Modified E2 Glycoprotein of Hepatitis C Virus Enhances Proinflammatory Cytokines and Protective Immune Response

Vijayamahantesh, Vijayamahantesh; Patra, Tapas; Meyer, Keith; Alameh, Mohamad-Gabriel; Reagan, Erin; Weissman, Drew; Ray, Ranjit

doi:10.1128/jvi.00523-22

Cited by 13 publications

(12 citation statements)

References 51 publications

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“…However, the effect of MF59 appeared to be reduced in the immunized volunteers, as suggested from IL-10 induction, and an undetectable level of IL-12. A similar induction of IL-10, but not IL-12, was observed using human macrophages in our subsequent in vitro study using purified recombinant E2 glycoprotein 7 , and reinforced in a recent study using in vitro samples, and vaccinated mice 8 . HCV entry into hepatocytes is facilitated by binding with CD81, which represents a major site of vulnerability for consideration in vaccine design.…”

Section: Introductionsupporting

confidence: 82%

“…We examined whether impairing the E2-CD81 interaction by using modified E2 with point mutations and the insertion of a glycosylation site (F442NYT) altered cytokine parameters associated with an improved proinflammatory response. Soluble ectodomain regions of E1/E2 F442NYT delivered as an mRNA-LNP candidate vaccine exhibited improved T-helper cell function, neutralizing antibody response, and afforded robust cellular immunity in mice during a surrogate challenge infection using recombinant vaccinia virus expressing HCV E1-E2-NS2 (aa134–966) 8 . Our findings could potentially lead to the further development of a multi-genotype mRNA- LNP HCV vaccine approach to promote protective humoral and cellular immune responses for future human use.…”

Section: Introductionmentioning

confidence: 99%

“…HCV envelope glycoproteins, E1 and E2 contain multiple epitopes for both T and B cells 2 , 12 – 15 . We recently examined whether impairing the E2-CD81 interaction can promote stronger T-helper cell function and induce a robust HCV antigen-specific immune responses 8 . Our previous results indicated that immunization with native HCV E2 has reduced cellular immunity, a decreased ability to neutralize surrogate HCVpp from the same genotype (H77), and has a cytokine profile that indicates a reduced potential for a Th1 response.…”

Section: Introductionmentioning

confidence: 99%

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Hepatitis C virus E1 and modified E2 delivered from an mRNA vaccine induces protective immunity

et al. 2023

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Hepatitis C virus (HCV) is characterized by a high number of chronic cases due to an impairment of protective innate and adaptive immune responses. Here, we examined the contribution of the individual ectodomains of E1, E2, or a modified E2 with reduced CD81 binding and an inserted N-linked glycosylation site in combination as vaccine antigen mRNA-lipid nanoparticles (LNPs). The induction of a protective immune response to surrogate recombinant vaccinia virus (VV) expressing homologous HCV glycoprotein(s) challenge infection in a BALB/c mouse model was observed. Vaccination with a mRNA-LNP expressing soluble E1 (sE1) significantly reduced vv/HCV titer in the mouse ovary. However, the addition of sE2 mRNA-LNP for immunization impaired the efficacy of the sE1 construct. Further analysis showed that Th1 related cytokine responses to the sE1 mRNA-LNP were significantly altered in the presence of sE2 following co-immunization. Evaluation of immunogenicity revealed that the use of modified sE2F442NYT nucleoside mRNA-LNP vaccine results in an improved cellular immune response, IgG2a isotype switching, enhanced total IgG, and an increase in the neutralizing antibody response against HCV pseudotype virus. HCV cross genotype specific reactivity to peptides representing conserved E2 specific linear epitopes were enhanced in modified E2 vaccinated animal sera. In the absence of a suitable immunocompetent small animal model for HCV infection, protection from surrogate HCV vaccinia challenge infection model was observed in the immunized mice as compared to sE1 alone or an unmodified sE2 mRNA-LNP vaccine. Inclusion of sE1 with modified sE2F442NYT as mRNA-LNP vaccine candidate appeared to be beneficial for protection.

