AUTO-ANTI-CD4 ANTIBODIES IN HIV INFECTION

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The role of human CD4 as the receptor for human immunodeficiency virus (HIV) has led to extensive study of the molecular nature of CD4-gpl2O interactions. Data supports the hypothesis that anti-lymphocyte antibodies may play a critical role in the course of HIV disease, either protective or pathogenic. Sera from HIV infected individuals will be screened for anti-CD4 antibodies and those antibodies will be characterized for CD4 binding, blocking of a number of recombinant gpl2O's, and neutralization of infection by distinct viral isolates. The potential role of auto-anti-CD4 in the progression of HIV disease will be assessed by assaying the antisera for immunocytopathic effects. In addition, immunophenotypic profiles of select patients will be followed with particular attention to the presence of auto-antibodies bound to the surface of cells. Continued analyses of protein structure involved in expression of the antibody and envelope glycoprotein binding epitopes on CD4 are proposed using select CD4 mutants. Using these reagents, the molecular nature of interactions between auto-antibodies against CD4 arising during HIV infection will be investigated. The possible existence of molecular mimicry between autologous anti-CD4 antibodies and viral gpl2O will also be evaluated. From select individuals, anti-CD4 antibody producing lymphocytes will be used to generate combinatorial immunoglobulin expression libraries to clone and express the anti-CD4 antibodies. These recombinant Fab's will then be characterized structurally and mapped for binding to native and mutant CD4's. They will be analyzed for their ability to block different recombinant gpl2O's, and to inhibit viral infection in vitro. Structural information relevant to virus/CD4 interactions potentially useful for protection, immune intervention, and/or rational drug design will be obtained through these further molecular characterizations.