Neutralization Takes Precedence Over IgG or IgA Isotype-related Functions in Mucosal HIV-1 Antibody-mediated Protection

Autor: Hua-Xin Liao, Guido Ferrari, Punnee Pitisuttithum, Thomas N. Denny, Justin Pollara, Nicole L. Yates, Georgia D. Tomaras, Florian Hladik, George M. Shaw, Barton F. Haynes, M. Juliana McElrath, Georgeanna Morton, Katharine Westerberg, Tiffany Hensley-McBain, Shi-Mao Xia, Linh Mach, Sampa Santra, Benjamin Mildenberg, Gregory J. Mize, Ranjit Warrier, Rena D. Astronomo, Jaranit Kaewkungwal, Christina Ochsenbauer, Sorachai Nitayapan, Supachai Rerks-Ngarm, Lamar Ballweber-Fleming, Laura L. Sutherland, David C. Montefiori
Rok vydání: 2016
Předmět:
0301 basic medicine
Immunoglobulin A
Non-human primate rectal challenge model
Vaginal explants
Simian Acquired Immunodeficiency Syndrome
pIgR
Polymeric IgA receptor
GI
Gastrointestinal
HIV Infections
ADCC
Antibody-dependent cell-mediated cytotoxicity
HIV Antibodies
Immunoglobulin G
sIgA
Secretory IgA
Leukocytes
T/F
Transmitted/founder
CD4bs
CD4 binding site
Antibody-dependent cell-mediated cytotoxicity
biology
General Medicine
Isotype
3. Good health
mIgA
Monomeric IgA
dIgA
Dimeric IgA
Vagina
Mucosal immunology
Female
Simian Immunodeficiency Virus
Antibody
MPER
Membrane-proximal external region
IDV
Indinivir
IgA
Research Paper
AZT
Zidovudine
ARV
Anti-retroviral
IgG
nnAb
Non-neutralizing antibody
030106 microbiology
LED
Lowest effective dose
Neutralizing antibodies
General Biochemistry
Genetics and Molecular Biology
snLuc
Secreted nanoluciferase
Antibodies
Immunophenotyping
GalCer
Galactosyl ceramide
03 medical and health sciences
Neutralization Tests
SC
Secretory component
Animals
Humans
FcRn
Neonatal Fc receptor
Immunity
Mucosal
IMC
Infectious molecular clone
bnAb
Broadly neutralizing antibody
Mucous Membrane
Virology
Antibodies
Neutralizing
Macaca mulatta
Disease Models
Animal
030104 developmental biology
Immunoglobulin class switching
Immunology
biology.protein
HIV-1
mAb
Monoclonal antibody
GU
Genitourinary
Ex vivo
Biomarkers
Zdroj: EBioMedicine
ISSN: 2352-3964
DOI: 10.1016/j.ebiom.2016.11.024
Popis: 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-CSF and HIV-1Bal26 infection. 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.
Highlights • Only broadly-neutralizing IgG and IgA Abs were protective in two relevant mucosal models of HIV-1 infection. • IgG isotype variants were typically more protective than the IgA isotype variants against vaginal or rectal challenge. • Neutralization rather than IgA-specific functions may afford better protection against mucosal HIV-1 infection. Antibodies are likely to play a key role in preventing HIV-1 infection following mucosal exposure. We used two mucosal models, in conjunction with IgG and IgA versions of the same antibodies, to identify protective antibody properties relevant to vaginal and rectal transmission. Antibodies that can potently neutralize most HIV-1 strains were protective against viral challenge, but those without this capability were non-protective. The IgA antibodies were no more protective than their IgG counterparts even though IgA antibody forms are more abundant in the mucosa. These findings can help prioritize vaccine designs to those that induce potent broadly neutralizing IgG antibodies.
Databáze: OpenAIRE
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