Infection of the Macrophage by the Human Immunodeficiency Virus (HIV) is an important factor in the pathology and resistance to chemotherapy observed in AIDS. Since liposomes are actively phagocytosed by macrophages, the ability of liposome encapsulated anti-viral compounds to inhibit HIV replication and persistence in cultured Human peripheral blood monocytes (PBM) will be studied. We will also characterized the factors that control liposome binding and uptake to Human PBM that have been infected with HIV. Liposomes, containing various anti-viral agents, will be prepared by established methods and characterized as to size, encapsulation efficiency and stability of the liposome-drug combination. The compounds to be tested include reverse transcriptase inhibitors, anti-HIV sense oligonucleotides and HIV protease inhibitors. Novel pH sensitive liposome combinations will be used to deliver the high molecular weight compounds into the cytoplasm of the macrophage. The liposome encapsulated anti-viral agents will be tested for HIV specific killing/virus neutralization in both acute and chronic HIV infected PMB. Protection from HIV infection in cultured PBM will be quantitated by measuring changes in cytoplasmic HIV p24 antigen in the presence and absence of liposome encapsulated drugs. To increase macrophage-liposome interactions, liposomes with appropriate ligands will be targeted to either the mannosyl or Fc receptor on the macrophage. To achieve specific targeting to HIV infected macrophages, either anti-envelope human monoclonal antibodies or synthetic peptides from the region(s) of CD4 that interact with the envelope glycoprotein will be attached to the liposome surface. Emphasis will be placed on treating chronically infected PBM. Anti-viral effects will be correlated with cell association, internalization and metabolism of the liposome and its associated encapsulated drug. Fluorescence markers and radiolabeled compounds will be employed as tracers to quantitate liposome-cell interactions.
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