Foamy Virus Vector for Immunodeficiency Viruses Therapy

描述（由申请人提供）：在接受高活性抗逆转录病毒治疗的患者中，耐药病毒的日益流行和潜伏感染CD4+细胞的存在已成为药物治疗的障碍。一种对抗HIV感染的新疗法是基因疗法，它涉及引入抗HIV基因来抑制病毒基因表达，从而限制HIV复制。已经建立了许多不同的抗HIV基因治疗方法来抑制病毒复制，这些策略已被推动到HIV感染发育治疗的前沿。尽管这些研究令人鼓舞，但开发一种安全有效的载体来传递抗病毒基因仍然是一个挑战。目前用于HIV基因治疗临床试验的载体效率低下，主要原因是它们不能在非分裂细胞中繁殖，或者它们的基因组不能有效地整合到宿主DNA中。基于慢病毒（如HIV）的载体很有希望，因为它们既可以感染分裂细胞，也可以感染非分裂细胞。虽然慢病毒在人类基因治疗中的可行性仍在探索中，但慢病毒载体存在引起人类疾病的潜在风险。即使第三代艾滋病毒载体排除了产生野生型艾滋病毒的可能性，安全问题仍将留在公众的视线中。最近观察到静脉注射慢病毒载体治疗小鼠肝脏肿瘤的发展，这使情况进一步复杂化。泡沫病毒有几个固有的特征，使它们成为理想的载体系统。这些病毒不会在受感染的个体中引起疾病，并且在细胞类型和物种方面具有广泛的宿主范围。泡沫病毒载体基因组与宿主染色体的整合分析显示，与慢病毒相比，泡沫病毒载体突变或激活细胞基因的风险降低，证实了泡沫病毒感染的非致病性表型。我们开发了一种高效的泡沫病毒载体系统。目前的建议是继续使用SFV-1在新型严重联合免疫缺陷（SCID）小鼠（NOD/LtSz-scid IL2Rgnull）中对免疫缺陷病毒进行有效抗病毒治疗。NOD/LtSz-scid IL2Rgnull小鼠允许人类淋巴细胞的有效再生，并随后减轻病毒攻击研究。这一建议的研究将有助于设计SFV-1载体介导的人类HIV感染基因治疗方案

DESCRIPTION (provided by applicant): An increasing prevalence of resistant viruses and the presence of latently infected CD4+ cells in patients receiving highly active antiretroviral therapy have become an impediment to drug therapy. One evolving therapy to combat HIV infection is gene therapy, which involves the introduction of anti-HIV genes to inhibit viral gene expression thereby limiting HIV replication. Many different anti-HIV gene therapy approaches have been established to inhibit virus replication and these strategies have been propelled to the forefront of developmental therapies for HIV infection. Although these studies are encouraging, development of a safe and efficient vector to deliver the antiviral genes still remains a challenge. The current vectors utilized in clinical trials for HIV gene therapy are inefficient for the main reason that they can not be propagated in non-dividing cells or their genome does not efficiently integrate into host DNA. Vectors based on lentiviruses such as HIV are promising since they can infect both dividing and non-dividing cells. Although the feasibility of lentiviruses in human gene therapy is still being explored, lentivirus vectors suffer from the potential risk of causing disease in humans. The safety concern will remain in the public eye even with third generation HIV vectors where the possibility of creating a wild type HIV is excluded. This is further complicated by the recent observation of the development of liver tumors in mice treated intravenously with a lentivirus vector. Foamy viruses have several inherent features that make them an ideal vector system. These viruses do not cause disease in an infected individual and have a broad host range with respect to cell types and species. Integration analysis of foamy virus vector genome into host chromosome reveals a reduced risk for mutating or activating cellular genes when compared to lentiviruses, corroborating the non-pathogenic phenotype of foamy virus infection. We have developed an efficient foamy virus vector system for the present study. The current proposal is a continuation of the use of SFV-1 for effective antiviral therapy against immunodeficiency viruses using novel severe combined immunodeficiency (SCID) mice (NOD/LtSz-scid IL2Rgnull). The NOD/LtSz-scid IL2Rgnull mouse allows the efficient repopulation of human lymphocytes and subsequently eases virus challenge studies. Studies from this proposal will help devise protocols for SFV-1 vector mediated gene therapy against HIV infection in humans