Following the discovery of hepatitis C Virus (HCV), it became clear that there are cases of post-transfusion hepatitis that are not caused by hepatitis B virus (HBV) or HCV (1). Since none of the hepatitis viruses are readily cultivated in laboratory cell culture systems, progress in identifying additional etiologies of post-transfusion hepatitis proved difficult. In the mid-1990s, two companies independently used recently developed molecular methodologies to identify a human RNA virus in samples obtained from individuals with non-A, non-B, non-C post-transfusion hepatitis (2–4). The viral genome sequence and organization shared many similarities with HCV and other members of the Flaviviridae (2, 4–6), and one of the groups discovering the virus named it Hepatitis G Virus (HGV) (4), while the other was called GB virus type C (GBV-C) (2). “G.B.” were the initials of a surgeon who developed fulminant hepatitis in the 1960s, and whose serum caused transmissible hepatitis in marmosets [reviewed in (1, 7]. This “GB” serum was passaged in marmosets, and two viruses were identified in these materials that were called GB virus A and B (GBV-A, GBV-B) (3). Using these viral sequences as a guide, PCR methods were developed that identified a human virus and this virus was called GBV-C (2).

The “GB” serum reagents were extensively studied in the 1960s and 70s under the premise that they may contain the elusive cause of post-transfusion hepatitis, which ultimately proved to be HCV and not the GB agent (8–10). Following identification of HGV/GBV-C, virologic and serologic studies found that this virus is common in humans and that infection correlates with exposure to blood-born and sexually transmitted infections (4, 11–23). The related GBV-A and GBV-B proved to be non-human primate viruses, and there is no evidence that the surgeon “GB” was infected with GBV-C (reviewed in (7, 24). Further, numerous studies demonstrated that HGV is not specifically associated with acute or chronic hepatitis (14, 21, 25–28). In the majority of infections viremia persists for more than one year and may persist for decades in a subset of individuals (17, 18, 29). The underlying host factor(s) responsible for viral clearance remain unknown.

Since the virus does not appear to cause hepatitis, and there is no evidence that the surgeon G.B. was infected with this virus, the two names describing this virus were not logical. A 2011 proposal to assign the “GB viruses” into a novel genus named “Pegivirus” this was accepted by the International Committee on the Taxonomy of Viruses (ICTV) in 2013 (7, 30). Pegiviruses were comprised of viruses that demonstrated distant sequence relatedness to other members of the family Flaviviridae based on phylogenetic alignments of the RNA dependent, RNA polymerase. In addition to having a distinct phylogenetic position most closely related with the hepaciviruses within the Flaviviridae, pegiviruses differ from other hepaciviruses in genome organization features including an apparent lack of a nucleocapsid protein, a different internal ribosomal entry site (IRES) structure in the 5’ non-coding genome region, and less predicted glycosylation of the envelope glycoprotein E2 (reviewed in (7). The name “pegivirus” was derived from “Pe” for “persistent” and “G” representing the historical naming of the virus as HGV and GBV-C (7).

Although initially found only in primates and bats, the host range of pegiviruses has greatly expanded following the advent of next-generation sequencing (31–34). The genus currently has at least 11 host species (Pegivirus A to K) and additional host species are continuing to be identified. Pegivirus A members infect New World primate monkeys (35–37), and bats (38), while members of Pegivirus C infect humans and chimpanzees (2, 4, 39, 40) and other Old World monkeys (41, 42). Human pegivirus is regularly called HPgV-1 although this has not been formally assigned by the ICTV. Excluding HPgV-1 (pegivirus C), species B through J infect a wide range of primates and non-primate hosts including horses, domestic cats, lemurs, bats, dolphins, pigs, and rodent species (31, 38, 43–50). Figure 1 outlines the chronology of Pegivirus discovery.

