Research Project
3546741
The causative agent of the acquired immune deficiency syndrome (AIDS), an inevitably fatal disease, appears to be a member of a closely related family of RNA viruses, called human T- lymphotropic virus type III (HTLV-III) or lymphadenopathy- associated virus (LAV). The host range of this virus is associated with cells which bear the surface glycoprotein T4. Clinical studies suggest that the progression of disease can be correlated with depletion of a functional class of immune system regulatory cells, T-helper lymphocytes, which display the T4 surface protein, and that this T-cell depletion, with ensuring immunological compromise, may result from recurrent cycles of infection and growth. This suggests therapeutic strategies for the treatment of AIDS and pre-AIDS. First, we propose that recombinant soluble T4 protein will serve to sequester free HTLV-III/LAV by acting as soluble virus receptor, and that this will retard or completely inhibit virus growth in infected individuals. A second approach is to combine the recombinant soluble T4 gene with human immunoglobulin (Ig) constant region genes such that expression of the Ig/T4 sequences in animal cells produces a chimeric antibody molecule able to recognize and bind HTLV-III/LAV-infected cells that express virus envelope surface antigen. Ig/T4 binding to infected cells should target these cells for complement-mediated cell-killing, which will diminish the spread of virus. Finally, a strategy to inactivate virus by the formation of immune complexes that is based on the theory of complementary shapes is proposed. The plan is to raise antiidiotype antibodies against anti-T4A, an antibody that recognizes the apparent HTLV-III/LAV receptor, T4 antigen. Such antibodies could be functionally equivalent to T4 antigen for binding to virus, and therefore compete with T4-bearing cells for virus. Antiidiotype-virus complexes could be subsequently removed by immune clearance. The steps toward producing recombinant soluble T4, the Ig/T4 chimeric antibody, and antiidiotypic anti-T4, and testing their potential as therapies in the treatment of AIDS are straightforward and they are outlined in this proposal.
