Examination of the value of treatment of decompensated viral hepatitis patients by intentionally coinfecting them with an apathogenic IBDV and using the lessons learnt to seriously consider treating patients infected with HIV using the apathogenic hepatitis G virus
“…In any event, reverse genetics allowed us to clone the IBDV V903/78 serotype genome and recreate it as the artificial virus R903/78. The two viruses have identical genomes, although the later can be manufactured without any concerns of labor intensive re‐plaquing in case of the appearance of contaminant quasispecies or interfering small plaque mutant viruses , which is especially important if the virus is to be used in human therapy . Consequently, we investigated several basic characteristics of the R903/78 virus and so this agent might be used in a planned human clinical trial to eliminate HBV and HCV viral loads employing superinfection therapy .…”
Section: Discussionmentioning
confidence: 99%
“…Nevertheless, in cases when both viruses are pathogenic, the disease persists and hepatitis remains. However, the patient may benefit from superinfection with a nonpathogenic dsRNA virus such as IBDV . Our unpublished preclinical data indicates that R903/78 is a potent activator of the interferon‐dependent innate antiviral gene program, which could explain its strong interference with unrelated viruses.…”
Repeat oral administration of R903/78 was successful despite the presence of neutralizing antibodies. Single oral and intravenous administration indicated that IBDV does not replicate in mammalian liver alleviating some safety related concerns. These data supports the development of an orally delivered anti-hepatitis B virus/ anti-hepatitis C virus viral agent for human use.
“…In any event, reverse genetics allowed us to clone the IBDV V903/78 serotype genome and recreate it as the artificial virus R903/78. The two viruses have identical genomes, although the later can be manufactured without any concerns of labor intensive re‐plaquing in case of the appearance of contaminant quasispecies or interfering small plaque mutant viruses , which is especially important if the virus is to be used in human therapy . Consequently, we investigated several basic characteristics of the R903/78 virus and so this agent might be used in a planned human clinical trial to eliminate HBV and HCV viral loads employing superinfection therapy .…”
Section: Discussionmentioning
confidence: 99%
“…Nevertheless, in cases when both viruses are pathogenic, the disease persists and hepatitis remains. However, the patient may benefit from superinfection with a nonpathogenic dsRNA virus such as IBDV . Our unpublished preclinical data indicates that R903/78 is a potent activator of the interferon‐dependent innate antiviral gene program, which could explain its strong interference with unrelated viruses.…”
Repeat oral administration of R903/78 was successful despite the presence of neutralizing antibodies. Single oral and intravenous administration indicated that IBDV does not replicate in mammalian liver alleviating some safety related concerns. These data supports the development of an orally delivered anti-hepatitis B virus/ anti-hepatitis C virus viral agent for human use.
“…Therefore, viral competition was exploited using a non-pathogenic, attenuated vaccine strain of IBDV to resolve acute and persistent HBV or HCV infections. In the above context, we also discussed in the past an intentional superinfection strategy for the control and treatment of AIDS in view of the improved survival of HIV infected patients naturally infected with the GB virus C [ 20 , 21 ].…”
Section: Introductionmentioning
confidence: 99%
“…A striking feature of SIT was the regeneration of the cirrhotic liver over several years of follow up (Fig. 1 ) [ 20 , 25 , 26 ]. 4 5 Fig.…”
BackgroundViral hepatitis deaths from acute infection, cirrhosis, and liver cancer have risen from the tenth to the seventh leading cause of death worldwide between 1990 and 2013. Even in the oral direct acting antiviral (DAA) agent era there are still large numbers of patients with unmet needs. Medications approved for treatment of chronic hepatitis B virus (HBV) infection do not eradicate HBV often requiring treatment for life associated with risks of adverse reactions, drug resistance, nonadherence, and increased cost. Although DAAs increased virologic cure rates well over 90% in all hepatitis C virus (HCV) genotypes, HCV infection still cannot be cured in a small but significant minority of patients. While most of the medical issues of HCV treatment have been solved, the current costs of DAAs are prohibitive.ResultsThe post-infection viral superinfection treatment (SIT) platform technology has been clinically proven to be safe and effective to resolve acute and persistent viral infections in 42 HBV and HCV patients (20 HBV, 22 HCV), and in 4 decompensated patients (2 HBV, 2 HCV). SIT employs a non-pathogenic avian double stranded RNA (dsRNA) virus, a potent activator of antiviral gene responses. Unexpectedly, SIT is active against unrelated DNA (HBV) and RNA (HCV) viruses. SIT does not require lifelong therapy, which is a major advantage considering present HBV treatments. The new viral drug candidate (R903/78) is homogeneously produced by reverse genetics in Vero cells. R903/78 has exceptional pH and temperature stability and also excellent long-term stability; therefore, it can be orally administered, stored and shipped without freezing. Since R903/78 is easy to stockpile, the post-infection SIT could also alleviate the logistic hurdles of surge capacity in vaccine production during viral pandemics.ConclusionTo help large number of HBV and HCV patients with unmet needs, broad-spectrum antiviral drugs effective against whole classes of viruses are urgently needed. The innovative SIT technological platform will be a great additional armament to conquer viral hepatitis, which is still a major cause of death and disability worldwide.
