Evaluation of Therapies for Preventing the Onset of AIDS

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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.