This grant focuses on the role of idiotype-anti-idiotype complexes (both internal image and non-internal image) in the peripheral destruction of platelets in HIV-1-related immunologic thrombocytopenic purpura (HIV-1-ITP). HIV-1-ITP patients have markedly elevated levels of PEG-precipitable immune complexes in their sera and on their platelets. These are macromolecular complexes containing IgG, IgM, C3, and anti-HIV-1gp120 idiotype-anti-idiotype complexes (Ab1-Ab2). Ab2 correlates with thrombocytopenia, r=0.9, P is less than 0.001. Internal image idiotype-anti-idiotype complexes bind 10 fold greater to platelets, than non-internal image complexes. HIV-1-ITP patients also have markedly elevated levels of %CD5+ B cells, implicated in autoimmunity by the production of a low affinity multispecific predominantly IgM antibody against self, other antigens and the Fc portion of IgG. These Ab's have been implicated in the production of a primordial idiotype-anti-idiotype network. %CD5+ B cells correlated with thrombocytopenia, r=0.5, p is less than 0.01. We propose to: I. Study the mechanism of binding of PEG-precipitable immune complexes to platelets (internal image vs non-internal image). It is not via the platelet Fc receptor. Is it via a C3b/C3bi receptor?. II. Study the mechanism of binding of affinity-purified Ab1-Ab2 complexes + complement to platelets. III. Investigate the possible presence of other idiotype-anti-idiotype IgG complexes as well as IgM-IgG complexes or HIV-1 virus-Ab complexes. IV. Determine whether CD5+ B cells of HIV-1-ITP patients secrete anti-idiotype and/or anti-Fc antibodies against HIV-1 patient's IgG as well as antibodies against platelets. V. Study the effect of PEG-precipitable complexes and laboratory-assembled affinity-purified complexes on the adhesive and phagocytic interaction of platelets with monocytes. Study the role of the LeuCAM integrins in platelet-monocyte adhesion and phagocytosis by employing specific anti-functional MoAb's. These studies could help understand the basic immunologic pathophysiology of HIV-1 infection as well as devise clinical strategies for the treatment and/or eradication of HIV-1 -ITP.
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