Human pegivirus infection after transplant: Is there an impact?

The microbiome's role in transplantation has received growing interest, but the role of virome remains understudied. Pegiviruses are single-stranded positive-sense RNA viruses, historically associated with liver disease, but their path-ogenicity is controversial. In the transplantation setting, pegivirus infection does not seem to have a negative impact on the outcomes of solid-organ and hematopoietic stem cell transplant recipients. However, the role of pegiviruses as proxies in immunosuppression monitoring brings novelty to the field of virome research in immunocompromised individuals. The possible immunomodulatory effect of pegivirus infections remains to be elucidated in further trials.


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INTRODUCTION
The microbiome's role in transplantation has received growing interest, but the role of virome remains understudied. Several studies have shown that the virome changes upon immunosuppression initiation [1,2]. Most notable is the increase in the anelloviruses but also in pegiviruses.
Pegiviruses are single-stranded positive-sense RNA viruses, most closely related to hepatitis C virus (HCV) in terms of genome organization with structural genes located at the 5' genomic region and non-structural genes at the 3' end [3]. The genome encodes a polyprotein that is co-and post-translationally cleaved into individual viral proteins. Structural proteins common to all pegiviruses are the envelope glycoproteins (E1 and E2), and non-structural proteins are NS2-NS5B[4]. Pegiviruses are classified into eleven species (pegivirus A-K) within the genus Pegivirus in the Flaviviridae family. Two pegiviruses are known to infect humans, the human pegivirus (HPgV) and the HPgV-2, but their pathogenicity is limited and no clear association with any human disease has been established [5].
HPgV was discovered in 1995 from the sera of patients with hepatitis by two independent investigator groups, who named it GB virus C and hepatitis G virus (HGV), respectively. The HPgV's E2 glycoprotein, involved in the adhesion and fusion with the host cells, targets the production of anti-HPgV antibodies, which appear after the viral clearance and provide partial protection against reinfection [6]. The virus is efficiently transmitted through sexual contact and intravenous substance use, vertically from mother to child, and through exposure to infected blood and blood components [7].
Available data suggest a high prevalence of HpgV viremia (> 40%) in populations with parenteral exposure risk [8]. Although early studies indicated that the HPgV is hepatotropic, numerous subsequent studies have shown that HPgV is rarely detectable in infected individuals' liver tissue. In addition, no evidence of a liver disease potentially linked to HPgV was observed during the follow-up of different patient categories [7].
HPgV-2 was isolated in 2015 from the plasma of HCV-infected patients with multiple blood-borne exposures in the United States [8]. A low prevalence of HPgV-2 viremia has been noted in the general population, but there is an increase in patients with HCV infection and injecting drug users co-infected with HCV[9]. Further studies indicated that HPgV-2 is a lymphotropic but not a hepatotropic virus, which may explain the lack of association with liver disease [10].
HPgVs are distributed globally, and viral RNA is present in roughly 750 million people[6], making it ubiquitous in human populations. The prevalence of HPgV viremia from cross-sectional studies of healthy blood donors in developed countries ranges between 1% and 5%. Nearly 200000 units of HPgVs-contaminated blood products are transfused each year in the United States [11]. In comparison, in developing countries, up to 20% of blood donors have an active infection [12]. Data suggest that approximately 1.5-2.5 billion people are currently infected or have evidence of prior HPgV infection [6].
Numerous studies examined the presence of HPgV in several countries. Generally, a high HPgV prevalence is observed among subjects with parenteral exposure, including those exposed to blood and blood products, those on hemodialysis, those with a history of intravenous substance use, and patients with chronic hepatitis C or human immunodeficiency virus (HIV) infection[13].

