCC history, history of acute hepatitis, alcohol use and cigarette smoking. In conclusion, fluctuations of high-titer viremia may indicate increased hepatocellular damage and at least short-term increases in HCC risk. Long-term longitudinal studies are needed to clarify this relationship and its potential usefulness as a prognostic marker in chronic HBV infection.
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