Foamy Virus Vector for Immunodeficiency Viruses Therapy

描述（由申请人提供）：随着多种联合药物治疗的出现，延长艾滋病患者的生命取得了重大进展。然而，在未接受抗逆转录病毒治疗的慢性感染者以及正在接受高效抗逆转录病毒治疗（HAART）的慢性感染者中，已证实存在潜伏感染的、静止的CD4细胞携带具有复制能力的HIV。不能靶向潜伏感染的静止细胞是药物治疗的主要障碍。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的表达，从而限制HIV的复制。已经建立了许多不同的抗艾滋病毒基因治疗方法来抑制病毒复制，并且该策略已推动到艾滋病毒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，因为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。尽管慢病毒在人类基因治疗中的可行性仍在利用动物模型进行探索，但慢病毒载体存在导致人类疾病的潜在风险。基于动物慢病毒的载体已被认为是人类基因治疗中HIV载体的替代品。然而，最近关于FIV可感染具有临床症状的非人类灵长类动物的报告表明，使用基于动物慢病毒的载体进行人类基因治疗存在风险。此外，尽管慢病毒载体可以在非分裂细胞中实现有效和持续的转导和表达，但它们不能有效地转导静止的CD4细胞，而在静止的CD4细胞中，HAART治疗失败了。泡沫病毒有几个固有的特征，使它们成为理想的载体系统。目前的建议是继续开发新的泡沫病毒载体，用于在严重联合免疫缺陷（SCID）小鼠中有效地抗病毒治疗猴免疫缺陷病毒（SIV）。这一建议的研究将有助于设计SFV-1载体介导的针对猴子SIV感染的基因治疗方案，并最终用于人类HIV感染。

DESCRIPTION (provided by applicant): Significant progress has been made with the advent of multiple-combination drug therapy to prolong the lives of AIDS patients. However, the presence of latently infected, resting CD4 cells carrying replication-competent HIV has been demonstrated in chronically infected individuals who are antiretroviral naive as well as in those who are receiving highly active antiretroviral therapy (HAART). The failure to target the latently infected resting cells is a major impediment in 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 the HIV replication. Many different anti-HIV gene therapy approaches have been established to inhibit virus replication and the strategy has 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 as they cannot 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 using animal models, lentivirus vectors suffer from the potential risk of causing disease in humans. Vectors based on animal lentiviruses have been implicated as an alternative to HIV vectors for human gene therapy. However, the recent report that FIV can infect non-human primates with clinical signs indicates the risk associated with the usage of animal lentivirus based vectors for human gene therapy. Furthermore, even though lentivirus vectors can achieve effective and sustained transduction and expression in non-dividing cells they cannot efficiently transduce resting CD4 cells, where HAART therapy failed. Foamy viruses have several inherent features that make them an ideal vector system. The current proposal is a continuation in the development of novel foamy virus vectors for effective antiviral therapy against simian immunodeficiency virus (SIV) in severe combined immunodeficiency (SCID) mice. Studies from this proposal will help devise protocols for SFV-1 vector mediated gene therapy against SIV infection in monkeys and eventually for HIV infection in humans.