“…It has also been reported that IBDV therapy improved the condition of an HCV patient that had become resistant to conventional treatment, developed decompensated chronic viral hepatitis, and received disability status (2). Importantly, during the treatment of patients, it emerged that to ensure an "artificial viremia" with IBDV, the viral preparation needs to be given in large doses and continuously over a long period (1). These findings further support the therapeutic application of IBDV in humans without detrimental effects.…”
The delivery of foreign epitopes by a replicating nonpathogenic avian infectious bursal disease virus (IBDV) was explored. The aim of the study was to identify regions in the IBDV genome that are amenable to the introduction of a sequence encoding a foreign peptide. By using a cDNA-based reverse genetics system, insertions or substitutions of sequences encoding epitope tags (FLAG, c-Myc, or hepatitis C virus epitopes) were engineered in the open reading frames of a nonstructural protein (VP5) and the capsid protein (VP2). Attempts were also made to generate recombinant IBDV that displayed foreign epitopes in the exposed loops (P BC and P HI ) of the VP2 trimer. We successfully recovered recombinant IBDVs expressing c-Myc and two different virus-neutralizing epitopes of human hepatitis C virus (HCV) envelope glycoprotein E in the VP5 region. Western blot analyses with anti-c-Myc and anti-HCV antibodies provided positive identification of both the c-Myc and HCV epitopes that were fused to the N terminus of VP5. Genetic analysis showed that the recombinants carrying the c-Myc/HCV epitopes maintained the foreign gene sequences and were stable after several passages in Vero and 293T cells. This is the first report describing efficient expression of foreign peptides from a replication-competent IBDV and demonstrates the potential of this virus as a vector. (26), has been used as a therapeutic agent without any toxicity in clinical trials with patients suffering from acute and chronic hepatitis C virus (HCV) infections (2,8). IBDV belongs to the genus Avibirnavirus of the Birnaviridae family, and its genome consists of two segments of double-stranded RNA (11). The smaller segment, B, encodes VP1, a 97-kDa multifunctional protein with polymerase and capping enzyme activities (21, 27). The larger segment, A, encodes a 110-kDa precursor polyprotein in a single large open reading frame (ORF) which is cotranslationally processed by the viral protease VP4 (4, 24) into the VP2 precursor (pVP2), VP3, and VP4. pVP2 is further processed by several proteolytic cleavages at its C terminus for conversion into mature VP2 (10). Segment A also encodes VP5, a 17-kDa nonstructural (NS) protein, in a small ORF partly preceding and overlapping the polyprotein ORF. VP5 is dispensable for viral replication in vitro and in vivo (29), which makes it a prime candidate for the construction of marked vaccines carrying deletions. These marked vectors could be easily distinguished from the wild-type virus and could also trigger a specific cellular immune response in the host species. The available structural data for VP2 (7,14,17) reveal that the protein is folded into three different domains (base B, shell S, and projection P). Expression of VP2 by itself leads to dodecahedral subviral particles (SVPs) containing 20 VP2 trimers (6) and exposing the four loops of the P domain (named P BC , P DE , P FG , and P HI ). Here, we explore the possibility of displaying foreign epitopes stably in recombinant IBDV by either inserting or replacing sequences ...
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