A196 Identification of an Immunosuppressive Domain in Human Betaretrovirus

Rahbari, Mandana; Sharon, David; Houghton, Michael; Mason, Alleson

doi:10.1093/jcag/gwy008.197

Cited by 2 publications

(3 citation statements)

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“…Retroviruses may harbor immunosuppressive domains in their envelope protein that inhibit immune responses by stimulating the regulatory cytokine, interleukin 10 [127]. By immunoscreening healthy peripheral blood mononuclear cells with overlapping 15-20mer peptides derived from the HBRV envelope protein, we characterized three immunosuppressive domains that trigger IL-10 to inhibit immune responses [128]. Notably, a similar process has been described in neonatal mice, where MMTV infection triggers IL-10 production and inhibits the production of neutralizing antibodies [82].…”

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confidence: 77%

Linking Human Betaretrovirus with Autoimmunity and Liver Disease in Patients with Primary Biliary Cholangitis

Syed

Penner

Mason

2022

Viruses

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Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by the production of diagnostic antimitochondrial antibodies (AMA) reactive to the pyruvate dehydrogenase complex. A human betaretrovirus (HBRV) resembling mouse mammary tumor virus has been characterized in patients with PBC. However, linking the viral infection with the disease is not a straight-forward process because PBC is a complex multifactorial disease influenced by genetic, hormonal, autoimmune, environmental, and other factors. Currently, PBC is assumed to have an autoimmune etiology, but the evidence is lacking to support this conjecture. In this review, we describe different approaches connecting HBRV with PBC. Initially, we used co-cultivation of HBRV with biliary epithelial cells to trigger the PBC-specific phenotype with cell surface expression of cryptic mitochondrial autoantigens linked with antimitochondrial antibody expression. Subsequently, we have derived layers of proof to support the role of betaretrovirus infection in mouse models of autoimmune biliary disease with spontaneous AMA production and in patients with PBC. Using Hill’s criteria, we provide an overview of how betaretrovirus infection may trigger autoimmunity and propagate biliary disease. Ultimately, the demonstration that disease can be cured with antiviral therapy may sway the argument toward an infectious disease etiology in an analogous fashion that was used to link H. pylori with peptic ulcer disease.

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confidence: 77%

Linking Human Betaretrovirus with Autoimmunity and Liver Disease in Patients with Primary Biliary Cholangitis

Syed

Penner

Mason

2022

Viruses

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“…ELISA studies using HBRV Env have revealed significantly increased seroprevalence in PBC patients and breast cancer patients as compared to age-matched controls [ 22 ]. However, the serological frequency was somewhat low, possibly related to the presence of immunosuppressive domains harbored by the betaretrovirus Env protein [ 23 ]; similar observations have been made in neonatal mice, in which MMTV infection triggers IL-10 production, limiting neutralizing antibody formation [ 24 ]. Nevertheless, a much higher prevalence of infection has been detected using cellular immune assays, and intrahepatic lymphocytes from PBC patients undergoing liver transplantation have been found to generate robust proinflammatory responses [ 25 ].…”

Section: Introductionmentioning

confidence: 91%

“…In our PBC patients treated with LPV/r, a transient rise in aminotransferases was observed shortly after initiating treatment, which tended to resolve without the discontinuation of therapy [ 28 ]. While this may be related to transient LPV/r drug-induced liver injury, we characterized an immunosuppressive domain in the HBRV Env protein, suggesting that immune reconstitution with a reduction in viral load may provide an alternative hypothesis [ 23 ]. The propensity to develop chronic hepatitis was observed in a liver transplant recipient treated with LPV/r and TDF/FTC.…”

Section: Antiretroviral Adverse Effects In People Living With Hiv (Pl...mentioning

confidence: 99%

Apples to Apples? A Comparison of Real-World Tolerability of Antiretrovirals in Patients with Human Immunodeficiency Virus Infection and Patients with Primary Biliary Cholangitis

Turvey

Saxinger

Mason

2022

Viruses

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We previously characterized a human betaretrovirus and linked infection with the development of primary biliary cholangitis (PBC). There are in vitro and in vivo data demonstrating that antiretroviral therapy used to treat human immunodeficiency virus (HIV) can be repurposed to treat betaretroviruses. As such, PBC patients have been treated with nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), alone and in combination with a boosted protease inhibitor or an integrase strand transfer inhibitor in case studies and clinical trials. However, a randomized controlled trial using combination antiretroviral therapy with lopinavir was terminated early because 70% of PBC patients discontinued therapy because of gastrointestinal side effects. In the open-label extension, patients tolerating combination therapy underwent a significant reduction in serum liver parameters, whereas those on NRTIs alone rebounded to baseline. Herein, we compare clinical experience in the experimental use of antiretroviral agents in patients with PBC with the broader experience of using these agents in people living with HIV infection. While the incidence of gastrointestinal side effects in the PBC population appears somewhat increased compared to those with HIV infection, the clinical improvement observed in patients with PBC suggests that further studies using the newer and better tolerated antiretroviral agents are warranted.

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A196 Identification of an Immunosuppressive Domain in Human Betaretrovirus

Cited by 2 publications

References 0 publications

Linking Human Betaretrovirus with Autoimmunity and Liver Disease in Patients with Primary Biliary Cholangitis

Linking Human Betaretrovirus with Autoimmunity and Liver Disease in Patients with Primary Biliary Cholangitis

Apples to Apples? A Comparison of Real-World Tolerability of Antiretrovirals in Patients with Human Immunodeficiency Virus Infection and Patients with Primary Biliary Cholangitis

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