Wednesday, February 5, 2025
2/5/2025
Abstract Chronic HBV infection is a critical public health problem affecting approximately 296 million individuals worldwide. A better understanding of the underlying mechanisms of HBV persistence will facilitate the development of new antivirals for the treatment of chronic HBV infection; however, these efforts are hampered by deficiencies in current animal models susceptible to HBV infection. The Eastern woodchuck, naturally infected with the woodchuck hepatitis virus (WHV) that is closely related to HBV, is a well-established animal model for the study of HBV infection. The HBV PreCore gene, which encodes the secreted e antigen (eAg), is the least characterized viral gene due to technical constraints. Studies in woodchucks have shown that the PreCore gene is dispensable for WHV replication but necessary for facilitating chronic infection. We have recently discovered a novel PreCore-encoded protein, named PreC, which is also secreted in HBV-infected patients and chimpanzees and in WHV-infected woodchucks following alternative processing to eAg. Both the HBV and WHV PreC and eAg show heterogeneous density distributions. These results suggest that the PreC protein may have a function(s) distinct from eAg to facilitate chronic infection, and that both PreC and eAg functions may be related to their density distributions. Thus, in Aim 1 we propose to explore the functions of PreCore-derived proteins in modulating WHV infection. This will be achieved by liver transfection of woodchucks with a WHV construct containing a single point mutation, which increases the efficiency of signal peptide cleavage and thus increases the eAg level relative to PreC, and by comparing the course of infection by the mutant to wildtype WHV. In Aim 2, we propose to explore the dynamic changes of the WHV PreC/eAg density profile during infection and antiviral treatment in woodchucks and the composition of the HBV and WHV low-density PreC/eAg populations. This will be achieved by analyzing a large set of archival serum samples from woodchucks infected as neonates or adults or treated with nucleos(t)ide analogs or interferon-alpha. Presence of the low-density PreC/eAg population may cause or at least be associated with the chronic outcome of WHV infection, while reduction or loss may be associated with, or predict, effective viral suppression or functional cure of chronic infection under certain antiviral treatments. The composition of the low-density PreC/eAg proteins will be explored by analyzing their association with one or more extracellular vesicles or with lipoproteins. Successful completion of the proposed research will have a significant impact on identifying new viral and host factors involved in HBV persistence and may establish the low-density PreC/eAg population as a potential biomarker for predicting progression to chronic HBV infection and/or outcome of antiviral treatment.
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