Limited information suggests that pegiviruses do not transmit readily between host species; however, HPgV-1 can infect chimpanzees (51), and a baboon isolate of Pegivirus C can infect rhesus macaques (42, 52). Remarkably, novel viruses sharing pegivirus and hepacivirus features are found in non-mammalian hosts including sharks, lizards (Australian gecko), and geese (53–56). The goose pegivirus is reported to replicate in goslings, embryonated goose eggs, and primary goose embryo fibroblasts, and thus is the first pegivirus efficiently cultured in vitro (55). Until the goose pegivirus was recently described, no pegivirus has been described that replicate efficiently in cell culture systems and this has greatly hampered understanding of the biology of this enigmatic virus. The ability of all of the pegiviruses to cause persistent infection has not been confirmed.

A second human pegivirus closely associated with HCV infection was discovered in 2015 (57, 58). This virus is referred to as HPgV-2 or HHPgV-1, while the original HGV/GBV-C is referred to as HPgV-1. HPgV-2/HHPgV-1 is closely associated with HCV and is a different virus (not a different genotype) than HPgV-1. HPgV-2 is much less prevalent. Although there are few reports elucidating the pathogenic outcomes of this infection, in contrast with HPgV-1, the virus shares some virologic features with HCV including a predicted type IV IRES and highly glycosylated E2 protein (58). 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.

HPgV-1 infection occurs globally, and phylogenetic studies identify 7 genotypes that are geographically distributed (60–64). The virus is thought to be ancient based on several lines of evidence. First, genotypes are distributed in patterns that mimic human migration from Africa (7, 61) and the genetic distance between genotypes is similar to that of mitochondrial DNA between peoples of different races (61). South American populations comprised of mixed European and indigenous ancestry have a mixture of genotypes 2 (European/N. American) and 3 (Asian), while indigenous South Americans have genotype 3. Further, the prevalence of the virus in indigenous populations is similar to that of other regions of the world (61, 65–67). Finally, HPgV-1 is closely related to both old world and new world pegiviruses, suggesting that the virus was in primates prior to the split of the continents (61). Taken together, it has been suggested that HPgV-1 was present in primordial humans. Of note, recombination between genotypes has been described, which may complicate phylogenetic analyses and interpretation of genotypic distributions (68).

HPgV-1 shares many features with HCV. The viral genome is ~ 9.4 kB long, has a positive polarity and serves as the messenger RNA being translated off of its 5’ non-coding IRES (2, 4, 6, 35, 69, 70). The genome includes a long open reading frame that is translated into a C-terminal polyprotein with structural proteins post-translationally processed by cellular signal peptidase, and nonstructural proteins processed by two viral proteases (NS2 and NS3) and the NS3 co-factor (NS4A) (71, 72). A schematic of the viral genome, translation product polyprotein, and final protein composition is shown in Figure 2 .

HPgV-1 is transmitted via blood exposure, sexual exposure, and from mother to child (11, 12, 17, 21, 73–79). Based on transfusion studies, HPgV-1 infection typically lasts for > 6 months and is cleared in more than 50% of infections within 2 years (12, 18, 80). In a subset of individuals, viremia persists for more than two years, and for longer in some individuals (29, 81). In those who clear viremia, antibodies to the major viral envelope glycoprotein (E2) are usually detected and these antibodies are somewhat, though not completely protective (82–84). Interestingly, more than 90% of viremic individuals do not have detectable E2 antibodies, and no reproducible antibody pattern against any viral protein is elicited, suggesting a mechanism of immune evasion not described for other virus infections (reviewed in (7, 24, 28).

Based on E2 antibody and viremia prevalence studies, HPgV-1 is extremely common (12, 17, 21, 76, 84, 85). Viremia prevalence among healthy blood donors in developed countries ranges from 1.8% to 6% and E2 antibody prevalence ranges from 10 to 15% (7, 29, 67, 84, 86–89). The prevalence of infection in developed countries is estimated to be as high as 20% based on viremia and antibody determination, and infection is two to five times more frequent in developing countries and in individuals with other sexually transmitted or bloodborne infections (7, 29, 67, 84, 86–89). Since antibodies are lost in some individuals over time, prevalence estimates based on viremia and antibody detection likely represent an underestimate of true infection rates. A recent analysis of 79 studies including a meta-analysis of 63 of these found the global prevalence in healthy volunteer blood donors to be 3.1%, with geographic differences ranging from 1.7% in North America to 9.1% in South America (88). Complicating determinations of prevalence, reinfection of people who have lost antibodies is described (29, 90), and a small proportion of viremic individuals have detectable E2 antibodies (29, 91). The mechanisms underlying viral clearance and the combination of viremia with E2 antibodies are unclear.

