Humanity's oldest, deadliest, and fastest evolving threat

In contrast to the ICTV, the Baltimore classification system places viruses into seven groups based solely on the type of genome; dsDNA, ssDNA, dsRNA, positive-sense (+) single- stranded (SS) RNA viruses, negative-sense (–) ssRNA viruses, ssRNA-RT viruses, and dsDNA- RT viruses (Figure 1). As of 2017, 4,853 species of viruses have been defined by the ICTV broken into 803 genera (ICTV Master Species List 2018a v1). Among those viruses exist the Flaviviridae family, which is broken into four genera; Flavivirus, Hepacivirus, Pegivirus, and Pestivirus.

The smallest genus of the Flaviviridae family are the Pestiviruses. Though only four viruses have been classified to this genus, infections resulting from these viruses account for important animal diseases. Two diseases caused by Pestiviruses, Classical swine fever (CSFV) and Bovine viral diarrhea/Mucosal disease (BVDV), are designated as reportable by the World Organization for Animal Health (OIE-Listed diseases 2019). BVDV is capable of infecting cattle, sheep, goats, pigs, and other ungulate species (Becher P, et al., 1999), while CSFV is restricted to pigs and wild boars (Vilcek S and Nettleton PF, 2006). One characteristic trait of pestiviruses such as BVDV is a unique ability to establish a persistent infection during pregnancy (Quintero Barbosa J, et al., 2019). As a result of the potential impact on global meat supply, numerous eradication programs are underway in many countries (Charoenlarp W, et al., 2018; Hanon JB, et al., 2018; Gómez-Vázquez JP, 2019).

The Pegivirus genus contains eleven named species (Pegivirus A–K). These viruses infect all human populations with an estimated 750 million people actively infected (Chivero ET and Stapleton JT, 2015). Furthermore, antibody screening from blood donors in developed and developing countries suggest 1.5-2.5 billion people are currently infected or previously were infected with HPgV (Gutierrez RA, et al., 1997; Tacke M, et al., 1997). The virus can be transmitted sexually, via exposure to contaminated blood, and mother to child (ICTV). In addition to human infection, Pegiviruses are known to infect chimpanzees (Adams NJ, et al., 1998, Birkenmeyer LG, et al., 1998), Old world monkeys (Muerhoff AS, et al., 1995), horses (Kapoor A, et al., 2013; Chandriani S, et al., 2013), pigs (Baechlein C, et al., 2016), and different species of rodents and bats (Kapoor A, et al., 2013; Quan PL, et al., 2013). Human Pegivirus A (HPgV) was originally called hepatitis G virus (HGV) as it was shown to result in acute hepatitis in marmosets (Deinhardt F, et al., 1967). Later worked showed HPgV did not cause hepatitis, which led to the birth of the Pegivirus genus (Stapleton JT, et al., 2012). Though the genome is organized similar to hepatitis C virus (HCV) and both are capable of causing persistent infection in humans, human disease resulting from HPgV has not been conclusively shown (Bhattarai Nand Stapleton JT, 2012; Mohr EL and Stapleton JT, 2009). However, a handful of studies have identified a positive correlation between HPgV viremia and an increased risk of non-Hodgkin’s lymphoma (Chang CM, et al., 2014; Civardi G, et al., 1998; De Renzo A, et al., 2002; Giannoulis E, et al., 2004; Krajden M, et al., 2010). Currently, sufficient in vitro models for growing HPgV do not exist resulting in a lack of knowledge in the field (Chivero ET and Stapleton JT, 2015).

The hepacivirus genus members include the notorious hepatitis C virus (HCV), in addition to hepacivirus A and B, and hepacivirus D – N. The most well-understood virus in this genus is HCV, which is classified as a member of the species Hepacivirus C and the only named species within the genus (Smith DB, et al., 2016). Humans are the only known host of HCV, which is transmitted primarily through exposure to contaminated blood and can result in chronic hepatitis (Kolykhalov A, et al., 1997). In addition to the human host, other hepaciviruses have been isolated from Old World monkeys, rodents and bat species, and cattle (Sibley SD, et al., 2014; Firth C, et al., 2014; Walter S, et al., 2017). Transmission routes of the other hepaciviruses are poorly understood in part due to a lack of cell culture model systems. GB virus B (GBV-B) was the only other member of the Hepacivirus genus besides HCV before 2011. GBV-B was associated with liver disease but was not fully characterized until the mid-1990s when a novel GBV-A was isolated from liver sera of tamarins in addition to GBV-B (Simon JN, et al., 1995).

