The neutralizing function of the anti-HTLV-1 antibody is essential in preventing in vivo transmission of HTLV-1 to human T cells in NOD-SCID/¿cnull (NOG) mice

Abstract

Background: Human T-cell leukemia virus type 1 (HTLV-1) causes both neoplastic and inflammatory diseases, including adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Because these life-threatening and disabling diseases are not yet curable, it is important to prevent new HTLV-1 infections.Findings: In this study, we have established a simple humanized mouse model of HTLV-1 infection for evaluating prophylactic and therapeutic interventions. In this model, HTLV-1-negative normal human peripheral blood mononuclear cells (PBMCs) are transplanted directly into the spleens of severely immunodeficient NOD-SCID/γcnull (NOG) mice, together with mitomycin-treated HTLV-1-producing T cells. Using this model, we tested the efficacy of monoclonal antibodies (mAbs) specific to HTLV-1 as well as human IgG isolated from HAM/TSP patients (HAM-IgG) in preventing HTLV-1-infection. One hour before and 24 h after transplantation of the human cells, each antibody sample was inoculated intraperitoneally. On day 14, human PBMCs isolated from the mouse spleens were tested for HTLV-1 infection. Whereas fresh CD4-positive and CD8-positive T cells isolated from untreated mice or mice treated with isotype control mAb, HTLV-1 non-neutralizing mAbs to envelope gp46, gag p19, and normal human IgG were all infected with HTLV-1; the mice treated with either HTLV-1 neutralizing anti-gp46 mAb or HAM-IgG did not become infected.Conclusions: Our data indicate that the neutralizing function of the antibody, but not the antigen specificity, is essential for preventing the in vivo transmission of HTLV-1. The present animal model will also be useful for the in vivo evaluation of the efficacy of candidate molecules to be used as prophylactic and therapeutic intervention against HTLV-1 infection.

A Simple Mouse Model for the Study of Human Immunodeficiency Virus

“…However, a recent study demonstrated that human T cells could be efficiently engrafted by direct transplantation of human PBMCs into the spleen of irradiated NOD/SCID/c c -/mice, creating an animal model for studying primary human T cell leukemia virus type-1 (HTLV-1) infection in vivo. 14 Interestingly, reconstitution of human T cells was barely detectable in any of the NSG mice early (2 weeks) after intraperitoneal injection of human PBMCs (Fig. 1B).…”

“…Although the upgraded nonobese diabetic (NOD/SCID) mouse has led to improved human cell engraftment, the percentage of engrafted human cells following intraperitoneal injection has remained suboptimal and highly variable. [6][7][8][9][10] NOD/SCID mice harboring either a null allele at the b 2microglobulin locus (NOD/SCID/b2m -/-) 11 or a truncated common cytokine receptor c chain (cc) mutant lacking its cytoplasmic region (NOD/SCID/c c -/-) [12][13][14] were developed as model animals. In these mice, natural killer (NK) cells as well as T and B cells are disrupted because b2m is necessary for major histocompatibility complex (MHC) class I-mediated innate immunity and cc (IL-2Rc chain) is an indispensable component of receptor heterodimers for many lymphoidrelated cytokines, such as interleukin (IL)-2, IL-7, IL-9, IL-12, IL-15, and IL-21.…”

A Potential of an Anti-HTLV-I gp46 Neutralizing Monoclonal Antibody (LAT-27) for Passive Immunization against Both Horizontal and Mother-to-Child Vertical Infection with Human T Cell Leukemia Virus Type-I

“…Then, we tested the protective efficacy of hu-LAT-27 mAbs against in vivo infection with HTLV-I using our humanized mouse model as reported previously [ 18 ]. PBMCs from HTLV-I-negative donors were transplanted directly into the spleen of NOG mice together with the mitomycin-C-treated HTLV-I-producing cells.…”

“…Indeed, LAT-27 reacted all HTLV-I-producing cell lines tested, including naturally infected cell lines from ATL and HAM/TSP patients and asymptomatic carriers. So far, the potential of passive immunization with IgG from HTLV-I carriers has been show in rabbit [ 25 , 26 ], monkey [ 27 ] and humanized NOG mouse models [ 18 ]. Since polyclonal antibodies contain non-neutralizing antibodies, the efficacy of neutralization by neutralizing antibody could be interfered with by those non-neutralizing anti-gp46 antibodies.…”

“…On the way to establishing a basis for vaccine development against HTLV-I, we previously reported that our anti-gp46 neutralizing mAb (LAT-27) was capable of blocking of HTLV-I infection by direct neutralization and eradicating HTLV-I-infected cells via antibody-dependent-cellular-cytotoxicity (ADCC) in vitro [ 17 ]. Recently, we showed that LAT-27 is also capable of blocking primary HTLV-I infection in a humanized mouse model [ 18 ].…”