title: 9G4+ antibodies isolated from HIV-infected patients neutralize HIV-1 and have distinct autoreactivity profiles.
abstract: Potent HIV-1 specific broadly neutralizing antibodies (BNA) are uncommon in HIV infected individuals, and have proven hard to elicit by vaccination. Several, isolated monoclonal BNA are polyreactive and also recognize self-antigens, suggesting a breach of immune tolerance in persons living with HIV (PLWH). Persons with systemic lupus erythematosus (SLE) often have elevated levels of autoreactive antibodies encoded by the VH4-34 heavy chain immunoglobulin gene whose protein product can be detected by the 9G4 rat monoclonal antibody. We have recently found that levels of these "9G4+" antibodies are also elevated in PLWH. However, the putative autoreactive nature of these antibodies and the relationship of such reactivities with HIV neutralization have not been investigated. We therefore examined the autoreactivity and HIV neutralization potential of 9G4+ antibodies from PLWH. Results show that 9G4+ antibodies from PLWH bound to recombinant HIV-1 envelope (Env) and neutralized viral infectivity in vitro, whereas 9G4+ antibodies from persons with SLE did not bind to Env and failed to neutralize viral infectivity. In addition, while 9G4+ antibodies from PLWH retained the canonical anti-i reactivity that mediates B cell binding, they did not display other autoreactivities common to SLE 9G4+ antibodies, such as binding to cardiolipin and DNA and had much lower reactivity with apoptotic cells. Taken together, these data indicate that the autoreactivity of 9G4+ antibodies from PLWH is distinct from that of SLE patients, and therefore, their expansion is not due to a general breakdown of B cell tolerance but is instead determined in a more disease-specific manner by self-antigens that become immunogenic in the context of, and possibly due to HIV infection. Further studies of 9G4+ B cells may shed light on the regulation of B cell tolerance and interface between the generation of specific autoreactivities and the induction of antiviral immunity in persons living with HIV.
authors.affiliation: Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, United States of America ; Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Danielle C
authors.initials: DC
authors.lastname: Alcéna
authors.affiliation: Division of Infectious Diseases, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: James J
authors.initials: JJ
authors.lastname: Kobie
authors.affiliation: Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Denise A
authors.initials: DA
authors.lastname: Kaminski
authors.affiliation: Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Rosenberg
authors.affiliation: Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Jonelle L
authors.initials: JL
authors.lastname: Mattiacio
authors.affiliation: Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Matthew
authors.initials: M
authors.lastname: Brewer
authors.affiliation: Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Stephen
authors.initials: S
authors.lastname: Dewhurst
authors.affiliation: Division of Infectious Diseases, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Carrie
authors.initials: C
authors.lastname: Dykes
authors.affiliation: Division of Infectious Diseases, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Xia
authors.initials: X
authors.lastname: Jin
authors.affiliation: Division of Infectious Diseases, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Keefer
authors.affiliation: Lowance Center for Human Immunology and Division of Rheumatology, Department of Medicine, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Sanz
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000097:blood / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D015483:HIV Antibodies / Q000097:blood / Q000276:immunology*; D015658:HIV Infections / Q000097:blood / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007108:Immune Tolerance; D019169:Jurkat Cells; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000276:immunology; D008297:Male; D008875:Middle Aged; D051381:Rats
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D015483:HIV Antibodies