The second human pegivirus HPgV-2 is a novel blood-borne virus that is strongly associated with the hepatitis C virus (HCV) infection. However, the molecular evidence for their association as well as the natural history and tissue tropism of HPgV-2 remain to be elucidated. In this longitudinal study, a total of 753 patients including 512 HIV-1 and HCV co-infected patients were enrolled to characterize the natural history of HPgV-2 infection. Peripheral blood mononuclear cells (PBMCs) and liver biopsies were collected to determine the tissue tropism of HPgV-2 using immunohistochemical staining of the HPgV-2 antigen and in situ hybridization of HPgV-2 RNA. We documented both persistent HPgV-2 infection with the presence of HPgV-2 viral RNA and antibodies up to 4.6 years and resolved HPgV-2 infection, accompanied by a simultaneous decline of anti-HPgV-2 antibodies and clearance of HPgV-2 viremia. Furthermore, we observed the clearance of HCV, but not HPgV-2, by treatment with direct-acting antivirals (DAAs). Biochemical tests and pathological analyses did not reveal any indication of hepatic impairment caused by HPgV-2. HPgV-2 RNA and nonstructural antigen were detected in the lymphocytes, but not in the hepatocytes present in the liver biopsy samples. In addition, both positive- and negative-strand HPgV-2 RNAs were detected in PBMCs, especially in B cells. The present study is the first to provide evidence that HPgV-2 is a lymphotropic, but not a hepatotropic virus and that HPgV-2 replication is independent of HCV viremia. These new findings let us gain insights into the evolution and persistent infection of RNA viruses in humans.

中文翻译：

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有证据表明第二种人类佩吉病毒（HPgV-2）主要是淋巴病毒，可以独立于HCV复制而复制。

第二种人类佩吉病毒HPgV-2是一种新型的血源性病毒，与丙型肝炎病毒（HCV）感染密切相关。然而，有关其结合以及HPgV-2的自然史和组织嗜性的分子证据仍有待阐明。在这项纵向研究中，共纳入753名患者，其中包括512名HIV-1和HCV合并感染的患者，以表征HPgV-2感染的自然史。使用HPgV-2抗原的免疫组织化学染色和HPgV-2 RNA的原位杂交，收集外周血单个核细胞（PBMC）和肝脏活检样本，以确定HPgV-2的组织嗜性。我们记录了持续存在的HPgV-2感染（存在HPgV-2病毒RNA）和长达4.6年的抗体，并解决了HPgV-2感染，同时出现抗HPgV-2抗体下降和HPgV-2病毒血症清除的情况。此外，我们观察到通过直接作用抗病毒药（DAA）治疗可清除HCV，但未清除HPgV-2。生化测试和病理分析未发现任何由HPgV-2引起的肝功能损害的迹象。在肝活检样本中的淋巴细胞中检测到HPgV-2 RNA和非结构性抗原，但未检测到。另外，在PBMC中，特别是在B细胞中，检测到正链和负链HPgV-2 RNA。本研究是第一个提供证据证明HPgV-2是淋巴病毒，而不是肝病毒，并且HPgV-2复制与HCV病毒血症无关。这些新发现使我们对人类RNA病毒的进化和持续感染有了更深入的了解。