RECENT ADVANCED MODELS IN VACCINE TESTING AND IMMUNOTHERAPY APPROACHES FOR HIV-1

Abstract

HIV infection continues to be a global health problem, and novel immunetherapeutic strategies will be necessary to develop an effective HIV-1 vaccine or to block the infection. HIV-1 has limited species tropism, which can only replicate and cause disease in humans; however, animal models will be important in evaluating new therapeutic strategies. One novel strategy is to use the natural antiGal antibodies that develop in primates (including humans) to increase the immunogenicity of viral epitopes. Current murine models cannot be used to test the efficacy of these novel vaccines as mice, unlike humans, normally express αGal epitopes and lack the anti-Gal antibodies. Therefore, we developed a novel mouse strain, lacking α-Gal epitopes and engrafting human cells, by crossing C57BL/6 α1,3GT knockout (GTKO) mouse strain with immunodeficient mouse strain NSG by in vitro fertilization (IVF). Moreover, these mice engraft normal human CD34 + hematopoietic stem cells and develop human T cells, B cells, and myeloid cells. Additionally, we demonstrated that these humanized animals will develop human anti-Gal antibodies. Thus, the new NSG-GTKO mouse model mimics the human’s immune system and produces human anti-Gal antibodies offering a system to test vaccines expressing α-Gal epitopes with human immune cells. Another novel approach is to block and neutralize the HIV-1 infection. Therefore, we studied a new approach for the long-term production of broadly neutralizing HIV-1 antibodies (bNAb) by transducing human adipose tissuederived mesenchymal stem cells (hASCs) with a lentiviral vector (LV) expressing a potent bNAb. After modifying ASCs, we confirmed gene transfer and expression by qPCR and ELISA. Subsequently, we demonstrated that wild type HIV-1 (HIV-1 Bal), HIV-1 Env pseudotyped (Tier 1, 2 and 3), SHIV-infected rhesus macaque PBMC, and HIV-1 infected human primary PBMC were successfully neutralized using the TZM-bl in vitro assay. Together, these two models using different antibody-based immunotherapeutic approaches for HIV-1 offer pre-clinical evaluation to prevent HIV-1 replication and pathogenesis.