Of note, no country screens blood donors for HPgV, despite the fact that viremia is common (2, 4). The argument against screening includes the fact that roughly one in 30 donations would need to be discarded in the U.S., greatly reducing blood availability for an infection, HPgV-1, that does not appear to cause significant disease. A recent study found that there are more than 17.9 million units of blood products transfused in the U.S. in 2017 (92), suggesting that approximately 1,000 blood product units containing HPgV-1 are transfused every day in the United States (92).

As noted above, HPgV-1 prevalence is higher among individuals who are highly exposed to bloodborne or sexually transmitted infections compared to healthy blood donors (21, 67, 76, 93, 94). In people living with HIV (PLWH) for example, 39% were viremic and 45% had detectable E2 antibody in the Multicenter AIDS Cohort study group, suggesting near universal infection (29). The proportion of PLWH who cleared viremia over six years of observation also appears to be lower than that of healthy blood donors (29, 81). Viremia rates in PLWH vary between studies, ranging from 15% to 41% [reviewed in (84, 95–97]. Further evidence of reduced clearance in PLWH is drawn from the finding that the ratio of E2 antibody to viremia is higher among people living with HCV infection (98). Given the rate of HPgV-1 viremia in healthy blood donors and the increase prevalence among people with other transmission risks, it appears that perhaps one third of humans experience HPgV-1 infection during their lifetime (7, 84).

HPgV-1 infection has been studied in a wide variety of people with and without chronic diseases. Taken together, studies do not show that the virus is clearly responsible for any acute or chronic disease (1, 28, 95, 98–105). Specifically, HPgV-1 is not associated with more extensive HCV-related disease, post-transplant liver disease or non-A to non-E hepatitis. This appears to be related to viral tropism, as evidence strongly suggests that the virus is lymphotropic. Supporting this hypothesis, removal of the donor liver in HCV/HPgV-1 co-infected individuals undergoing liver transplant results in a transient, but profound reduction in HCV viral load with no significant change in quantitative HPgV-1 viremia (106). HPgV-1 RNA is found in T bone marrow and spleen tissues (107–109), and in circulating T and B lymphocytes, monocytes, and NK cells (94, 110–116). Epidemiological studies also suggest that HPgV-1 is lymphotropic, and viral transmission mimics that of HIV (21, 76, 91, 94, 97, 117, 118).

Incubation of HPgV-1 with healthy donor peripheral blood mononuclear cells (PBMCs) or culture of PBMCs from HPgV-1 viremic individuals results in low level release of viral RNA into culture supernatant fluids, and T cell and NK cell functions are altered in vitro and in vivo (see below) (111–115, 119–121). The virus cannot be passaged for more than a few cycles in cell culture, and thus circulating PBMCs do not appear highly permissive for infection (94, 113). The primary cell type infected by HPgV-1 has not been identified, and there is no animal model of HPgV-1 infection to address this question directly. A pegivirus animal model was developed in rhesus macaques using a baboon pegivirus as the inoculum (42, 52). The distribution of baboon pegivirus RNA was consistent with studies of humans showing that bone marrow is the major location of both positive and negative (replicative) forms of HPgV-1 RNA (42, 109). Of note, this model may not be predictive of human pegivirus 1 infection, as there are sequence differences between simian and human viruses in critical regions of the genome.

