title: An HIV gp120-CD4 Immunogen Does Not Elicit Autoimmune Antibody Responses in Cynomolgus Macaques.
abstract: A promising concept for human immunodeficiency virus (HIV) vaccines focuses immunity on the highly conserved transition state structures and epitopes that appear when the HIV glycoprotein gp120 binds to its receptor, CD4. We are developing chimeric antigens (full-length single chain, or FLSC) in which gp120 and CD4 sequences are flexibly linked to allow stable intrachain complex formation between the two moieties (A. DeVico et al., Proc Natl Acad Sci U S A 104:17477-17482, 2007, doi:10.1073/pnas.0707399104; T. R. Fouts et al., J Virol 74:11427-11436, 2000, doi:10.1128/JVI.74.24.11427-11436.2000). Proof of concept studies with nonhuman primates show that FLSC elicited heterologous protection against simian-human immunodeficiency virus (SHIV)/simian immunodeficiency virus (SIV) (T. R. Fouts et al., Proc Natl Acad Sci U S A 112:E992-E999, 2016, doi:10.1073/pnas.1423669112), which correlated with antibodies against transition state gp120 epitopes. Nevertheless, advancement of any vaccine that comprises gp120-CD4 complexes must consider whether the CD4 component breaks tolerance and becomes immunogenic in the autologous host. To address this, we performed an immunotoxicology study with cynomolgus macaques vaccinated with either FLSC or a rhesus variant of FLSC containing macaque CD4 sequences (rhFLSC). Enzyme-linked immunosorbent assay (ELISA) binding titers, primary CD3(+) T cell staining, and temporal trends in T cell subset frequencies served to assess whether anti-CD4 autoantibody responses were elicited by vaccination. We find that immunization with multiple high doses of rhFLSC did not elicit detectable antibody titers despite robust responses to rhFLSC. In accordance with these findings, immunized animals had no changes in circulating CD4(+) T cell counts or evidence of autoantibody reactivity with cell surface CD4 on primary naive macaque T cells. Collectively, these studies show that antigens using CD4 sequences to stabilize transition state gp120 structures are unlikely to elicit autoimmune antibody responses, supporting the advancement of gp120-CD4 complex-based antigens, such as FLSC, into clinical testing.
authors.affiliation: Profectus Biosciences, Inc., Baltimore, Maryland, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Schwartz
authors.affiliation: Profectus Biosciences, Inc., Baltimore, Maryland, USA.
authors.forename: Ilia
authors.initials: I
authors.lastname: Prado
authors.affiliation: BIOQUAL, Inc., Rockville, Maryland, USA.
authors.forename: Johnathan
authors.initials: J
authors.lastname: Misamore
authors.affiliation: BIOQUAL, Inc., Rockville, Maryland, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Weiss
authors.affiliation: Advanced Bioscience Laboratory, Inc., Rockville, Maryland, USA.
authors.forename: Jesse
authors.initials: J
authors.lastname: Francis
authors.affiliation: Advanced Bioscience Laboratory, Inc., Rockville, Maryland, USA.
authors.forename: Ranajit
authors.initials: R
authors.lastname: Pal
authors.affiliation: Advanced Bioscience Laboratory, Inc., Rockville, Maryland, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Huaman
authors.affiliation: Advanced Bioscience Laboratory, Inc., Rockville, Maryland, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Cristillo
authors.affiliation: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: George K
authors.initials: GK
authors.lastname: Lewis
authors.affiliation: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Gallo
authors.affiliation: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Anthony L
authors.initials: AL
authors.lastname: DeVico
authors.affiliation: Profectus Biosciences, Inc., Baltimore, Maryland, USA fouts@profectusbiosciences.com.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Fouts
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood*; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology*; D018791:CD4 Lymphocyte Count; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015483:HIV Antibodies / Q000097:blood*; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000276:immunology*; D008252:Macaca fascicularis; D008297:Male; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology
chemical_list: D001323:Autoantibodies; D015704:CD4 Antigens; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D011994:Recombinant Proteins; C514793:gp120 protein, Human immunodeficiency virus 1