Superantigens (SA) are microbial glycoproteins that act as potent T cell activators. They bind to major histocompatibility complex (MHC) class II proteins, but T cell recognition of SA is not restricted by MHC alleles, and there is no requirement for antigen processing, as with regular peptide antigens. Typically, alpha-beta T cell antigen receptors (TCR) of T cells responding to a given SA express the same V beta variable region gene products. Thus SA are also called V beta-selective elements. By preparing a panel of monoclonal antibodies to human V beta gene products, the investigators have developed a novel technique for rapid isolation of homogeneous cell lines expressing the same V beta. These IL-2 dependent non- transformed cells were used as targets for HIV-1 infection in vitro. HIV replication measured by gag encoded p24 varied up to 100 fold depending on V beta expression with V beta 12, but not V beta 6.7a cell lines, supporting high level HIV-1 replication of three divergent isolates. This effect is not MHC restricted and can be blocked with anti-MHC class II mAb. Using ex vivo lymphocytes from seropositive donors they found that V beta 12 cells expressed more gp120 and contained more HIV-l DNA than control V beta subsets. Non-T cells from such donors selectively stimulated a V beta 12 cell line and not a V beta 6.7a cell line consistent with expression of a SA. They propose to (l) define the HIV-1 associated SA using divergent and defective viral isolates. In particular, they will use two isolates with different V beta specificity patterns to produce chimeras and map the gene encoding V beta selectivity; and (2) investigate the functional effects of the HIV-l SA. They propose experiments to compare the HIV-V beta selective element to microbial SA, to examine the effects of the possible SA in vivo in HIV-1 seropositive patients, in HIV-l infected hu/SCID mice, and in TCR V beta 12 and TCR V beta 6.7a transgenic mice. They suggest that blocking the effects of an HIV-1 SA in vivo could represent a novel therapeutic approach to AIDS.
Showing the most recent 10 out of 18 publications
