Evidence that the second human pegivirus (HPgV-2) is primarily a lymphotropic virus and can replicate independent of HCV replication

Abstract

Tang (2020) Evidence that the second human pegivirus (HPgV-2) is primarily a lymphotropic virus and can replicate independent of HCV replication, Emerging Microbes & Infections, 9:1,[485][486][487][488][489][490][491][492][493][494][495] ABSTRACT 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 coinfected 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.

Difference of Intrahost Dynamics of the Second Human Pegivirus and Hepatitis C Virus in HPgV-2/HCV-Coinfected Patients

“…These results suggest that HPgV-2 per se does not stimulate strong innate immune response to pose high selection pressure upon HPgV-2 infection. Our results are in line with our previous findings that HPgV-2 infection results in limited or absence of pathogenicity (Wang et al, 2018b;Sridhar et al, 2019) and is at least not associated with viral hepatitis although it always coinfects with HCV (Wang et al, 2018b;Wan et al, 2020). Therefore, for HPgV-2/HCV-coinfected subjects, even though HPgV-2 confronts strong immune selective pressure, the immune responses may be mainly induced by HCV while the specific immune response against HPgV-2 may be moderate, which is in accordance with the decreased pro-inflammatory cytokines expression after HCV elimination (Figure 4A).…”

RNA-Dependent RNA Polymerase of the Second Human Pegivirus Exhibits a High-Fidelity Feature

“…Our previous studies showed that sofosbuvir can inhibit HCV replication but not HPgV-2 replication ( 13 , 14 ). Sofosbuvir is a uridine analog and a nucleotide inhibitor (NI) of RdRp for the treatment of chronic HCV infection ( 21 – 23 ).…”

“…Moreover, our previous studies indicated that direct-acting antiviral (DAA) treatment, such as the nucleotide inhibitor (NI) sofosbuvir targeting viral RdRp, could eliminate HCV but not HPgV-2 infection ( 13 , 14 ). The preclinical assessments and clinical analysis of sofosbuvir trials have shown that mutations in HCV RdRp lead to a decrease in drug susceptibility ( 15 – 18 ) and that the drug resistance is closely related to RdRp fidelity ( 19 , 20 ).…”

Human Pegivirus Type 1: A Common Human Virus That Is Beneficial in Immune-Mediated Disease?

“…Nevertheless, a recent study shows that, like HPgV-1, HPgV-2 appears to be lymphotropic. More study of this virus is needed ( 59 ). Since current knowledge related to HPgV-2 is limited, the virus is not in the same phylogenetic lineage as HPgV-1 and is not known to influence other diseases, HPgV-2 will not be discussed further in this review.…”