The overall goal of this project is to analyze in detail the humoral immune response to HtLV-I among intravenous drug users (IVDU) and other individuals who have been exposed to this virus. Immunogenic epitopes of HTLV-I will be identified through the generation and characterization of virus specific human monoclonal antibodies (HMAbs) using peripheral B cells obtained from HTLV-I seropositive IVDU and other individuals. In addition to subsequent biochemical characterization of their target molecules, HMAbs will be tested for their ability to mediate virus neutralization, inhibition of virus binding, complement mediated lysis, antibody dependent cell mediated cytotoxicity and to inhibit HTLV-I induced T cell activation. Using a HMAB to HTLV-I gp46 glycoprotein (0.5 alpha) to immunoscreen a lambda gt11 expression library derived from HTLV-I genome, we have isolated a fragment, MTA-4, and determined that it is a unique and immunodominant epitope among individuals exposed to HTLV-I. Since HMAb 0.5 alpha is known to inhibit HTLV-I induced mitogenic stimulation, an immediate goal of this project is to determine whether the MTA-4 epitope stimulates T cells and/or is responsible for virus binding to T cells. Because HTLV-I viral antigens expressed on the surface of infected cells are probable mediators of the immune response, a particular emphasis will be placed on the development of HMAbs to these targets. Because of structural homology between HTLV-I and HTLV-II, unique and shared retroviral epitopes as identified by these HMAbs will also be two viruses. These studies should allow us to define a series of immunogenic epitopes of HTLV-I and possibly, the virus receptor. The results should prove useful in the design of anti-HTLV-I therapies as well as a potential HTLV-I vaccine.
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