Baenziger Stefan, Tussiwand Roxane, Schlaepfer Erika, Mazzucchelli Luca, Heikenwalder Mathias, Kurrer Michael O, Behnke Silvia, Frey Joachim, Oxenius Annette, Joller Helen, Aguzzi Adriano, Manz Markus G, Speck Roberto F
Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland.
Proc Natl Acad Sci U S A. 2006 Oct 24;103(43):15951-6. doi: 10.1073/pnas.0604493103. Epub 2006 Oct 12.
Because of species selectivity, HIV research is largely restricted to in vitro or clinical studies, both limited in their ability to rapidly assess new strategies to fight the virus. To prospectively study some aspects of HIV in vivo, immunodeficient mice, transplanted with either human peripheral blood leukocytes or human fetal tissues, have been developed. Although these are susceptible to HIV infection, xenoreactivity, and short infection spans, resource and ethical constraints, as well as biased HIV coreceptor tropic strain infection, pose substantial problems in their use. Rag2(-/-)gamma(c)(-/-) mice, transplanted as newborns with human CD34(+) cells, were recently shown to develop human B, T, and dendritic cells, constituting lymphoid organs in situ. Here we tested these mice as a model system for HIV-1 infection. HIV RNA levels peaked to up to 2 x 10(6) copies per milliliter of plasma early after infection, and viremia was observed for up to 190 days, the longest time followed. A marked relative CD4(+) T cell depletion in peripheral blood occurred in CXCR4-tropic strain-infected mice, whereas this was less pronounced in CCR5-tropic strain-infected animals. Thymus infection was almost exclusively observed in CXCR4-tropic strain-infected mice, whereas spleen and lymph node HIV infection occurred irrespective of coreceptor selectivity, consistent with respective coreceptor expression on human CD4(+) T cells. Thus, this straightforward to generate and cost-effective in vivo model closely resembles HIV infection in man and therefore should be valuable to study virus-induced pathology and to rapidly evaluate new approaches aiming to prevent or treat HIV infection.
由于物种选择性，HIV研究主要局限于体外研究或临床研究，而这两种研究在快速评估对抗该病毒的新策略方面能力有限。为了前瞻性地研究HIV在体内的某些方面，已培育出移植了人类外周血白细胞或人类胎儿组织的免疫缺陷小鼠。尽管这些小鼠易受HIV感染，但存在异种反应性和感染跨度短的问题，资源和伦理限制以及有偏向性的HIV共受体嗜性毒株感染，在其使用中带来了重大问题。最近有研究表明，新生时移植了人类CD34(+)细胞的Rag2(-/-)gamma(c)(-/-)小鼠能够发育出人类B细胞、T细胞和树突状细胞，并在原位形成淋巴器官。在此，我们测试了这些小鼠作为HIV-1感染的模型系统。感染后早期，HIV RNA水平最高达到每毫升血浆2×10(6)拷贝，并且观察到病毒血症持续了长达190天，这是观察到的最长时间。在感染CXCR4嗜性毒株的小鼠外周血中出现了明显的相对CD4(+) T细胞耗竭，而在感染CCR5嗜性毒株的动物中这种情况则不太明显。几乎仅在感染CXCR4嗜性毒株的小鼠中观察到胸腺感染，而脾脏和淋巴结的HIV感染与共受体选择性无关，这与人类CD4(+) T细胞上各自的共受体表达情况一致。因此，这种易于构建且成本效益高的体内模型与人类HIV感染非常相似，因此对于研究病毒诱导的病理学以及快速评估旨在预防或治疗HIV感染的新方法应该具有重要价值。