Nevertheless, the specific cell type that is primarily infected and produces HPgV-1 in vivo remains a key unanswered question in HPgV-1 biology. Given the bone marrow location and distribution of virus RNA in human PBMCs, it has been speculated that a hematopoietic stem cell is the primary site of infection, and that a key replication factor (receptor, transcription factor, etc.) necessary for efficient and productive infection is lost during cell differentiation. Nevertheless, high total body levels of virus are present in infected individuals, with average plasma viral loads ranging from 1 x 10⁵ genome equivalents/mL (GE/mL) to as high as 1 x 10⁷ GE/mL (67, 122). Of note, viral load is distributed in a bi-phasic pattern. Approximately two thirds of healthy blood donors have an average viral load of 5 x 10⁶ GE/mL while the remaining one third of individuals have a viral load of approximately 8 x 10³ GE/mL (67). The reason for this biphasic distribution in viral load is unclear but may relate to host specific immunity, or perhaps to prior infection with some existing adaptive immune responses. It would be interesting to follow these subjects longitudinally to see if clearance rates over time differ based on viral load.

A variety of diseases have been studied to determine if there is an association with HPgV-1, and there is no clear association with fulminant hepatitis (98, 123, 124), aplastic anemia (15, 125, 126), hepatocellular carcinoma (103, 127, 128), multiple sclerosis (MS) (129), porphyria cutanea tarda (130), oral lichen planus or oral carcinoma (131), and others reviewed in (26–28, 95). However, there are two clinical situations in which HPgV-1 is associated with disease, non-Hodgkin’s lymphoma (NHL) and sporadic encephalitis.

In several studies including a meta-analysis, HPgV-1 infection is associated with approximately a 2.8-fold increased risk of developing NHL (132–135). HPgV-1 has also been associated with sporadic encephalitis, and viral RNA and antigens were detected in post-mortem brain tissues from two people with this condition (136, 137). A variant of HPgV-1 containing a deletion in the NS2 coding region was identified in the brain tissue of one subject, and this NS2 deletion virus appeared to replicate better in astrocytes than the wild type HPgV-1. HPgV-1 replication has recently been demonstrated in human astrocytes and microglia in vitro, though replication was not identified in neurons or an oligodendrocyte-derived cell line (137). HPgV-1 infection of human glia cells led to the suppression of peroxisome-associated gene expression which was accompanied by reduced expression of interferon-beta, interferon regulatory transcription factors 1 and 3, and mitochondrial antiviral signaling protein. These changes were consistent with findings in the brain tissue obtained from the patients with HPgV-1 and sporadic encephalitis (137). Given the high prevalence of HPgV, the high serum and PBMC viral load, and low rates of sporadic encephalitis, it remains unclear if HPgV-1 commonly infects neural tissue or has any direct neurological outcomes in those without encephalitis. Of note, in the rhesus model of pegivirus infection neural tissues did not demonstrate increased levels of viral RNA (42). It will be important to clarify the host feature(s) associated with putative HPgV-1-related encephalitis.

Among pegivirus infections in non-human species, no definitive association has been identified with a specific disease entity. Early reports suggested that a divergent member of the pegivirus genus found in horses (called Theiler’s disease-associated virus) was responsible for Theiler’s disease (44, 138). However, this conclusion was later shown to be spurious (139, 140). More recently, a novel pegivirus was identified in a research colony of common marmosets (Callithrix jacchus) in animals that died of lymphocytic enterocolitis (34). The investigators named this new virus the “southwest bike trail virus” (SOBV). Although identified in ill marmosets, a prospective analysis of a colony of 85 common marmosets failed to identify an association between SOBV infection and lymphocytic enterocolitis or any other disease. The prevalence of SOBV in common marmoset was high (34%) illustrating the difficulty in assigning disease causality for a prevalent virus (34). To date, SOBV has not been identified in common marmosets found in the wild and it is not clear if this species is the natural host for SOBV (34, 141).

In the first 5 years following the discovery of HPgV, more than 600 papers were published examining the potential clinical outcomes of infection, with most of these studies conducted by research groups whose focus was on viral hepatitis. Once there was clear evidence that HPgV-1 does not cause acute or chronic liver disease (26, 27), research interest and publication rates fell rapidly. However, small studies from Japan, Germany, the U.S. and France described the role of HPgV-1 in liver disease in HIV coinfection (76, 83, 142, 143). These reports confirmed that HPgV-1 was not associated with liver disease; however, people with HIV and HPgV-1 coinfection appeared to have prolonged survival compared to those with HIV alone. These data were subsequently confirmed in two large, cross-sectional studies of people with HIV infection. The relative risk of mortality was 3.7-fold (95% C.I. 2.5 – 5.4) higher among those without HPgV-1 infection in a U.S. study (94) and also significantly higher in a German study (122), although relative hazard rates and confidence intervals were not described for the latter. Interestingly, HPgV-1 viral loads were inversely related to HIV RNA levels, and HPgV-1 infection did not prevent CD4 depletion (67, 94, 122, 144). Nevertheless, CD4 counts were higher overall in those with HPgV-1 compared to those uninfected in several studies (67, 76, 94, 122, 145, 146).

