Evaluation of defective HIV as factors for AIDS pathogenesis

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Infection with human immunodeficiency virus type 1 (HIV-1) leads to AIDS within about 10 years. There are several features ascribed to the AIDS pathogenesis : 1) clinical staging of the disease is significantly correlated with HIV-1 load, 2) potent antiretroviral drugs produce a dramatic drop in plasma viremia, and 3) the anti-HIV-1 drugs are effective for HIV-1 derived from short-lived productively infected cells, but not so effective for HIV-1 derived from latent reservoirs. We have found that infection by HIV-1 with mutations at accessory genes such as vif, vpr, and/or vpu can establish persistent or latent infection in human T-cell line, MT-4. During serial passage of wild-type HIV-1, similar mutations naturally occurred and established latent infection. In contrast, HIV-1 with mutation at nef did not establish persistent infection, indicating that nef gene is necessary for persistent infection of HIV-1. We also found that soluble Nef protein has a function to reactivate HIV-1 from … More latency. In additon, we have found that HIV-1 virion adsorption can generate effector cells to induce apoptosis in bystander uninfected T-cells. These phenomena seem to be important to understand HIV-1-induced pathogenesis. However, all these results were obatined only by characterization of HIV-1 clade B.On the other hand, the HIV-1 spreading in South Eastern Asia including Thailand is clade E.In this international joint research project, we have further characterized HIV-1 clade E from Thai HIV-1 carriers. The full-length sequence of Thai E HIV-1 was first reported in 1996. The E virus for the sequence was isolated from a 21-year-old Thai man, who was determined to be seropositive for HIV-1 at 1990. However, we found that the polymerase chain reaction with primers prepared according to the reported sequence was difficult to amplify the clade E HIV-1 in most of the blood samples recently collected from HIV-1 clade E-seropositive asymptomatic carriers in Thailand, indicating advanced mutations in currently spreading Thai E HIV-1. We could amplify Thai HIV-1 sequences at nef from four isolates of two clade B-seropositive and two E-seropositive carriers using primers according to clade A sequence. The results showed 6.43% genetic variability between two HIV-1 clade E isolates and -13% genetic variability between clade B and E HIV-1 in Thailand. In fact, 13 murine monoclonal antibodies prepared by immunization with clade B Nef protein did not cross-react with these clade E HIV-1 isolates. On th other hand, we confirmed that apoptosis in bystander T-cells was also observed in the blood T-cells prepared from Thai clade E infected carriers by similar mechanism as we have observed by in vitro studies using clade B HIV- particle adsorption. Less