HPGV AFTER TRANSPLANTATION OF SOLID ORGANS AND NON-SOLID ORGANS
HPgVs have received much attention due to the possible beneficial immunomodulatory effects by reducing immune activation in patients with other viral diseases such as HIV infection, hepatitis B, and Ebola virus disease[14-17]. On the other hand, HPgV viremia has also been associated with the development of non-Hodgkin lymphoma (NHL). HPgV is a lymphotropic virus that may cause persistent infection in T and B lymphocytes, reduced Fas-mediated apoptosis, and impaired T cell and interleukin-2 receptor signaling [18]. HPgV infection anticipates the development of NHL by several years and resolved infection was not associated with NHL risk [19]. Pegiviruses have been studied both in hematopoietic stem cell transplantation (HSCT) and solid-organ transplant (SOT) recipients (Table 1).
Studies in HSCT recipients are limited. The prevalence of HPgV in HSCT patients ranges from 18.6%, as described in the study from Switzerland[20], to almost 30% in an earlier French study [21]. As in the general population, the risk of viremia rises with the number of received blood products [20,22]. No significant influence of pegiviruses on HSCT patient outcomes was found. On the other hand, no beneficial effect of pegivirus infections is currently proven; therefore, some studies warrant HPgV donor screening for blood products used in HSCT recipients until more conclusive studies are performed [22].
Early studies in SOT recipients were done mostly in liver transplant (LT) recipients, due to the presumed hepatotropic nature of the virus, all showing a high prevalence but no significant influence on patient outcomes [23][24][25][26]. The largest of the studies included in this review is the recent Japanese study on 313 LT recipients. This monocentric study showed an increased prevalence of HPgV in LT recipients compared to hepatectomy controls [27]. As in the earlier studies, there was no significant association between HPgV infection and LT outcomes. The study showed that HPgV infection induced the up-regulation of interferon-stimulated gene (ISG) expression in peripheral blood mononuclear cells [27].
HPgV is transmitted through parenteral, sexual, and perinatal routes [28]. Parenterally exposed individuals such as hemodialysis patients, therefore, have a higher risk of infection. An Indian study using univariate analysis showed that the prevalence of GB virus C/HGV RNA was significantly associated with ≥ 20 hemodialysis sessions [29]. After the transition from dialysis, the prevalence remains high in kidney transplant (KT) recipients, ranging from 12% to 47% in different countries [30][31][32][33]. A large Italian study in KT recipients (n = 155) showed an HGV RNA and anti-HGV prevalence of 24% and 17%, respectively [34]. None of the studies above, found any influence on patient outcomes, including kidney or liver function. On the other hand, the largest study in KT recipients (Germany, n = 221) [33] showed that a much higher proportion of KT recipients were exposed to HGV, than that suggested by HGV RNA detection alone. The prevalence of HGV RNA and anti-HGV in the study was 14% and 40%, respectively. Most infected individuals eliminate the virus over time. Unfortunately, the majority of other studies did not include serological analyses. Most of the studies on HPgV were done immediately after the discovery of the virus, focusing mostly on hepatic function or the function of the transplanted organ. Only the most recent study[1] tried to include other post-transplant complications in the analysis, e.g., new-onset diabetes after transplantation or nephrotoxicity in LT recipients. The study highlighted a potential use of anellovirus infection as a proxy for determining the immunological status. At the moment there is no standard way to measure total immunosuppression, besides the widely available through levels of immunosuppressant drugs. In the same study, all of the HPgV positive participants were still alive 5 years after LT, indicating a protective role of HPgV in posttransplantation survival[1].
The paucity of other SOT recipient studies probably reflects the proportionately lower number of those transplants performed. We found no studies evaluating HPgV in simultaneous pancreas-kidney transplantations or lung transplant recipients. The studies in heart transplant recipients are concordant to those in other SOT, showing no adverse outcome but a high HPgV prevalence, up to 36%[35-42].

CONCLUSION
To conclude, pegivirus infection does not seem to have a negative impact on the outcome of transplant recipients. Nevertheless, studies are limited and lacking prospective data. What remains to be elucidated is the possible immunomodulatory effect of pegivirus infections. Also, the role of pegiviruses as proxies in immunosuppression monitoring brings novelty to the field of virome research in immunocompromised individuals. The subject deserves further research and evaluation.