Tropism of human pegivirus (formerly known as GB virus C/hepatitis G virus) and host immunomodulation: insights into a highly successful viral infection

Abstract

Human pegivirus (HPgV; originally called GB virus C/hepatitis G virus) is an RNA virus within the genus Pegivirus of the family Flaviviridae that commonly causes persistent infection. Worldwide, 750 million people are actively infected (viraemic) and an estimated 0.75-1.5 billion people have evidence of prior HPgV infection. No causal association between HPgV and disease has been identified; however, several studies described a beneficial relationship between persistent HPgV infection and survival in individuals infected with human immunodeficiency virus. The beneficial effect appeared to be related to a reduction in host immune activation. HPgV replicates well in vivo (mean plasma viral loads typically .1¾10 7 genome copies ml -1 ); however, the virus grows poorly in vitro and systems to study this virus are limited. Consequently, mechanisms of viral persistence and host immune modulation remain poorly characterized, and the primary permissive cell type (s) has not yet been identified. HPgV RNA is found in liver, spleen, bone marrow and PBMCs, including Tand B-lymphocytes, NK-cells, and monocytes, although the mechanism of cell-to-cell transmission is unclear. HPgV RNA is also present in serum microvesicles with properties of exosomes. These microvesicles are able to transmit viral RNA to PBMCs in vitro, resulting in productive infection. This review summarizes existing data on HPgV cellular tropism and the effect of HPgV on immune activation in various PBMCs, and discusses how this may influence viral persistence. We conclude that an increased understanding of HPgV replication and immune modulation may provide insights into persistent RNA viral infection of humans. IntroductionHuman pegivirus (HPgV) is an RNA virus within the Pegivirus A species and family Flaviviridae (Adams et al., 2013;Stapleton et al., 2012a). The virus was originally called hepatitis G virus (HGV)/GB virus type C (GBV-C). The letters 'GB' represented the initials of a surgeon with acute hepatitis whose sera caused hepatitis in marmosets (Deinhardt et al., 1967). Subsequent studies found that this virus did not cause hepatitis and there was no direct evidence that the surgeon ('G. B.') was infected with HPgV. Thus, the virus (HGV/GBV-C), along with several related primate and bat viruses (GBV-A, GBV-C czp , GBV-D), was assigned to a new genus (Pegivirus) and renamed as HPgV (Adams et al., 2013;Stapleton et al., 2012a). HPgV has a 9.4 kb positive-sense ssRNA genome that is organized similarly to hepatitis C virus (HCV) (Fig. 1). HPgV and HCV are unusual amongst RNA viruses in that they commonly cause persistent infection in immune-competent humans.Although HPgV is not as efficient at establishing persistent infection as HCV, an estimated 25 % of infections persist and the other 75 % clear viraemia within 2 years of infection (Gutierrez et al., 1997;Tanaka et al., 1998a). The prevalence of HPgV viraemia in cross-sectional serum surveys of healthy blood donors in developed countries is between 1 and 5 %, whilst up to 20 % of blood donors in ...

Human Pegivirus (HPgV; formerly known as GBV-C) inhibits IL-12 dependent natural killer cell function

“…HPgV replicates in peripheral blood mononuclear cells (PBMC) ex vivo, but the primary type of cell(s) that support HPgV replication in vivo are not well characterized (Chivero and Stapleton, 2015). Among chronically infected individuals, HPgV RNA is found in multiple blood cell types including T and B lymphocytes, monocytes and natural killer (NK) cells (Chivero et al, 2014;George et al, 2006).…”

Human pegivirus isolates characterized by deep sequencing from hepatitis C virus‐RNA and human immunodeficiency virus‐RNA–positive blood donations, France

“…Of note, however, human immunodeficiency (HIV)‐HPgV association studies were extensively explored, due to a possible beneficial effect in HIV infection motivating investigations about HIV‐HPgV interactions at the molecular level . Mechanisms of viral persistence and host‐immune modulation remain also poorly characterized . Previous studies allowed the identification of the viral genome in liver, spleen, bone marrow, and peripheral blood mononuclear cells, including T and B lymphocytes, NK cells, and monocytes; the infection of progenitor hematopoietic stem cells as possible primary targets of the virus had been also suggested …”

Discovery of a Novel Human Pegivirus in Blood Associated with Hepatitis C Virus Co-Infection

“…Previous studies have revealed frequent detection of pegivirus GBV-C (HPgV, referred herein as HPgV-1) in HCV-infected individuals [3,15]. Since HPgV-2 was discovered in an HCV coinfected individual (UC0125.US), initial screening of 200 plasmapheresis donors positive for HCV by NAT and Ab testing (HCV NAT+/Ab+) was performed for HPgV-2 using a real-time RT-PCR directed against a region spanning the NS2 and NS3 genes (S2A Fig).…”