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。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 开发有效的HIV-1预防性疫苗的一个重大障碍在于缺乏合适的动物模型。为此，通过用人造血干细胞重建新生Balb/c-Rag 2-/-gc-/-小鼠来产生人源化小鼠。用编码HIV-1进化枝C包膜蛋白的两种衍生物（gp 145 DCFI和gp 140 DCFI）的重组腺病毒血清型5载体（rAd 5）接种动物。在初次-加强rAd 5：gp 145免疫后，观察到对rAd 5和亚型C gp 120的显著细胞因子（主要是IFN-g）和体液免疫应答。用rAd 5：gp 140接种，然后用利用CCR 5的进化枝C HIV-1C 1157攻击，导致产生病毒特异性抗体。值得注意的是，与未接种疫苗的对照组相比，接种疫苗和随后的HIV-1攻击诱导了接种疫苗的人源化小鼠淋巴组织中幼稚CD 4+和效应CD 8+细胞的快速耗竭。这项工作表明，人类免疫系统可以在小鼠环境中发挥作用。该研究还表明，需要仔细监测HIV-1疫苗接种者的突破性感染。我们的结论是，用编码HIV-1包膜蛋白的腺病毒载体免疫人源化小鼠诱导特异性免疫应答，但不诱导病毒保护。

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. A significant obstacle in the development of an effective preventive vaccine for HIV-1 rests in the absence of a suitable animal model. To this end, humanized mice were generated by reconstitution of newborn Balb/c-Rag2-/-gc-/- mice with human hematopoietic stem cells. Animals were vaccinated with recombinant Adenovirus serotype 5 vectors (rAd5) encoding two derivatives of the HIV-1 clade C envelope proteins (gp145DCFI and gp140DCFI). After a prime-boost rAd5:gp145 immunization, significant cytokine (predominantly IFN-g) and humoral immune responses to both rAd5 and subtype C gp120 were observed. Vaccination with rAd5:gp140 followed by challenge with CCR5-utilizing clade C HIV-1C1157 resulted in the generation of virus-specific antibodies. Notably, vaccination and subsequent HIV-1 challenge induced rapid depletion of na¿ve CD4+ and effector CD8+ cells from lymphoid tissue of vaccinated humanized mice compared to non-vaccinated controls. The work demonstrates that a human immune system can function in a murine environment. The study also suggests the need for careful monitoring of breakthrough infections in HIV-1 vaccine recipients. We concluded that immunization of humanized mice with adenoviral vector encoding HIV-1 envelope protein induces specific immune responses but not viral protection.