SUBTYPE C HIV VACCINE TESTING IN HUMANIZED MICE

这个子项目是众多研究子项目之一

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The specificity of HIV-1 for human cells precludes virus infection in most mammalian species and limits the utility of small animal models for studies of disease pathogenesis, therapeutic and vaccine development. One way to overcome this limitation is by human cell xenotransplantation in immune deficient mice. However, this has proved inadequate as engraftment of human immune cells is limited (both functionally and quantitatively) following transplantation of mature human lymphocytes or fetal thymus/liver. To this end, a human immune system was generated from umbilical cord blood derived CD34(+) hematopoietic stem cells in Balb/c-Rag2(-/-)gamma chain (-/-) double knockout mice. Intrapartum busulfan administration followed by irradiation of newborn pups resulted in uniform engraftment characterized by human T cell development in thymus, B cell maturation in bone marrow, lymph node development, IgM/IgG production and humoral immune responses following ActHIB(R) vaccination. Infection of reconstituted mice by CCR5 co-receptor utilizing HIV-1ADA and subtype C 1157 viral strains elicited productive viral replication and lymphadenopathy in dose dependent fashion. We conclude that humanized Balb/c-Rag2(-/-) gammac(-/-) mice represent a unique and valuable resource for HIV-1 pathobiology studies. Three vaccine candidates were studied in this model. These vaccines were constructed by using HIV-1 subtype C envelope proteins (gp145 and gp140) and two delivery vectors: Herpes Simplex Virus-1 amplicon (HSV) and adenonovirus type 5 (Ad5).