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dc.contributor.authorShubin, Zhanna
dc.date.accessioned2017-01-25T17:20:16Z
dc.date.available2017-01-25T17:20:16Z
dc.date.issued2016
dc.identifier.urihttp://hdl.handle.net/10713/6280
dc.descriptionUniversity of Maryland, Baltimore. Molecular Microbiology and Immunology. Ph.D. 2016en_US
dc.description.abstractA goal for HIV prevention programs is to develop safe and effective vaccines that elicit durable and broadly protective antibodies against both sexual and blood-borne HIV transmission. Many vaccine programs focus on the immune responses to critical epitopes in the HIV envelope glycoprotein (Env) and seek to improve the quality and quantity of antibodies by altering the conformation, oligomerization or glycosylation of Env gp120. As a complementary strategy, we envisioned that attaching an Fc moiety from IgG to immunogens would allow binding to neonatal Fc receptor (FcRn) for FcRn-mediated mucosal delivery. We reasoned that Fc fusion protein immunogens may also mimic immune complexes by binding Fc gamma receptors (Fc?R) on immune cells and would increase the potency of antibody responses. We developed Fc fusion immunogens consisting of either HIVBaL gp120 (Env-Fc) or critical epitopes in the V1V2 region of Env expressed within a carrier protein that provides highly multivalent epitope display (Gag-V1V2-Fc). Fc fusion proteins were attached at their carboxyl terminus to a Gly/Ser linker that is in turn fused to each half of the dimeric Fc domain from rhesus macaque IgG1 (Env-Fc). Env-Fc retained a capacity to bind both cell surface CD4 and Fc?Rs, which led to protein internalization and accumulation in cytoplasmic vesicles. In a rhesus macaque immunization study, Env-Fc was more potent compared to Env (gp120 monomer) in several ways. Env-Fc elicited higher gp120 binding antibody titers with increased breadth, including the capacity for recognizing CD4-induced epitopes, neutralizing activity against Tier 1A HIV pseudotyped viruses, and antibodies mediating antibody-dependent cellular cytotoxicity (ADCC). Serum antibodies produced in Env-Fc immunized macaques had increased durability compared to Env monomer immunization. A Gag-V1V2-Fc fusion protein was constructed to test whether a self-assembling macromolecular structure was a more effective method for directing antibody responses to specific V1V2 regions of the Envelope glycoprotein. This immunogen crossed nasal epithelium barriers more efficiently than HIV Gag (p24 monomer), and elicited V1V2-specific IgG responses. Our work suggests that adding IgG1 Fc to engineered monomeric or oligomeric Env-based immunogens may improve the protective serum antibody response and contribute to the development of a protective HIV vaccine.en_US
dc.language.isoen_USen_US
dc.subjectFc fusion proteinen_US
dc.subjectFc gamma receptoren_US
dc.subjectHIV envelope glycoproteinen_US
dc.subjectimmune complexen_US
dc.subjectRhesus macaquesen_US
dc.subject.meshAntigen-Antibody Complexen_US
dc.subject.meshHIV Envelope Protein gp120en_US
dc.subject.meshImmunizationen_US
dc.subject.meshMacaca mulattaen_US
dc.subject.meshReceptors, IgGen_US
dc.titleHIV envelope glycoprotein-Fc fusion proteins target Fc gamma receptors and elicit effector antibody responses in rhesus macaquesen_US
dc.typedissertationen_US
dc.contributor.advisorPauza, C. David
refterms.dateFOA2019-02-21T02:09:44Z


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