A legitimate criticism of these early studies related to the fact that the duration of HIV infection was unknown at the time of HPgV-1 sampling. If HPgV-1 were acquired late in infection this would bias prevalence towards those living longer with HIV (118). An alternative explanation for the beneficial observation suggested that HPgV, increasingly recognized as a lymphotropic virus, was simply a marker of conserved CD4 cells. If so, CD4 depletion accompanying HIV infection would lead to a loss of HPgV-1 viremia (Van der Bij et al., 2005). This latter explanation was not consistent with the finding that survival was reduced in PLWH who presented with very low CD4 counts (< 50/mm³) (94, 147).

To address these limitations, two studies were conducted in HIV cohorts with known or an estimated time of HIV infection. In the Multicenter AIDS Cohort Study group, HPgV-1 viremia and E2 antibody were characterized in 271 individuals with documented HIV seroconversion within 12 months of the first positive HIV antibody test. In this “early” group, no survival benefit was observed; however, follow up testing 5-6 years following seroconversion found that those without HPgV-1 infection were 2.83-fold more likely to die in subsequent observation compared to those who were persistently HPgV-1 viremic (29). In addition, almost 20% of HPgV-1 viremic individuals cleared HPgV-1 in the first 5 to 6 years after seroconversion. Individuals who cleared viremia had significantly higher mortality than those who were persistently viremic (3.85-fold) suggesting either that HPgV-1 clearance results in the loss of a beneficial factor, or that clearance of viremia is related to a host variable that overcomes HPgV-1 immune escape mechanisms and which hastens HIV-related disease. Two additional studies confirmed that loss of HPgV-1 viremia was associated with significantly increased mortality (118, 148).

The Amsterdam HIV Study Group also examined the role of HPgV-1 on survival in people living with HIV. Although their data were highly consistent with the MACS study, the authors applied several statistical models to the data and came to different conclusions (118). Similar to the MACS study, the primary, unadjusted analysis found that mortality was significantly lower (RH 0.52, 95% CI 0.32-0.85) in those with persistent HPgV-1 infection. Three additional statistical models were applied to these data. In the first model, which was controlled for age at seroconversion, antiretroviral therapy, CCR5 genotype, baseline CD4, and HIV RNA 1 year after seroconversion, persistent HPgV-1 viremia was significantly associated with reduced mortality (RH 0.57, 95% CI 0.35-0.94). In the second model, the same variables plus time-varying HIV viral load were controlled and there remained a survival benefit (relative hazard of mortality 0.47, 95% CI 0.35 – 0.93) in those with persistent HPgV-1 infection. In the third model, time-varying CD4 count was added to the other cotrolled variables, and there remained a survival benefit (RH mortality 0.74, 95% CI 0.45 – 1.25); however, statistical significance was lost. The authors concluded from these data that HPgV-1 viremia is a marker of CD4 T cell number and that HPgV-1 is not a causative factor in the improved survival observed in the other models (118).

Limitations of the Amsterdam study include that the date of seroconversion was calculated and not measured directly. Since the calculated method of HIV infection has a relatively wide time window for seroconversion (149), the duration of HIV infection in this group was far less accurate than in the MACS study. Secondly, several studies demonstrate that CD4 decline is slowed in HPgV-1 infected PLWH (29, 76, 94, 122, 145). Since death in HIV-1 infection is caused by immune deficiency directly correlated to CD4 depletion, CD4 count is in the causal pathway for death. Controlling for time-varying CD4 removes the differences in CD4 decline in those with and without HPgV-1 infection, and from a statistical standpoint, controlling avariable in the causal pathway should remove any potential benefit of HPgV-1 (147). Nevertheless, there remained a 26% reduction in mortality in those with persistent HPgV in this model. This suggests that pegivirus viremia influences mortality by more than expected from its altered rate of CD4 depletion (147, 150). A meta-analysis of published studies meeting rigorous criteria confirmed a reduction in mortality in HIV infection for those with HPgV-1 co-infection (RH 0.41) (96).