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Section: Introductionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hepatitis C virus E1 and modified E2 delivered from an mRNA vaccine induces protective immunity

et al. 2023

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“…Cellular immune responses play an important role in the pathogenesis of chronic hepatitis C [ 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 ]. The secretion of cytokines such as interleukin (IL)-2, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α by CD4 + and CD8 + T lymphocytes activates antiviral mechanisms [ 76 ].…”

Section: Mechanism Of Acute Exacerbation and Alanine Aminotransferase...mentioning

confidence: 99%

“…Hiura et al also reported a case of severe acute hepatitis C and delayed antibody production due to rituximab [ 75 ]. These reports suggest the presence of stronger antibody-mediated immune pressure on HCV infection [ 89 , 90 ]. As innate and acquired immune responses play a role in the control of HCV replication [ 76 , 91 , 92 , 93 ] in the pathogenesis of the acute exacerbation and hepatic flare of chronic HCV infection, cellular, as well as humoral, immunological responses may be involved ( Figure 1 ).…”

Section: Mechanism Of Acute Exacerbation and Alanine Aminotransferase...mentioning

confidence: 99%

Chronic Hepatitis C: Acute Exacerbation and Alanine Aminotransferase Flare

Matsumoto

Ishii

Arima

et al. 2023

Viruses

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The hepatitis C virus (HCV) causes acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma, as well as extrahepatic manifestations such as malignant lymphoma. Currently, direct-acting antiviral agents (DAAs) against HCV infection can lead to a sustained virological response (SVR) in almost all HCV-infected patients. In this review article, we discuss acute exacerbation and alanine aminotransferase (ALT) flare in patients with chronic HCV infection. Although acute liver failure caused by HCV infection is rare, careful attention should be paid to the cases with ALT elevation during the natural course of chronic HCV infection. HCV genotype 2 infection, the use of rituximab, and a higher dose of corticosteroid are factors associated with HCV acute exacerbation and ALT flare. Treatment regimens for cancer have been interrupted or changed due to ALT flare due to HCV infection in some patients undergoing chemotherapy for cancer. The pathogenesis of HCV acute exacerbation and ALT flare could involve cellular as well as humoral immune responses. In the DAA era, the earlier introduction of DAAs may prevent chronic HCV-infected patients with acute exacerbation and ALT flare from developing into a more severe form, although DAAs may not be effective for all of them.

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High‐Precision Synthesis of RNA‐Loaded Lipid Nanoparticles for Biomedical Applications

Seo

Jeon

Kwon

et al. 2023

Adv Healthcare Materials

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The recent development of RNA-based therapeutics in delivering nucleic acids for gene editing and regulating protein translation has led to the effective treatment of various diseases including cancer, inflammatory and genetic disorder, as well as infectious diseases. Among these, lipid nanoparticles (LNP) have emerged as a promising platform for RNA delivery and have shed light by resolving the inherent instability issues of naked RNA and thereby enhancing the therapeutic potency. These LNP consisting of ionizable lipid, helper lipid, cholesterol, and poly(ethylene glycol)-anchored lipid can stably enclose RNA and help them release into the cells' cytosol. Herein, the significant progress made in LNP research starting from the LNP constituents, formulation, and their diverse applications is summarized first. Moreover, the microfluidic methodologies which allow precise assembly of these newly developed constituents to achieve LNP with controllable composition and size, high encapsulation efficiency as well as scalable production are highlighted. Furthermore, a short discussion on current challenges as well as an outlook will be given on emerging approaches to resolving these issues.

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Modified E2 Glycoprotein of Hepatitis C Virus Enhances Proinflammatory Cytokines and Protective Immune Response

Abstract: Hepatitis C virus (HCV) E2-CD81 binding dampens protective immune response. We have identified that an alteration of amino acids in the front layer of soluble E2 (sE2) disrupts CD81 interaction and alters the cytokine response.

Cited by 13 publications

References 51 publications

Hepatitis C virus E1 and modified E2 delivered from an mRNA vaccine induces protective immunity

Hepatitis C virus E1 and modified E2 delivered from an mRNA vaccine induces protective immunity

Chronic Hepatitis C: Acute Exacerbation and Alanine Aminotransferase Flare

High‐Precision Synthesis of RNA‐Loaded Lipid Nanoparticles for Biomedical Applications

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