The impact of quasi-envelopment on hepatitis virus infection and immunity

 描述（由申请人提供）：甲型肝炎病毒（HAV）和戊型肝炎病毒（HEV）感染是世界欠发达地区流行性食源性和水源性肝炎的常见原因。近年来，在发达国家，散发性HEV感染已成为一种重大的公共卫生危害。人畜共患病和血液传播的戊型肝炎病毒的传播及其在免疫抑制个体中持续存在的能力也令人担忧。大约20%的美国人口对HEV呈血清阳性，表明HEV暴露比以前认为的更常见。虽然两者都被认为是无包膜病毒，但最近的研究表明，HAV和HEV作为“准包膜”颗粒在血液中循环。这些新型颗粒与经典包膜病毒的不同之处在于，它们的膜表面上不存在病毒抗原，因此对中和抗体具有高度抗性。这种“准病毒化”对肝炎病毒生命周期、免疫和发病机制的影响尚不清楚。本研究将探讨类包膜HAV和HEV进入细胞并被抗体中和的机制。目的1将测试的假设，即进入“准包膜”HAV和HEV是通过细胞外囊泡摄取的细胞机制。目的2将确定中和准包膜HAV和HEV的机制。这些目标的完成将解决几个最重要的差距，我们的理解准包膜病毒的生命周期和发病机制。

 DESCRIPTION (provided by applicant): Hepatitis A virus (HAV) and hepatitis E virus (HEV) infections are common causes of epidemic food-borne and water-borne hepatitis in under-developed regions of the world. Recently sporadic HEV infections have emerged as a significant public health hazard in well-developed countries. The recognition of zoonotic and blood-borne HEV transmission and its ability to persistent in immunosuppressed individuals is also alarming. Approximately 20% of the U.S. population is seropositive for HEV, indicating that HEV exposure is more common than previously thought. Although both recognized as non-enveloped viruses, recent studies show that HAV and HEV circulate in the blood as "quasi-enveloped" particles. These novel particles differ from classic enveloped viruses in that no viral antigens are present on the surface of their membrane, therefore are highly resistant to neutralizing antibodies. The impact of this "quasi-envelopment" on hepatitis virus life cycle, immunity, and pathogenesis is poorly understood. This proposal will explore the mechanisms by which quasi- enveloped HAV and HEV enter the cells and are neutralized by antibodies. Aim 1 will test the hypothesis that entry of "quasi-enveloped" HAV and HEV is through a cellular mechanism for extracellular vesicular uptake. Aim 2 will determine the mechanism of neutralization for quasi-enveloped HAV and HEV. Completion of these aims will address several of the most significant gaps in our understanding of the quasi-enveloped virus life cycle and pathogenesis.