Inhibitory effect of HIV-specific neutralizing IgA on mucosal transmission of HIV in humanized mice.
HIV-1 infections are generally initiated at mucosal sites. Thus, IgA antibody, which plays pivotal roles in mucosal immunity, might efficiently prevent HIV infection. However, mounting a highly effective HIV-specific mucosal IgA response by conventional immunization has been challenging and the potency of HIV-specific IgA against infection needs to be addressed in vivo. Here we show that the polymeric IgA form of anti-HIV antibody inhibits HIV mucosal transmission more effectively than the monomeric IgA or IgG1 form in a comparable range of concentrations in humanized mice. To deliver anti-HIV IgA in a continual manner, we devised a hematopoietic stem/progenitor cell (HSPC)-based genetic approach using an IgA gene. We transplanted human HSPCs transduced with a lentiviral construct encoding a class-switched anti-HIV IgA (b12-IgA) into the humanized bone marrow-liver-thymus (BLT) mice. The transgene was expressed specifically in B cells and plasma cells in lymphoid organs and mucosal sites. After vaginal HIV-1 challenge, mucosal CD4(+) T cells in the b12-IgA-producing mice were protected from virus-mediated depletion. Similar results were also obtained in a second humanized model, "human immune system mice." Our study demonstrates the potential of anti-HIV IgA in immunoprophylaxis in vivo, emphasizing the importance of the mucosal IgA response in defense against HIV/AIDS.
Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.
Eun Mi
EM
Hur
Sonal N
SN
Patel
Saki
S
Shimizu
Dinesh S
DS
Rao
Priyanthi N P
PN
Gnanapragasam
Dong Sung
DS
An
Lili
L
Yang
David
D
Baltimore
D000818:Animals; D057134:Antibodies, Neutralizing / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000914:Antibodies, Viral / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D057809:HEK293 Cells; D015658:HIV Infections / Q000276:immunology* / Q000517:prevention & control / Q000635:transmission; D015497:HIV-1 / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000378:metabolism; D006801:Humans; D018928:Immunity, Mucosal / Q000276:immunology*; D007070:Immunoglobulin A / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008221:Lymphoid Tissue / Q000276:immunology / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009092:Mucous Membrane / Q000276:immunology / Q000378:metabolism; D010950:Plasma Cells / Q000276:immunology / Q000378:metabolism
D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; C507942:Il2rg protein, mouse; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D053631:Interleukin Receptor Common gamma Subunit