SUBTYPE C HIV VACCINE TESTING IN HUMANIZED MICE

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 研究中心，而研究中心不一定是研究者所在的机构。 HIV-1对人类细胞的特异性排除了大多数哺乳动物物种中的病毒感染，并限制了小动物模型用于疾病发病机制、治疗和疫苗开发研究的效用。克服这一限制的一种方法是在免疫缺陷小鼠中进行人细胞异种移植。然而，这已被证明是不够的，因为在移植成熟人淋巴细胞或胎儿胸腺/肝脏后，人免疫细胞的植入是有限的（功能上和数量上）。为此，在Balb/c-Rag 2（-/-）γ链（-/-）双敲除小鼠中从脐带血来源的CD 34（+）造血干细胞产生人免疫系统。分娩期白消安给药，随后对新生幼仔进行辐照，导致一致的植入，其特征在于胸腺中的人T细胞发育、骨髓中的B细胞成熟、淋巴结发育、IgM/IgG产生和ActHI B（R）疫苗接种后的体液免疫应答。重组小鼠感染CCR 5共受体利用HIV-1ADA和亚型C 1157病毒株引起生产性病毒复制和淋巴结病的剂量依赖性方式。我们的结论是，人源化Balb/c-Rag 2（-/-）gammac（-/-）小鼠代表了HIV-1病理生物学研究的独特和有价值的资源。在该模型中研究了三种候选疫苗。这些疫苗通过使用HIV-1亚型C包膜蛋白（gp 145和gp 140）和两种递送载体：单纯疱疹病毒-1扩增子（HSV）和腺病毒5型（Ad 5）构建。

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).