HIV-1 infection is usually associated with a quantitative deficiency of CD4 helper/inducer T cells. Patients with HIV-1 infection have severely impaired CD4 helper/inducer T cell function. This is manifested by cutaneous anergy, decreased T cell proliferation to antigens and failure of antigen specific antibody production. The CD4 helper cell defect appears to be qualitative in that immunologic unresponsiveness in HIV-1 infected patients can occur despite normal numbers of circulating CD4 T lymphocytes. This is particularly true in children with maternally acquired HIV infection. A detailed understanding of the CD4 helper cell defect is important for devising rational therapies in HIV infection. We propose to study the CD4 helper T cell activation defect in children with maternally acquired HIV infection by examining: (1) T cell activation via the TCR/CD3-CD4 supramolecular complex. We will measure proliferation, IL-2R expression, and IL-2 synthesis in response to heteroconjugates of anti-CD3 and anti-CD4 mAbs. (2) Signalling via CD4. We will measure (a) proliferation, IL-2R expression and IL-2 synthesis in response to a mitogenic anti-CD4 mAb (mAb B66.6), (b) signal transduction following cross linking of surface C-D4 as evidenced by activation of the CD4 associated tyrosine kinase (p56IcK ) and by phosphorylation of CD3 C zeta. (3) Signalling via TCR/CD3. We will measure, (a) proliferation, IL-2R expression, and IL-2 synthesis in response to anti-TCR and anti-CD3 mAb, (b) signal transduction in T cells stimulated with anti-TCR and anti-CD3 mAbs as evidenced by generation of second messengers, Ca++ fluxes, and activation of protein kinase C, (c) the composition of the TCR/CD3 receptor complex. The results of these studies have important implications for the therapy of HIV infection and for understanding CD4 helper cell defects in immunodeficiency, infection and autoimmunity.
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