KSHV targets multiple leukocyte lineages during long-term productive infection in NOD/SCID mice
KSHV targets multiple leukocyte lineages during long-term productive infection in NOD/SCID mice
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DOI：
10.1172/jci27249
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发表时间：
2006-07-01
影响因子：
15.9
通讯作者：
Kedes, Dean H.
中科院分区：
文献类型：
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作者：
Parsons, Christopher H.;Adang, Laura A.;Kedes, Dean H.
为了开发一种卡波西肉瘤相关疱疹病毒（KSHV）感染的动物模型，该模型特别适合于评估病毒基因表达、细胞嗜性和免疫应答的纵向模式，我们用纯化的病毒静脉注射NOD/SCID小鼠，并在随后的4个月内测量远端器官中的潜伏和裂解病毒转录物。我们观察到的第一个潜在的，然后裂解KSHV基因表达的顺序升级，再加上电子显微镜证据的病毒粒子生产在小鼠脾脏。使用新的技术，整合流式细胞术与免疫荧光显微镜，我们发现，病毒建立感染小鼠B细胞，巨噬细胞，NK细胞，并在较小程度上，树突状细胞。为了研究在这种免疫功能低下的宿主中人类KSHV特异性免疫应答的潜力，我们将功能性人类造血组织移植物（NOD/SCID-hu小鼠）植入NOD/SCID小鼠，并观察到一个动物子集产生人类KSHV特异性抗体。此外，在接种时用更昔洛韦治疗这些嵌合小鼠导致KSHV DNA和RNA水平的长期但可逆的抑制，表明KSHV可以在体内建立潜伏感染，尽管正在进行的裂解复制抑制。
To develop an animal model of Kaposi sarcoma-associated herpesvirus (KSHV) infection uniquely suited to evaluate longitudinal patterns of viral gene expression, cell tropism, and immune responses, we injected NOD/SCID mice intravenously with purified virus and measured latent and lytic viral transcripts in distal organs over the subsequent 4 months. We observed sequential escalation of first latent and then lytic KSHV gene expression coupled with electron micrographic evidence of virion production within the murine spleen. Using novel technology that integrates flow cytometry with immunofluorescence microscopy, we found that the virus establishes infection in murine B cells, macrophages, NK cells, and, to a lesser extent, dendritic cells. To investigate the potential for human KSHV-specific immune responses within this immunocompromised host, we implanted NOD/SCID mice with functional human hematopoietic tissue grafts (NOD/SCID-hu mice) and observed that a subset of animals produced human KSHV-specific antibodies. Furthermore, treatment of these chimeric mice with ganciclovir at the time of inoculation led to prolonged but reversible suppression of KSHV DNA and RNA levels, suggesting that KSHV can establish latent infection in vivo despite ongoing suppression of lytic replication.