A major problem with antiviral agents developed to control HlV infections is their inability to reach the sites of infection at sufficiently high concentrations, and their toxicity at the doses necessary to achieve activity. For example, the reverse transcriptase inhibitor AZT causes bone marrow suppression, while ddC causes peripheral neuropathy. Certain agents that are effective in inhibiting HIV gene expression or maturation, or cleaving viral RNA sequences, such as antisense oligodeoxynucleotides (oligo-dN), protease inhibitors or ribozymes, may have limited access to the cytoplasm, or may be too hydrophobic or prone to enzymatic degradation to be delivered effectively to sites of HIV infection in vivo. Delivery of drugs or immunomodulators encapsulated in liposomes (phospholipid vesicles) can reduce toxicity and achieve more effective doses in tissues of interest. The recent development of liposomes with prolonged circulation in the bloodstream (called """"""""stealth liposomes""""""""), with the ability to extravasate into tissues including lymph nodes, bone marrow, skin and intestines and to localize in tissue macrophages, has also provided the potential to deliver encapsulated antiviral agents to HIV-infected cells both in the circulation, and in tissues. We propose to establish the effectiveness of liposome-encapsulated antiviral agents against HIV infection in lymphocytes and macrophages. Specifically: (i) We will test the hypothesis that the delivery of certain antiviral drugs to HIV-1-infected macrophages via liposomes is more effective in inhibiting virus production in these cells than the free drug. Our studies will concentrate on the use of inhibitors of viral protein synthesis and assembly. (ii) We will determine whether liposomes with prolonged circulation in the bloodstream, and the ability to extravasate into tissues and localize in tissue macrophages (""""""""stealth liposomes""""""""), can effectively deliver antiviral agents to HIV-infected macrophages, and inhibit virus production. (iii) We will test the hypothesis that ligand-mediated targeting of anti viral-loaded liposomes to lymphocytes productively infected with HIV-l will enhance the therapeutic effect of the drugs. (iv) We will investigate whether liposome types that fuse with HIV-l, and encapsulating antiviral agents, can inhibit the infectivity of primary isolates of HIV- l, and whether such liposomes can inactivate preformed virions in macrophage vacuoles.
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