Vaccination to prevent T cell subversion can protect against persistent hepacivirus infection

Hartlage, Alex S.; Murthy, Satyapramod; Kumar, Arvind; Trivedi, Sheetal; Dravid, Piyush; Sharma, Himanshu; Walker, Christopher M.; Kapoor, Amit

doi:10.1038/s41467-019-09105-0

Cited by 28 publications

(84 citation statements)

References 66 publications

(69 reference statements)

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“…A well‐defined feature of HCV infection is CD8 + T‐cell escape mutants contributing to persistence, also observed in Lewis rats . Mutations were found concurrently in both the immunodominant CD8 + T‐cell epitopes defined in the present study; given that SD rats are outbred and the major histocompatibility complexes were not haplotyped, this is suggestive of escape mutation but not conclusive.…”

Section: Discussionmentioning

confidence: 52%

“…Boosting with ChAd‐NS or DNA‐NS or using a 7‐fold higher single dose enhanced resolution compared to ChAd‐NS at the standard priming dose. One third of these rats (6/18) showed no detectable RHV viremia at any time point, an outcome not seen with the standard dose of ChAd‐NS in SD or Lewis rats . This result demonstrates that a suboptimal vaccination regime against a hepacivirus can be transformed into a highly protective regime through boosting or a higher single dose, suggesting that in the case of clinical trials of HCV vaccines resulting in low but statistically significant efficacy, large improvements could be achievable with minor adjustments in the vaccination regimen, warranting such further clinical testing.…”

Section: Discussionmentioning

confidence: 92%

“…Such a model has been developed in inbred Lewis rats using a human adenoviral vector. (7) Here, we develop the model in outbred Sprague-Dawley (SD) rats, more closely mirroring human diversity, with a more clinically relevant chimpanzee adenovirus. We believe the SD rat RHV model will be highly beneficial to the HCV vaccine field in refining optimal antigens, delivery platforms, adjuvants, and prime/ boost regimes, all of which can help inform difficult and expensive clinical trials before they begin.…”

Section: And Peter Simmondsmentioning

confidence: 99%

“…RHV in rats has a profile very similar to that of HCV, making it an appropriate surrogate model for vaccine study . Like HCV, it is hepatotropic, generating persistent viremia detectable for over 1 year, and recapitulates many aspects of liver pathology, including microvesicular and macrovesicular steatosis, lymphoid aggregation, and evidence of biliary epithelial damage . RHV is predicted to encode similar proteins to HCV and possesses similar genetic structures in the untranslated regions flanking the coding region …”

mentioning

confidence: 99%

“…For these reasons, development of a small animal model is critically important for HCV vaccine development. Such a model has been developed in inbred Lewis rats using a human adenoviral vector . Here, we develop the model in outbred Sprague‐Dawley (SD) rats, more closely mirroring human diversity, with a more clinically relevant chimpanzee adenovirus.…”

mentioning

confidence: 99%

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Use of an Outbred Rat Hepacivirus Challenge Model for Design and Evaluation of Efficacy of Different Immunization Strategies for Hepatitis C Virus

Atcheson

Bliss

et al. 2019

Hepatology

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Background and Aims The lack of immunocompetent small animal models for hepatitis C virus (HCV) has greatly hindered the development of effective vaccines. Using rodent hepacivirus (RHV), a homolog of HCV that shares many characteristics of HCV infection, we report the development and application of an RHV outbred rat model for HCV vaccine development. Approach and Results Simian adenovirus (ChAdOx1) encoding a genetic immune enhancer (truncated shark class II invariant chain) fused to the nonstructural (NS) proteins NS3‐NS5B from RHV (ChAd‐NS) was used to vaccinate Sprague‐Dawley rats, resulting in high levels of cluster of differentiation 8–positive (CD8+) T‐cell responses. Following RHV challenge (using 10 or 100 times the minimum infectious dose), 42% of vaccinated rats cleared infection within 6‐8 weeks, while all mock vaccinated controls became infected with high‐level viremia postchallenge. A single, 7‐fold higher dose of ChAd‐NS increased efficacy to 67%. Boosting with ChAd‐NS or with a plasmid encoding the same NS3‐NS5B antigens increased efficacy to 100% and 83%, respectively. A ChAdOx1 vector encoding structural antigens (ChAd‐S) was also constructed. ChAd‐S alone showed no efficacy. Strikingly, when combined with ChAd‐NS, ChAD‐S produced 83% efficacy. Protection was associated with a strong CD8+ interferon gamma–positive recall response against NS4. Next‐generation sequencing of a putative RHV escape mutant in a vaccinated rat identified mutations in both identified immunodominant CD8+ T‐cell epitopes. Conclusions A simian adenovirus vector vaccine strategy is effective at inducing complete protective immunity in the rat RHV model. The RHV Sprague‐Dawley rat challenge model enables comparative testing of vaccine platforms and antigens and identification of correlates of protection and thereby provides a small animal experimental framework to guide the development of an effective vaccine for HCV in humans.