Despite a large number of studies showing survival advantage, lower HIV VL, and higher CD4 in those with HIV and HPgV-1 coinfection, the interpretation of the Amsterdam data continues to reduce acceptance of the apparent beneficial effect of HPgV-1 on HIV survival. Since there is not a good animal model for HPgV, and human challenge experiments proposed to the FDA were not allowed to proceed (using licensed blood products), Koch’s postulates have not been confirmed. A close proxy to Koch’s postulates was assessed by Vahidnia et al., who tested plasma samples obtained from people living with HIV who had received blood transfusions in the 1980s and 1990s. Pre- and post-transfusion samples and samples from the transfused blood product were available for HPgV-1 viremia testing, and individuals who acquired HPgV-1 from transfusion were found to have a reduced risk of death (RH 0.22) compared to those who did not acquire HPgV-1 (151), confirming a direct role for HPgV-1 infection and prolonged survival in HIV infection.

Finally, two studies found that HPgV-1 infection in women is associated with reduced HIV transmission from mother to child in the pre-highly active antiretroviral therapy era. A U.S. study found an association between maternal HPgV-1 viremia in the third trimester and reduced HIV infection in the child (152). A large study in Thailand found that, among infants who acquired HPgV-1 during delivery, HIV transmission was reduced by 87%, further supporting an HPgV-related reductions in HIV disease outcomes (78).

Taken together, the data demonstrating a survival benefit among PLWH who have HPgV-1 coinfection is thus supported by numerous clinical studies. Two papers recommend studying HPgV-1 infection as a “biotherapy” for HIV infection (153, 154). To date, regulatory groups have not approved this approach. The following section will summarize data investigating mechanisms by which HPgV-1 might influence HIV disease outcomes.

Viral-mediated interference with T cell activation may be a common feature of viral immune modulation (Stapleton JT, 2014), and in addition to HIV-1, there are at least three additional diseases in which HPgV-1 infection is association with beneficial clinical outcomes. Although studies of HCV and HPgV-1 did not identify synergistic pathology, a beneficial role for HPgV-1 infection was found in individuals with triple infection with HIV, HCV and HPgV-1 compared to those with HIV and HCV coinfection (216). Specifically, HPgV-1 infection was associated with slower progression of HCV-related liver disease, and also with reduced LCK activation in intrahepatic T cells (216, 217). Since HCV pathogenesis is driven by immunologic destruction of infected hepatocytes, reducing T cell activation and proliferation likely contributes to the improved outcomes in HCV-induced liver disease (24, 218).

Similarly, Ebola virus infection is associated with cytokine storm and high mortality rates (219). Studies in West Africans with Ebola found that mortality in those with HPgV-1 coinfection was 47% compared to 78% in those without HPgV-1 coinfection, presumably due to the effects of HPgV-1 on immune activation (219). Although there have not been studies reported to date to address this, it would be of interest to see if primary COVID-19 outcomes are ameliorated by HPgV-1 infection since severe SARS-CoV-2 infection is associated with cytokine storm (220).

One additional immune-mediated clinical disease may be influenced by HPgV-1 infection. Vu et al. found that, following stem cell transplantation, both the rate of severe graft-versus-host-disease and overall mortality were reduced in individuals with HPgV-1 infection (221). This finding requires confirmation, but given the effects of HPgV-1 on immune activation, there is biologic plausibility supporting a beneficial interaction (222).

