Pegiviruses (PgVs) are a genus of +ssRNA viruses currently classified within the Flaviviridae family [1,2]. Pegivirus infections are widespread in mammals, and two divergent PgVs have been discovered in humans: HPgV-1 (aka. Pegivirus hominis), which infects ~15% of the global human population; and the much rarer HPgV-2 (aka. Pegivirus columbiaense) [1,2]. These viruses cause high-titer viremia that can persist for years to decades, with the phenomenon of viral clearance being well-documented but poorly understood. Due to the high prevalence of HPgV infection in humans and the abundance of viral RNA in infected individuals, metagenomic studies on human samples routinely detect HPgV infections. Iatrogenic HPgV infections, via procedures like blood transfusion, are presumed to be common but HPgV diagnostics are not used clinically.

PgVs are phylogenetically related to several important human pathogens with hepatitis C virus (HCV) being the closest medically relevant virus, though these viruses share only ~50% nucleotide and ~30% amino acid sequence identity. However, unlike HCV, HPgV has never been shown to play a causal role in any disease. This is not for lack of effort: since the discovery of HPgV, the HPgV field has lurched from one disease association to the next. When HPgV was first identified in 1995 in patients with hepatitis, two different research groups gave it the names “Hepatitis G virus (HGV)” and “GB virus C (GBV-C)” with the assumption that this virus was hepatotropic and responsible for chronic hepatitis [3,4]. Indeed, due to its high prevalence in the human population and its shared modes of transmission with other hepatitis viruses, early studies consistently identified HGV in cohorts of patients with unexplained hepatitis. It took years of careful epidemiological studies comparing healthy and diseased populations to definitively rule out HGV/GBV-C as a cause of hepatitis (summarized in [1,5]), which was further confirmed by prospective longitudinal studies in chimpanzees [6]. Nevertheless, this misconception persists to this day [7]. In the 2000s, several large clinical studies associated HPgV (officially renamed from GBV-C/HGV in 2013) with improved outcomes in HIV+ individuals [8]. Since this time, the majority of research on HPgV has focused on understanding the interactions between HPgV and HIV/AIDS disease progression (summarized in [9]). Although some evidence suggests that HPgV may directly inhibit HIV replication (e.g., by reducing HIV receptor/co-receptor expression in CD4 T cells), the mechanism(s) underlying the observed clinical associations remain far from clear. Later, in the 2010s, several studies identified a weak association between HPgV infection and the development of various lymphoid malignancies (see [10] for a meta-analysis), though again, the mechanistic underpinnings of this association remain unclear.

Recently, several case reports and small case-control studies (including one published in the New England Journal of Medicine) have attempted to establish a link between HPgV infection and a spectrum of neurological disorders including encephalitis [11–16], osloclonus-myoclonus [17], optic neuritis and myelitis [18,19], and Parkinson’s disease [20]. Given the prevalence of HPgV, its identification in any population—including patients with neurological diseases—is unsurprising [21]. Nevertheless, a link has been pursued. Imaging and histologic analyses in these studies have revealed nonspecific abnormalities that could be due to any number of nonHPgV-related processes [11,13,15,18,20]. Detection of HPgV replication intermediates or proteins within neural tissues have relied upon techniques with a high potential for generating false-positive results (i.e., strand-specific PCR and/or immunohistochemistry), the results of which have been published without sufficient data on assay optimization, critical controls, quantification, or consideration for typical patterns of viral staining (e.g., cytoplasmic localization of viral RNA) [11,13,20]. Unconvincing arguments have also been built upon phylogenetic analyses that purport “compartmentalization” of HPgV replication within the central nervous system [11–13]. Small sample sizes and a lack of HPgV+ control cases without disease also limit the power of these studies. Altogether, the data show nothing more than what would be expected from a coincidental HPgV infection [11,12].

It remains possible that HPgV infection is associated with a range of diseases, and/or that HPgV may even play a causal role in the development of some diseases. However, the overwhelming evidence collected to date suggests that HPgV is nonpathogenic; thus, changing this consensus requires substantial evidence to the contrary—evidence that, in this author’s opinion, is currently lacking. While some of the recent articles are appropriately reserved when interpreting their findings [14,21,22], notable exceptions include causality-implying statements such as “neurological involvement due to Pegivirus” [19]; the suggestion that HPgV has “neurotropism and a causative role in pegivirus-associated encephalomyelitis” [11]; or the implication that HPgV plays an active role in “alter[ing] brain and and blood immune and transcriptomic profiles” [20]. The creation of terms like “pegivirus-associated encephalomyelitis” [11] now enshrining this tenuous connection via a self-perpetuating snowball effect that is all too common in medical literature.

As physicians and scientists, we must temper our urge to attribute infections to diseases without definitive evidence. This urge is particularly strong for viruses which, by definition, must infect the cells of its host to survive. Premature attribution of disease can have long-lasting harmful effects on a field. Ironically, the HPgV field is already a prime example of this, with rafts of speculative low-quality studies littering the HPgV literature over the past several decades. Ultimately, this has created an “unserious” reputation that discourages innovation and funding. The current disease-oriented culture of scientific funding is partially to blame, which has forced HPgV research to careen from one disease association to the next. However, if we are to move beyond association into the realm of causation, a concerted effort must be made to first understand the basic biology of PgVs (e.g., receptors, susceptible cell types, mechanisms of immune evasion, see Box 1). Such information could transform our understanding of how HPgV interacts with the human body. This “first-principles” approach would lay a foundation upon which connections to human diseases could be rationally investigated; however this approach would initially require a significant investment in basic PgV virology. This starts with the painstaking development of new tools for studying the highly novel biology of PgVs including robust cell culture systems, molecular clones, animal models, immunology and protein biochemistry tools, organoids, etc. Although daunting, the success of the HCV) research field—which initially faced many of the same challenges—has proven that this approach can work [23]. A solid foundation of basic PgV biology will ultimately spawn the development of better tools for clinical investigation of HPgV infections. Unfortunately, without such investments, the impact of HPgV infection on human health will likely remain an enigma.