In order to develop and test approaches for both active and passive immunization against natural HIV infection, it is imperative to understand how antibody mediates neutralization of HIV. Virus neutralization is a function of at least three variables: the antibody, the target cell and the virus. It is the aim of this proposal to understand how each of these variables contributes to virus/cell interaction and how changes in these parameters affect the ability of antibodies to inhibit virus infectivity. Experiments are designed to explore these variables based on the """"""""Velcro Hypothesis"""""""" which proposes that HIV, like many other viruses, attaches to cells through a multiplicity of molecules on its surface. Thus, the expression and interaction of the various receptors and ligands, on the surface of the virion and on the surface of the target cell, influence the efficiency with which a particular antibody or mixture of antibodies, will prevent infection. To test this hypothesis the investigator has designed experiments that will provide information about how changes in the combination of antibodies, target cells and viruses will affect HIV binding, infectivity and neutralization. The experiments are designed to address four related area:
Aim #1 will define the critical biologic parameters of the antibodies, target cells and viruses commonly used to study HIV neutralization.
Aim #2 will focus on how the choice of antibody, target cell and virus will affect the degree of neutralization measured.
Aim #3 will determine how and which monoclonal antibodies (or combinations of monoclonal antibodies) to HIV and to adhesion molecules are most effective at neutralizing various virus/target cell combinations. Finally, Aim #4 will test sera of immunized animals and humans, and infected humans, for neutralizing antibodies using various virus/target cell combinations. This final section will provide important insights into the role of neutralizing antibodies in protection against infection and the ability of various vaccines to induce neutralizing antibodies.
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