title: Live simian immunodeficiency virus vaccine correlate of protection: immune complex-inhibitory Fc receptor interactions that reduce target cell availability.
abstract: Principles to guide design of an effective vaccine against HIV are greatly needed, particularly to protect women in the pandemic's epicenter in Africa. We have been seeking these principles by identifying correlates of the robust protection associated with SIVmac239Δnef vaccination in the SIV-rhesus macaque animal model of HIV-1 transmission to women. We identified one correlate of SIVmac239Δnef protection against vaginal challenge as a resident mucosal system for SIV-gp41 trimer Ab production and neonatal FcR-mediated concentration of these Abs on the path of virus entry to inhibit establishment of infected founder populations at the portal of entry. In this study, we identify blocking CD4(+) T cell recruitment to thereby inhibit local expansion of infected founder populations as a second correlate of protection. Virus-specific immune complex interactions with the inhibitory FcγRIIb receptor in the epithelium lining the cervix initiate expression of genes that block recruitment of target cells to fuel local expansion. Immune complex-FcγRIIb receptor interactions at mucosal frontlines to dampen the innate immune response to vaginal challenge could be a potentially general mechanism for the mucosal immune system to sense and modulate the response to a previously encountered pathogen. Designing vaccines to provide protection without eliciting these transmission-promoting innate responses could contribute to developing an effective HIV-1 vaccine.
authors.affiliation: Department of Microbiology, Medical School, University of Minnesota, Minneapolis, MN 55455;
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Smith
authors.affiliation: Department of Microbiology, Medical School, University of Minnesota, Minneapolis, MN 55455;
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Wietgrefe
authors.affiliation: Department of Microbiology, Medical School, University of Minnesota, Minneapolis, MN 55455;
authors.forename: Liang
authors.initials: L
authors.lastname: Shang
authors.affiliation: Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN 55455;
authors.forename: Cavan S
authors.initials: CS
authors.lastname: Reilly
authors.affiliation: Department of Microbiology, Medical School, University of Minnesota, Minneapolis, MN 55455;
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Southern
authors.affiliation: Department of Microbiology, Medical School, University of Minnesota, Minneapolis, MN 55455;
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Perkey
authors.affiliation: Department of Microbiology, Medical School, University of Minnesota, Minneapolis, MN 55455;
authors.forename: Lijie
authors.initials: L
authors.lastname: Duan
authors.affiliation: Department of Microbiology and Immunology and Molecular Genetics, University of Kentucky, Lexington, KY 40536;
authors.forename: Heinz
authors.initials: H
authors.lastname: Kohler
authors.affiliation: ImmPheron Inc., Lexington, KY 40509;
authors.forename: Sybille
authors.initials: S
authors.lastname: Müller
authors.affiliation: Department of Pediatrics, Center for Infectious Diseases, Tulane University, New Orleans, LA 70112;
authors.forename: James
authors.initials: J
authors.lastname: Robinson
authors.affiliation: Department of Computer Science and Engineering, College of Science and Engineering, University of Minnesota, Minneapolis, MN 55455;
authors.forename: John V
authors.initials: JV
authors.lastname: Carlis
authors.affiliation: Nebraska Center for Virology, School of Biological Sciences, University of Nebraska, Lincoln, NE 68583;
authors.forename: Qingsheng
authors.initials: Q
authors.lastname: Li
authors.affiliation: New England Primate Research Center, Harvard Medical School, Southborough Campus, Southborough, MA 01772; Ragon Institute of MGH, MIT and Harvard, Charlestown, MA 02129; and Infectious Disease Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 02115.
authors.forename: R Paul
authors.initials: RP
authors.lastname: Johnson
authors.affiliation: Department of Microbiology, Medical School, University of Minnesota, Minneapolis, MN 55455; haase001@umn.edu.
authors.forename: Ashley T
authors.initials: AT
authors.lastname: Haase
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D000914:Antibodies, Viral / Q000276:immunology; D000917:Antibody Formation / Q000276:immunology; D000936:Antigen-Antibody Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D002584:Cervix Uteri / Q000276:immunology* / Q000821:virology; D005260:Female; D020869:Gene Expression Profiling; D015700:HIV Envelope Protein gp41 / Q000276:immunology; D007113:Immunity, Innate; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008253:Macaca mulatta; D009092:Mucous Membrane / Q000276:immunology; D017452:Receptors, IgG / Q000276:immunology*; D018449:SAIDS Vaccines / Q000008:administration & dosage / Q000276:immunology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000517:prevention & control; D015302:Simian Immunodeficiency Virus / Q000276:immunology*; D014611:Vaccination; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000276:immunology; D014621:Vagina / Q000276:immunology* / Q000821:virology
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000936:Antigen-Antibody Complex; D015700:HIV Envelope Protein gp41; D007074:Immunoglobulin G; D017452:Receptors, IgG; D018449:SAIDS Vaccines; D014613:Vaccines, Attenuated