HPgV-1 is associated with an increased risk of lymphoma and possibly with sporadic encephalitis. However, given the high prevalence of infection and lack of commonly recognized disease states, in concert with the finding that persistent infection is beneficial in HIV coinfected individuals (and possibly other disease states), HPgV appears to represent a largely symbiotic infection within the human virome that has little or no pathogenicity. Several direct anti-retroviral actions of HPgV-1 have been identified, and these likely contribute to the improved survival observed in people living with HIV. Examination of the structural components of anti-HIV peptides may facilitate the development of cellular-based, small molecule HIV inhibitors, and identifying the cross-reactive HIV antigen(s) recognized by HPgV-1 E2 antibody may facilitate development of HIV vaccines (159, 164, 165, 168, 169, 171, 173).

In addition to developing HIV therapeutics, HPgV-1 is highly associated with immune modulation of human T cells, B cells, NK cells and monocytes, suggesting that this aspect of the virus provides beneficial, anti-inflammatory effects without inducing clinically evident immune compromise (188, 189, 201). In persistently viremic individuals, high rates of viral replication are observed concurrently with reduced markers of immune activation and in most, no detectable anti-HPgV-1 antibodies detected (7).

As a relatively non-pathogenic, lymphotropic virus that infects and preferentially replicates in bone marrow and spleen, HPgV-1 potentially could be used as either a novel gene therapy delivery system or as a bio-vaccine for HIV (153, 154). Further study of the role of HPgV infection on disease outcomes in immune-mediated diseases could provide insights into the natural history of many immune-mediated diseases, including most recently COVID-19. The effect, if any of HPgV-1 on SARS-CoV-2 infection has not been examined at the time of writing.

Currently, the biggest problem hindering HPgV-1 development for therapeutic use relates to the difficulties in growing the virus in vitro. While virus replicates in lymphocytes, NK cells, and neural cells in vitro (110–113, 115, 116, 120, 137, 203), infection cannot be maintained in cell culture for more than handful of passages, suggesting either abortive infection or slow infection with dilutional loss of infected cells. Specifically, most of the cells in PBMC cultures obtained from HPgV-1 infected individuals die rapidly, leaving a small subset of primary mononuclear cells that survive for weeks to months producing low levels of virus (115). In CD4+ Jurkat T cell lines, intracellular viral RNA and antigens are detected following infection (113, 119); however, the amount virus released slowly decays, and after several passes of supernatant fluids to new, uninfected cells, the infection is lost. Since HPgV-1 slows cellular proliferation induced by IL-2 or TCR-stimulation (121, 199), this may reflect a virus-driven interference with Src kinase-mediated cellular proliferation, resulting in gradual loss of infected cells that produce such low levels of virus that infection of new cells is gradually lost.

Many approaches to identify specific cell types that support HPgV-1 replication have been attempted including use of CD34+ human stem cells, interferon-resistant cells, and other innate knockout cell lines without success (116). The recent finding that goose pegivirus replicates well in embryonated goose eggs and primary goose embryo fibroblasts raises hope that novel culture systems can be developed for HPgV-1 (55).

Another important limitation in HPgV-1 research is the validated association of HPgV-1 infection with the development of lymphoma and the recent suggestion of an association with encephalitis. Given the effects of HPgV-1 on immune activation, the most logical explanation for increased risk of lymphoma relates to a reduction in immune surveillance, though a direct causal effect on lymphoma needs to be excluded (133–135). The two to three-fold increase in risk of lymphoma in HPgV-1 viremic individuals is significant, but does not explain the vast majority of lymphoma cases. Further, the age of HPgV-1 infection (sexually active adolescents to late-mid life) is the opposite that of maximal lymphoma risk (223).

In summary, HPgV-1 is a highly prevalent, low- or non-virulent human infection that reaches high viral loads in plasma and is associate with reductions in human immune activation markers. Pegiviruses are increasingly being identified in diverse hosts, and their apparent longevity in humans and non-human primates suggests that they convey an overarching beneficial effect on health. Future studies to determine the breadth and magnitude of these effects are warranted.

The author confirms being the sole contributor of this work and has approved it for publication.

This study was supported in part by a Veterans Administration Merit Review grant (BX000207).

The author JS has patents related to the use of GB virus C in the potential treatment of HIV-1 infection.

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