Combination anti-retroviral drug therapy which targets reverse transcriptase and protease functions of human immunodeficiency virus (HIV) results in dramatic reduction in virus lead in HIV-infected subjects and improvement in clinical and hematological parameters. However, drug therapy alone is unlikely to permanently control HIV infection and a novel and highly effective adjuvant therapy is urgently needed. A significant consequence of reduced viral load induced by combination therapy is improve in immune system function, in particular improvement in T cell homeostasis and response to antigens. This normalization in T cell function strongly supports an immunologic approach to adjuvant therapy. We are developing a potent immunological therapy for HIV based on the dendritic cell with the aim of eliciting a broad T cell response to multiple viral antigens. We hypothesize that dendritic cell-based immunotherapy for HIV, in the face of minimal viral load and improved T cell homeostasis through potent drug therapy, will result in specific antiviral immunity and control of virus infection. We will test our hypothesis in the highly relevant rhesus macaque model using simian immunodeficiency virus (SIV). Infected monkeys will be treated with the nucleoside analogue PMPA to induce a rapid and predictable decrease in viremia. In this proposal, we will first characterize dendritic cells propagated from macaque blood and assess several methods for loading virus antigens into dendritic cells based on the capacity to induce broad T cell responses to several viral antigens. We will focus on transduction of cells with a replication-defective lentiviral vector and protein transfer using liposome-mediate delivery. We will then perform in vivo cell tracking experiments using antigen-loaded dendritic cells to ensure that antigen delivery does not impair the capacity of dendritic cells to migrate to lymph nodes and associate with T cells during SIV infection. Finally, we will use antigen-loaded dendritic cells to immunize normal monkeys and then to treat SIV-infected monkeys on long-term antiviral therapy. Animals will be monitored for virologic and immunologic responses during therapy. The ultimate goal of these studies is to produce long-term control of virus replication using the immune system once anti-retroviral drug therapy has ceased. The studies in this Project 1 interact closely with all other Projects in the Program and utilize all Cores. The work will greatly advance our understanding of HIV immunology and our ability to utilize the immune system to combat HIV infection.
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