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Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 92%

Section: And Peter Simmondsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Use of an Outbred Rat Hepacivirus Challenge Model for Design and Evaluation of Efficacy of Different Immunization Strategies for Hepatitis C Virus

Atcheson

Bliss

et al. 2019

Hepatology

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Pathogenesis, MicroRNA‐122 Gene‐Regulation, and Protective Immune Responses After Acute Equine Hepacivirus Infection

et al. 2021

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Equine hepacivirus (EqHV); hepatitis C virus (HCV); GB-virus B (GBV-B); non-primate hepacivirus, NPHV; untranslated region (UTR); peripheral blood mononuclear cell (PBMC); interferon (IFN); genome equivalents (GE); RNA-sequencing (RNA-seq); single cell RNA-sequencing (scRNA-seq); luciferase immunoprecipitation system (LIPS); equine pegivirus (EPgV); Theiler's disease associated virus (TDAV); human pegivirus (HPgV/GBV-C); differentially expressed (DE); IFN-stimulated genes (ISGs); rodent hepacivirus (RHV); simian pegivirus (SPgV); simian immunodeficiency virus (SIV); lower level of quantification (LLOQ); fold change (FC); spot forming units (SFU)

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Neutralization and receptor use of infectious culture–derived rat hepacivirus as a model for HCV

et al. 2022

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Background and Aims Lack of tractable immunocompetent animal models amenable to robust experimental challenge impedes vaccine efforts for HCV. Infection with rodent hepacivirus from Rattus norvegicus (RHV‐rn1) in rats shares HCV‐defining characteristics, including liver tropism, chronicity, and pathology. RHV in vitro cultivation would facilitate genetic studies on particle production, host factor interactions, and evaluation of antibody neutralization guiding HCV vaccine approaches. Approach and Results We report an infectious reverse genetic cell culture system for RHV‐rn1 using highly permissive rat hepatoma cells and adaptive mutations in the E2, NS4B, and NS5A viral proteins. Cell culture–derived RHV‐rn1 particles (RHVcc) share hallmark biophysical characteristics of HCV and are infectious in mice and rats. Culture adaptive mutations attenuated RHVcc in immunocompetent rats, and the mutations reverted following prolonged infection, but not in severe combined immunodeficiency (SCID) mice, suggesting that adaptive immune pressure is a primary driver of reversion. Accordingly, sera from RHVcc‐infected SCID mice or the early acute phase of immunocompetent mice and rats were infectious in culture. We further established an in vitro RHVcc neutralization assay, and observed neutralizing activity of rat sera specifically from the chronic phase of infection. Finally, we found that scavenger receptor class B type I promoted RHV‐rn1 entry in vitro and in vivo. Conclusions The RHV‐rn1 infectious cell culture system enables studies of humoral immune responses against hepacivirus infection. Moreover, recapitulation of the entire RHV‐rn1 infectious cycle in cell culture will facilitate reverse genetic studies and the exploration of tropism and virus–host interactions.

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Vaccination to prevent T cell subversion can protect against persistent hepacivirus infection

Cited by 28 publications

References 66 publications

Use of an Outbred Rat Hepacivirus Challenge Model for Design and Evaluation of Efficacy of Different Immunization Strategies for Hepatitis C Virus

Use of an Outbred Rat Hepacivirus Challenge Model for Design and Evaluation of Efficacy of Different Immunization Strategies for Hepatitis C Virus

Pathogenesis, MicroRNA‐122 Gene‐Regulation, and Protective Immune Responses After Acute Equine Hepacivirus Infection

Neutralization and receptor use of infectious culture–derived rat hepacivirus as a model for HCV

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