Evaluation of Therapies for Preventing the Onset of AIDS

人类免疫缺陷病毒型（HIV-1）是高度细胞病变，但在发展为艾滋病之前，在持续感染的状态下，可保持数月至数年的临床沉默。HIV-1感染的一个特征是HIV-1分离株在持续期间细胞病变的异质性。因此，在HIV-1感染后，调节细胞死亡或潜伏和/或在被感染的宿主细胞中持续存在的机制对于我们了解该疾病的发病机制和开发有效的疫苗至关重要。我们利用人类CD4^+T细胞系和HIV-1携带者衍生的外周血单个核细胞揭示了异常的HIV-1生命周期。特别是HIV-1 vif、vpr或vpu突变体感染后，在短暂细胞溶解后产生持续感染。然而，nef突变体感染未产生任何持续状态，表明nef对持续状态的产生至关重要。因此，我们将重点放在了Nef函数上。到目前为止，我们发现Nef在持续感染的细胞上表达，并且Nef可以与未感染的CD4^+ T细胞相互作用，从而降低细胞生长。我们还揭示了nef基因的准种，即在CD8 + T细胞存在或不存在的情况下，从同一携带者分离的HIV-1病毒的nef之间存在异质性。此外，Nef被证明具有激活潜伏感染的HIV-1的能力。最后，在BALB/c小鼠中发现了至少3个不同于具有这种免疫功能的结构域的表位诱导细胞毒性T淋巴细胞。

Human immunodeficiency virus type (HIV-1) is highly cytopathic, but can remain clinically silent for months to years, in a state of persistent infection, before the development of AIDS.A characteristic feature of HIV-1 infection is the heterogeneity of the cytopathicity of HIV-1 isolates in the persistent period. Therefore, the mechanisms that regulate either cell death or latency and/or the persistence in the infected host cells after HIV-1 infection are essential to our understanding of the pathogenesis of the disease and for development of effective vaccine.We have revealed an abnormal HIV-1 life cycle using human CD4^+T cell lines and HIV-1 carrier-derived peripheral blood mononuclear cells. Especially, the infection with HIV-1 vif, vpr or vpu mutants generates persistent infection after transient cytolysis. However, the infection with the nef mutant did not generate any persistent state, indicating that nef is essential for the generation of persistent state. Therefore, we focused on Nef functions. So far, we showed that Nef is expressed on persistently infected cells and the Nef can interact with uninfected CD4^+ T cells which can reduce the cell growth. The nef gene quasispecies were also revealed, i.e.the heterogeneity between the nef of HIV-1 isolated from the same carrier in the presence or absence of CD8^+ T cells. Furthermore, Nef was shown to have a ability to activate the latently infected HIV-1. Finally, that at least 3 epitopes, which differed from the domains showing such immunological functions, were identified to induce cytotoxic T lymphocytes in BALB/c mice.