Signal peptide exchange alters HIV-1 envelope antigenicity and immunogenicity.

Autor:	Upadhyay C; Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States., Rao P; Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States., Behzadi MA; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, United States., Feyznezhad R; Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States., Lambert GS; Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States., Kumar R; Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States., Kumar M; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, United States., Yang W; Department of Pathology, Johns Hopkins University, Baltimore, MD, United States., Jiang X; Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, United States., Luo CC; Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, United States., Nadas A; Department of Environment Medicine, New York University Grossman School of Medicine, New York, NY, United States., Arthos J; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States., Kong XP; Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, United States., Zhang H; Department of Pathology, Johns Hopkins University, Baltimore, MD, United States., Hioe CE; Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States.; Research Service, James J. Peters VA Medical Center, Bronx, NY, United States., Duty JA; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2024 Sep 24; Vol. 15, pp. 1476924. Date of Electronic Publication: 2024 Sep 24 (Print Publication: 2024).
DOI:	10.3389/fimmu.2024.1476924
Abstrakt:	Introduction: HIV-1 envelope (Env) is the key target for antibodies (Abs) against the virus and thus an important HIV-1 vaccine component. Env is synthesized from a gp160 precursor with a signal peptide (SP) at its N-terminus. This study investigated the influence of the SP on Env antigenicity and immunogenicity. Methods: Env proteins from two HIV-1 isolates, AA05 and AC02, were analyzed as gp120 and gp160 in their native wild-type (WT) forms and as chimeras with swapped SPs (AA05-02 and AC02-05). The WT and chimeric Env were assessed for antigenicity and glycosylation using monoclonal antibodies (mAbs) and glycan probes. Immunogenicity was tested in mice using three vaccine types: gp120 protein, gp120 DNA+gp120 protein, and gp120 DNA+gp160 DNA. Results: The recombinant AC02 gp120 protein was antigenically superior to AA05 as indicated by higher reactivity with most mAbs tested. When SPs were swapped, the antigenicity of the chimeric gp120s (AA05-02 and AC02-05) resembled that of the gp120s from which the SPs were derived; AA05-02 was similar to AC02 and vice versa. Glycan probe reactivity followed a similar pattern: AA05-02 and AC02 showed similar affinity to high-mannose specific mAbs and lectins. Interestingly, the antigenicity of gp160s showed an opposite pattern; membrane-bound gp160 expressed with the AA05 SP (AA05 and AC02-05) showed greater mAb binding than gp160 with the AC02 SP (AC02 and AA05-02). Mice immunized with gp120 protein showed that AA05-02 induced stronger cross-reactive binding Ab responses than AA05 WT, and AC02 elicited stronger responses than AC02-05, indicating AC02 SP enhanced gp120 immunogenicity. However, when DNA vaccines were included (gp120 DNA+gp120 protein and gp120 DNA+gp160 DNA), the use of heterologous SPs diminished the immunogenicity of the WT immunogens. Among the three vaccine regimens tested, only gp120 DNA+gp160 DNA immunization elicited low-level Tier 2 neutralizing Abs, with AA05 WT inducing Abs with greater neutralization capabilities than AA05-02. Conclusion: These data demonstrate that the SP can significantly impact the antigenicity and immunogenicity of HIV-1 Env proteins. Hence, while SP swapping is a common practice in constructing Env immunogens, this study highlights the importance of careful consideration of the effects of replacing native SPs on the immunogenicity of Env vaccines. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2024 Upadhyay, Rao, Behzadi, Feyznezhad, Lambert, Kumar, Kumar, Yang, Jiang, Luo, Nadas, Arthos, Kong, Zhang, Hioe and Duty.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu