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    • br Acknowledgments Authors are thankful

    2021-12-06


    Acknowledgments Authors are thankful to the participants of the study for their cooperation. Financial support from Higher Education Commission (HEC) of Pakistan is highly acknowledged. AZ is supported by indigenous PhD fellowship from HEC. Indigenous PhD Fellowship for 5k Scholars batch 2 PIN NO. 2BM1-566.
    Introduction The human variant of Pegivirus A, [HPgV; formerly GB Virus-C (GBV-C)], is a non-vector borne pan-lymphotropic pegivirus (George et al., 2006, Stapleton et al., 2011) which is spread by blood and body fluids, including sexual contact (Bjorkman et al., 2001, Lefrere et al., 1999, Scallan et al., 1998, Supapol et al., 2008). Approximately 2% of healthy blood donors have viral RNA in serum and 8% have antibodies against the HPgV E2 protein indicating prior infection (Alter et al., 1997). No clinical disease has been conclusively associated with HPgV infection in humans (Alter, 1997, Guidicelli et al., 2012, Jones et al., 2005, Krajden et al., 2010) or experimentally infected chimpanzees (Bukh et al., 1998). About 25–40% of HIV infected patients are coinfected with HPgV (Lefrere et al., 1999, Rey et al., 2000, Xiang et al., 2001). Persistent coinfection with HPgV in HIV infected patients is associated with higher survival rates, lower HIV viral loads, higher CD4+ T cell counts (Tillmann et al., 2001), decreased T cell activation (Rydze et al., 2012, Stapleton et al., 2012) and reduction in maternal to child HIV transmission (Handelsman et al., 2007, Supapol et al., 2008) in most though not all studies. HPgV is structurally and genetically similar to Hepatitis C virus (HCV) and GB Virus-B (GBV-B). All have positive-polarity single-stranded (~9400–9600bp) RNA genomes. HPgV and HCV have approximately 30% amino RI-1 sale sequence identity over the open reading frame (Tanaka et al., 1996). The HCV genome is translated as a single polyprotein, followed by co- and post-translational cleavage by cellular and viral proteases to form 10 mature proteins (Fig. 1A). The proteins produced by HPgV have not been fully characterized, but at least 8 mature proteins are predicted to be produced (Fig. 1A). Nonstructural protein 3 (NS3) encodes a serine protease/helicase-ATPase that cotranslationally cleaves the NS3/4A, NS4A/4B, NS4B/5A, and NS5A/5B boundaries in HCV and GBV-B (Fig. 1B) (Raney et al., 2010, Lee et al., 2001). The conservation between HPgV and HCV NS34A is 36%, and the protease catalytic triad is conserved between the two viruses. HPgV NS3 has been shown to cleave the NS3/4A, NS4B/5A, and NS5A/5B boundaries (Belyaev et al., 1998, George et al., 2012, Lee et al., 2001). The only experimentally identified nonstructural cleavage sites of HPgV are the NS2/3 and NS4B/5A boundaries (Belyaev et al., 1998). The NS5A/5B cleavage site has been predicted by deriving a consensus sequence from NS3/4A-mediated peptide cleavage in vitro. NS3 must be coexpressed with NS4A for maximal protease activity (Belyaev et al., 1998, Failla et al., 1994). The minimal necessary HPgV NS4A sequence required for NS3 protease activity has been partially determined by deletion mapping (Belyaev et al., 1998). In HCV NS3, the protease catalytic triad consists of histidine 57, aspartic acid 81 and serine 139, and independent mutation of H57 and S139 to alanine abolishes cleavage activity (Fig. 1A) (Bartenschlager et al., 1993, Grakoui et al., 1993, Hijikata et al., 1993). HPgV NS3 contains an analogous triad of histidine 56, aspartic acid 79, and serine 137, and mutating serine 137 to alanine (S137A) in HPgV NS3 also abrogates cleavage (Belyaev et al., 1998, George et al., 2012). We have previously shown that HPgV NS3/4A and NS3/4AB expression in CD4+ Jurkat cells inhibits HIV replication and mutating the S137 catalytic residue to alanine (S137A) abolishes this effect (George et al., 2012). The type I interferon response protects cells from viral infection by modulating cellular pathways which suppress viral replication. Intracellular double-stranded RNA (dsRNA) is an intermediate in HPgV and HCV viral replication which is sensed by retinoic acid-inducible gene 1 (RIG-I). RIG-I signals through mitochondrial antiviral signaling protein (MAVS) (Kato et al., 2006), which is attached to the mitochondrial surface (Kawai et al., 2005, Meylan et al., 2005, Seth et al., 2005, Xu et al., 2005). MAVS signals through cellular intermediates to induce phosphorylation and translocation to the nucleus of interferon regulatory factor 3 (IRF3). IRF3 induces transcription of type I interferons, interferon-α (IFN-α) and interferon-β (IFN-β) (Fitzgerald et al., 2003, Sato et al., 2003).