HCV has been classified into seven distinct genotypes that vary in genomic sequence, transmission, and geographic distribution (Simmonds PB, et al., 2012; Smith DB, et al., 2014). Within each genotype, HCV is further divided into subtypes with over 67 confirmed subtypes to date (Smith DB, et al., 2014). Genotype 1 infections account for the majority of infections within high-income locales such as North America and Europe (Hartlage AS, et al., 2016). HCV-infected patients in South and Southeast Asia most often harbor genotypes 3 and 6, while genotype 4 is most abundant within the Middle East and North Africa (Hartlage AS, et al., 2016). Although not as prevalent, genotype 5-associated HCV cases cluster in Southern Africa (Messina JP, et al., 2015), and only one isolate of genotype 7 has been identified from a patient in Central African immigrant in Canada (Murphy DG, et al., 2007). The distribution of HCV genotypes and subtypes has thoroughly been studied and provided likely explanations for why a specific subtype circulates in different regions (Simmonds P, 2013; Pybus OG, et al., 2005; Gray RR, et al., 2013).

The flavivirus genus contains at least 70 enveloped RNA viruses, many of which are arthropod-borne (arboviruses). Symptoms and severity associated with each virus varies from severe hemorrhaging or encephalitis to asymptomatic. Prior to a Zika outbreak in 2015, the most notable and highly human pathogenic flaviviruses included dengue virus (DENV), yellow fever virus (YFV), West Nile virus (WNV), and Japanese encephalitis virus (JEV), all of which contribute to a major international health problem (Gould EA and Solomon T, 2008; Mackenzie JS, et al., 2014). The health disparities often associated with flavivirus infections are compounded by the fact that most vectors transmitting these viruses are situated throughout the tropics and subtropics where some of the densest populations exist. The flavivirus genus can further be divided into two subgroups; viruses primarily transmitted by ticks and those transmitted by mosquitoes. Mosquito-borne flaviviruses are broadly grouped into those that are associated with neurotropic viruses (transmitted by the Culex species of mosquito) and those associated with attacking the internal organs or hemorrhagic disease in humans (transmitted by the Aedes species of mosquito).

Similar to the ebbs in transmission and outbreaks of mosquito-borne flaviviruses, transmission of tick-borne flaviviruses (TBFV) are also impacted by climate and ecology changes, human development, among others. Compared to viruses transmitted by their flying counterparts, TBFVs do not infect as many individuals. Because of a lower infection incidence and the geographic distribution of tick-borne viruses, less epidemiological data is available. Regardless of lower incident rates, TBFVs infections often present with much more severe cases. For example, less than 150 cases of Powassan virus were reported since its discovery in 1958 (Kemenesi G and Bányai K, 2018). Those infected with Powassan face a 10-15% case fatality rate with a prolonged sequelae in more than 50% individuals (Kemenesi G and Bányai K, 2018). Other TBFVs include hemorrhagic viruses like Omsk hemorrhagic fever virus and Kyasanur forest disease virus, as well as encephalitic viruses such as tick-borne encephalitis virus and Louping-ill virus.

Unlike mosquito-borne flaviviruses that suddenly emerge and can rapidly spread, the geographical locale of TBFVs are much more stable (Brackney DE, et al., 2008). Compared to mosquitoes, ticks live much longer and can take several years to develop from egg to adult (Parola P and Raoult D, 2001). Additionally, ticks take only one blood meal at each stage of their life stage (Ebel GD and Kramer LD, 2004). Accounting for a tick’s extended life and intervals between feeding, one might infer the life cycle and structure of TBFVs differ from mosquito- borne viruses. Indeed, the faster life cycle, high viral turnover, and mobility of mosquitoes compared to ticks has pushed the evolution of TBFVs to adopt a slower replication and a much more stable genome (Dobler G, 2010).

Considered the most important arbovirus in Russia and central and eastern European countries, TBEV is estimated to annually infect 13,000 individuals (Dobler G, et al., 2012). Nearly a 300% increase in the number of TBEV cases in Europe was recorded between 2000 and 2010, and since 2011 cases have appeared in new countries such as France, Sweden, Norway, and Italy (Süss J, 2011; Caracciolo I, et al., 2015; Jaenson TG, et al., 2012; Velay A, et al., 2018). However, humans are a dead-end host to TBEV and most other TBFVs. The slower viral life cycle and low viremia generated within humans does not support a continuous host-vector cycle (Labuda M, et al., 1993). This data begs the question as to why a primarily zoonotic disease has recently spiked in human cases. The increased case incidence has been attributed to population growth and climate change providing a more suitable environment for ticks (Randolph SE, 2010; Sumilo D, et al., 2008).