Foamy Virus Vector for Immunodeficiency Viruses Therapy

描述（由申请方提供）：耐药病毒的流行率不断增加，接受高效抗逆转录病毒治疗的患者中存在潜伏感染的CD 4+细胞，这已成为药物治疗的障碍。对抗HIV感染的一种不断发展的疗法是基因疗法，其涉及引入抗HIV基因以抑制病毒基因表达，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，并且这些策略已经被推到HIV感染的开发治疗的最前沿。尽管这些研究令人鼓舞，但开发安全有效的载体来递送抗病毒基因仍然是一个挑战。目前用于HIV基因治疗的临床试验的载体是低效的，主要原因是它们不能在非分裂细胞中繁殖或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的载体是有希望的，因为它们可以感染分裂和非分裂细胞。尽管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。安全性问题将仍然在公众的视线，即使第三代艾滋病毒载体的可能性，创造一个野生型艾滋病毒被排除。最近观察到用慢病毒载体静脉内治疗的小鼠中肝肿瘤的发展，这进一步使问题复杂化。 泡沫病毒具有使其成为理想载体系统的几个固有特征。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。 与慢病毒相比，泡沫病毒载体基因组整合到宿主染色体中的分析揭示了细胞基因突变或激活的风险降低，证实了泡沫病毒感染的非致病性表型。我们已经开发了一个有效的泡沫病毒载体系统，为本研究。目前的建议是继续使用SFV-1对免疫缺陷病毒进行有效的抗病毒治疗，使用新型严重联合免疫缺陷（SCID）小鼠（NOD/LtSz-scid IL 2 Rgnull）。NOD/LtSz-scid IL 2 Rgnull小鼠允许人淋巴细胞的有效再增殖，并随后简化病毒攻击研究。这项研究将有助于设计SFV-1载体介导的抗人类HIV感染的基因治疗方案

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