The Envelope-Based Fusion Antigen GP120C14K Forming Hexamer-Like Structures Triggers T Cell and Neutralizing Antibody Responses Against HIV-1

Frontiers in Immunology

Carlos Oscar S. Sorzano¹  Judith A. Burger²  Anna Schorcht²  Rogier W. Sanders³  Suresh C. Raman⁴  Cristina Sánchez-Corzo⁴  Mariano Esteban⁴  Beatriz Perdiguero⁴  Carmen E. Gomez⁴  Juan García-Arriaza⁴  Ernesto Mejías-Pérez⁴  Aneesh Vijayan⁴  Mar Pérez-Ruiz⁵  José L. Carrascosa⁵  Ana Cuervo⁵  Christiane Moog⁶  César Santiago⁷ 

[1] Biocomputing Unit, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CNB-CSIC), Madrid, Spain;Department of Medical Microbiology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands;Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY, United States;Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CNB-CSIC), Madrid, Spain;Department of Structure of Macromolecules, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CNB-CSIC), Madrid, Spain;INSERM U1109, Fédération Hospitalo-Universitaire (FHU) OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France;X-ray Crystallization Unit, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CNB-CSIC), Madrid, Spain;

关键词: GP120C14K;    VACV 14K protein;    MVA-HIV vaccine;    CD8 T cells;    GC B cells;    Tfh cells;   

DOI  :  10.3389/fimmu.2019.02793

来源: DOAJ

【 摘 要 】

There is an urgent need for the development of potent vaccination regimens that are able to induce specific T and B cell responses against human immunodeficiency virus type 1 (HIV-1). Here, we describe the generation and characterization of a fusion antigen comprised of the HIV-1 envelope GP120 glycoprotein from clade C (GP120C) fused at its C-terminus, with the modified vaccinia virus (VACV) 14K protein (A27L gene) (termed GP120C14K). The design is directed toward improving the immunogenicity of the GP120C protein through its oligomerization facilitated by the fused VACV 14K protein that results in hexamer-like structures. Two different immunogens were generated: a recombinant GP120C14K fusion protein (purified from a stable CHO-K1 cell line) and a recombinant modified vaccinia virus Ankara (MVA) poxvirus vector expressing the GP120C14K fusion protein (termed MVA-GP120C14K). The GP120C14K fusion protein is recognized by broadly neutralizing antibodies (bNAbs) against HIV-1. In a murine model, a heterologous prime/boost immunization regimen with MVA-GP120C14K prime followed by adjuvanted GP120C14K protein boost generated stronger and polyfunctional HIV-1 Env-specific CD8 T cell responses when compared with the delivery of the monomeric GP120C form. Furthermore, the immunization protocol MVA-GP120C14K/GP120C14K elicited higher HIV-1 Env-specific T follicular helper cells, germinal center B cells and antibody responses than monomeric GP120. In addition, a similar MVA-GP120C14K prime/GP120C14K protein boost regimen performed in rabbits triggered high HIV-1-Env-specific IgG binding antibody titers that were capable of neutralizing HIV-1 pseudoviruses. The extent of HIV-1 neutralization was comparable to that elicited by the current standard GP140 SOSIP trimers from clades B and C when immunized as MVA-SOSIP prime/SOSIP protein boost regimen. Overall, the novel fusion antigen and the corresponding immunization scheme provided in this report can therefore be considered as potential vaccine strategies against HIV-1.

【 授权许可】

Unknown