title: An HIV Envelope gp120-Fc Fusion Protein Elicits Effector Antibody Responses in Rhesus Macaques.
abstract: A goal for HIV prevention programs is to develop safe, effective vaccines that elicit durable and broadly protective antibodies. Many vaccine programs focus on the immune responses to critical epitopes in the gp120 portion of HIV envelope glycoprotein (Env) and seek to improve the quality and quantity of antibodies by altering the sequence, conformation, oligomerization, or glycosylation of gp120 to activate appropriate germ line B cells and mimic the subsequent maturation pathways seen in infected individuals. As a complement to these strategies, we developed dimeric fusion protein immunogens consisting of HIVBaLgp120 monomer attached to a Gly/Ser linker that is, in turn, fused to one half of the dimeric Fc domain from rhesus macaque IgG1 (Env-rFc). We envisioned that Env-rFc may mimic some aspects of immune complexes by binding Fc gamma receptors (FcγRs) on immune cells to increase the strength, breadth, and durability of Env-specific antibody responses. The Env-rFc retained a capacity to bind both cell surface CD4 and FcγRs. In a rhesus macaque immunization study, Env-rFc elicited higher gp120 binding antibody titers than Env and elicited antibodies that recognize CD4-induced epitopes. Env-rFc also induced antibodies capable of neutralizing tier 1A HIV pseudotyped viruses and mediating antibody-dependent cellular cytotoxicity, outcomes not observed with monomeric gp120 in our study. Serum antibodies produced in Env-rFc-immunized macaques had increased durability compared to that of Env monomer immunization. Our work suggests that adding IgG1 Fc to Env-based immunogens may stimulate increased effector capacity in the immune sera and improve the protective serum antibody response.
authors.affiliation: Institute of Human Virology and Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Zhanna
authors.initials: Z
authors.lastname: Shubin
authors.affiliation: Division of Immunology, VA-MD College of Veterinary Medicine, Maryland Pathogen Research Institute, University of Maryland, College Park, Maryland, USA.
authors.forename: Weizhong
authors.initials: W
authors.lastname: Li
authors.affiliation: Institute of Human Virology and Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Bhawna
authors.initials: B
authors.lastname: Poonia
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Guido
authors.initials: G
authors.lastname: Ferrari
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Celia
authors.initials: C
authors.lastname: LaBranche
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: David
authors.initials: D
authors.lastname: Montefiori
authors.affiliation: Division of Immunology, VA-MD College of Veterinary Medicine, Maryland Pathogen Research Institute, University of Maryland, College Park, Maryland, USA.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Institute of Human Virology and Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA cdpauza@americangene.com.
authors.forename: C David
authors.initials: CD
authors.lastname: Pauza
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D000917:Antibody Formation; D000920:Antibody-Dependent Cell Cytotoxicity; D015704:CD4 Antigens / Q000378:metabolism; D005260:Female; D015483:HIV Antibodies / Q000097:blood; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000276:immunology*; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000276:immunology*; D008253:Macaca mulatta; D008297:Male; D011485:Protein Binding; D017452:Receptors, IgG / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology*; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology
chemical_list: D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D015704:CD4 Antigens; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D007141:Immunoglobulin Fc Fragments; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; D014614:Vaccines, Synthetic; C514793:gp120 protein, Human immunodeficiency virus 1
keywords: Fc gamma receptor; HIV envelope gp120; immune complex; immunization; vaccine