The overall goal of this proposal is to develop an understanding of the interaction of complement-receptor expressing cells with either complement-treated HIV-infected cells or complement-treated HIV. After infection with HIV, cells express viral proteins on their surface which can lead to cell-surface deposition of complement breakdown products. Since many immune effector cells express receptors for-these complement breakdown products, the complement activation by infected cells could potentially have a great impact on infected cell survival or function. Cells that express complement receptors may also interact differently with HIV after it is exposed to complement; HIV can also potentially activate complement in vivo. The recent discovery that some CD4+ cells express complement receptors (CR2) suggests that this subset could be infected more easily by virus that bears complement-breakdown products on its surface. To address these problems, we specifically propose to; 1. Determine the ability of HIV-infected cells to activate complement. The complement pathway(s) by which complement is activated and requirements for cell type, virus strain and specific antibody will be assessed. Flow cytometric methods will be used. 2. Study the result of complement activation by HIV-infected cells on their destruction by complement-receptor positive effector cells. Macrophages, NK cells, and cells which mediate ADCC will be evaluated for complement-enhanced killing of infected targets. 51Cr-release, trypan blue and propidium iodide cytotoxic assays will be used to assess killing. 3.Determine the effect of complement activation by HIV on tropism for complement receptor positive cells. We will focus on the interaction of HIV with the recently described CR2+CD4+ subset of lymphocytes. Flow cytometric sorting and in vitro infection of uninfected cells will be performed. Possible in vivo infection of these cells will be assessed by obtaining them from infected persons and flow cytometrically analyzing and sorting to obtain subsets followed by HIV provirus DNA quatitation. The studies proposed here will help gain knowledge of the interaction between complement and HIV. An understanding of this interaction may enable the design of drugs or vaccine strategies which will bolster or supplement the ability of oomplement to benefit the infected person while avoiding any harmful effects.
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