title: Neutralization Takes Precedence Over IgG or IgA Isotype-related Functions in Mucosal HIV-1 Antibody-mediated Protection.
abstract: HIV-1 infection occurs primarily through mucosal transmission. Application of biologically relevant mucosal models can advance understanding of the functional properties of antibodies that mediate HIV protection, thereby guiding antibody-based vaccine development. Here, we employed a human ex vivo vaginal HIV-1 infection model and a rhesus macaque in vivo intrarectal SHIV challenge model to probe the protective capacity of monoclonal broadly-neutralizing (bnAb) and non-neutralizing Abs (nnAbs) that were functionally modified by isotype switching. For human vaginal explants, we developed a replication-competent, secreted NanoLuc reporter virus system and showed that CD4 binding site bnAbs b12 IgG1 and CH31 IgG1 and IgA2 isoforms potently blocked HIV-1JR-CSFand HIV-1Bal26infection. However, IgG1 and IgA nnAbs, either alone or together, did not inhibit infection despite the presence of FcR-expressing effector cells in the tissue. In macaques, the CH31 IgG1 and IgA2 isoforms infused before high-dose SHIV challenge were completely to partially protective, respectively, while nnAbs (CH54 IgG1 and CH38 mIgA2) were non-protective. Importantly, in both mucosal models IgG1 isotype bnAbs were more protective than the IgA2 isotypes, attributable in part to greater neutralization activity of the IgG1 variants. These findings underscore the importance of potent bnAb induction as a primary goal of HIV-1 vaccine development.
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Rena D
authors.initials: RD
authors.lastname: Astronomo
authors.affiliation: Center of Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: Sampa
authors.initials: S
authors.lastname: Santra
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Lamar
authors.initials: L
authors.lastname: Ballweber-Fleming
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Katharine G
authors.initials: KG
authors.lastname: Westerberg
authors.affiliation: Center of Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: Linh
authors.initials: L
authors.lastname: Mach
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Hensley-McBain
authors.affiliation: Duke Human Vaccine Institute, Duke School of Medicine, Durham, NC, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Sutherland
authors.affiliation: Center of Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Mildenberg
authors.affiliation: Center of Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: Georgeanna
authors.initials: G
authors.lastname: Morton
authors.affiliation: Duke Human Vaccine Institute, Duke School of Medicine, Durham, NC, USA.
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Yates
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Mize
authors.affiliation: Duke Human Vaccine Institute, Duke School of Medicine, Durham, NC, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Pollara
authors.affiliation: Department of Obstetrics and Gynecology, University of Washington, Seattle, WA, USA; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Florian
authors.initials: F
authors.lastname: Hladik
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Ochsenbauer
authors.affiliation: Duke Human Vaccine Institute, Duke School of Medicine, Durham, NC, USA.
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Denny
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Ranjit
authors.initials: R
authors.lastname: Warrier
authors.affiliation: Department of Disease Control, Ministry of Public Health, Nonthaburi, Thailand.
authors.forename: Supachai
authors.initials: S
authors.lastname: Rerks-Ngarm
authors.affiliation: Department of Clinical Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Punnee
authors.initials: P
authors.lastname: Pitisuttithum
authors.affiliation: Royal Thai Army Component, Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand.
authors.forename: Sorachai
authors.initials: S
authors.lastname: Nitayapan
authors.affiliation: Department of Tropical Hygiene, Mahidol University, Bangkok, Thailand.
authors.forename: Jaranit
authors.initials: J
authors.lastname: Kaewkungwal
authors.affiliation: Duke Human Vaccine Institute, Duke School of Medicine, Durham, NC, USA.
authors.forename: Guido
authors.initials: G
authors.lastname: Ferrari
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: George M
authors.initials: GM
authors.lastname: Shaw
authors.affiliation: Duke Human Vaccine Institute, Duke School of Medicine, Durham, NC, USA.
authors.forename: Shi-Mao
authors.initials: SM
authors.lastname: Xia
authors.affiliation: Duke Human Vaccine Institute, Duke School of Medicine, Durham, NC, USA.
authors.forename: Hua-Xin
authors.initials: HX
authors.lastname: Liao
authors.affiliation: Duke Human Vaccine Institute, Duke School of Medicine, Durham, NC, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Montefiori
authors.affiliation: Duke Human Vaccine Institute, Duke School of Medicine, Durham, NC, USA.
authors.forename: Georgia D
authors.initials: GD
authors.lastname: Tomaras
authors.affiliation: Duke Human Vaccine Institute, Duke School of Medicine, Durham, NC, USA.
authors.forename: Barton F
authors.initials: BF
authors.lastname: Haynes
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Medicine, University of Washington, Seattle, WA, USA; Department of Laboratory Medicine, University of Washington, Seattle, WA, USA; Department of Global Health, University of Washington, Seattle, WA, USA. Electronic address: jmcelrat@fhcrc.org.
authors.forename: Juliana M
authors.initials: JM
authors.lastname: McElrath
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D015415:Biomarkers; D004195:Disease Models, Animal; D005260:Female; D015483:HIV Antibodies / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology* / Q000517:prevention & control / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D018928:Immunity, Mucosal; D007070:Immunoglobulin A / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology*; D016130:Immunophenotyping; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism; D008253:Macaca mulatta; D009092:Mucous Membrane / Q000276:immunology* / Q000821:virology; D009500:Neutralization Tests; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000517:prevention & control / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000276:immunology; D014621:Vagina / Q000276:immunology / Q000821:virology
chemical_list: D057134:Antibodies, Neutralizing; D015415:Biomarkers; D015483:HIV Antibodies; D007070:Immunoglobulin A; D007074:Immunoglobulin G
keywords: Antibodies; HIV-1; IgA; IgG; Mucosal immunology; Neutralizing antibodies; Non-human primate rectal challenge model; Vaginal explants