Induction of Robust Cellular and Humoral Virus-Specific Adaptive Immune Responses in Human Immunodeficiency Virus-Infected Humanized BLT Mice
Induction of Robust Cellular and Humoral Virus-Specific Adaptive Immune Responses in Human Immunodeficiency Virus-Infected Humanized BLT Mice
复制标题
DOI：
10.1128/jvi.02207-08
复制
发表时间：
2009-07-15
影响因子：
5.4
通讯作者：
Tager, Andrew M.
中科院分区：
文献类型：
--
作者：
Brainard, Diana M.;Seung, Edward;Tager, Andrew M.
通过将人胎胸腺和肝组织以及CD 34（+）胎肝细胞共移植到非肥胖糖尿病/严重联合免疫缺陷小鼠中产生人源化BLT小鼠，允许长期重建功能性人免疫系统，其中人T细胞、B细胞、树突状细胞和单核细胞/巨噬细胞重新填充小鼠组织。在这里，我们发现人源化BLT小鼠持续高水平的播散性人类免疫缺陷病毒（HIV）感染，导致CD 4（+）T细胞耗竭和全身免疫激活。感染后3个月，所有小鼠均出现HIV特异性体液应答，感染9周后，在大多数受试小鼠中检测到HIV特异性CD 4（+）和CD 8（+）T细胞应答。然而，尽管HIV特异性反应很强，但感染BLT小鼠的病毒载量仍然升高，这增加了这些反应功能失调的可能性。最近，已经假定负共刺激因子PD-1的T细胞表达增加有助于慢性HIV感染中的T细胞功能障碍。正如在人类感染中所看到的，在HIV感染的BLT小鼠中，CD 4（+）和CD 8（+）T细胞均表现出PD-1表达增加，这些细胞中的PD-1水平与病毒载量呈正相关，与CD 4（+）细胞水平呈负相关。人源化BLT小鼠对HIV产生细胞和体液免疫应答的能力将允许进一步研究体内人类HIV特异性免疫应答，并表明这些小鼠能够提供评估候选HIV疫苗和其他免疫策略的平台。
The generation of humanized BLT mice by the cotransplantation of human fetal thymus and liver tissues and CD34(+) fetal liver cells into nonobese diabetic/severe combined immunodeficiency mice allows for the long-term reconstitution of a functional human immune system, with human T cells, B cells, dendritic cells, and monocytes/macrophages repopulating mouse tissues. Here, we show that humanized BLT mice sustained high-level disseminated human immunodeficiency virus (HIV) infection, resulting in CD4(+) T-cell depletion and generalized immune activation. Following infection, HIV-specific humoral responses were present in all mice by 3 months, and HIV-specific CD4(+) and CD8(+) T-cell responses were detected in the majority of mice tested after 9 weeks of infection. Despite robust HIV-specific responses, however, viral loads remained elevated in infected BLT mice, raising the possibility that these responses are dysfunctional. The increased T-cell expression of the negative costimulator PD-1 recently has been postulated to contribute to T-cell dysfunction in chronic HIV infection. As seen in human infection, both CD4(+) and CD8(+) T cells demonstrated increased PD-1 expression in HIV-infected BLT mice, and PD-1 levels in these cells correlated positively with viral load and inversely with CD4(+) cell levels. The ability of humanized BLT mice to generate both cellular and humoral immune responses to HIV will allow the further investigation of human HIV-specific immune responses in vivo and suggests that these mice are able to provide a platform to assess candidate HIV vaccines and other immunotherapeutic strategies.