Faculty Bibliography

Taken together, our studies suggest a mechanism of AIDS virus infection that initially involves the specific association of the AIDS virus with T4 molecules on the cell surface. This association does not require additional T-cell-specific molecules and can be demonstrated on both B lymphocytes and epithelial cell lines. The T4-AIDS virus complex is likely to be internalized in endosomes via receptor-mediated endocytosis. The virus can then fuse with the vacuolar membrane, releasing the viral nucleocapsid into the cytoplasm to undergo uncoating. Viral replication does not appear to require the environment of a T lymphocyte because active infection is also observed in human T4+ B lymphocytes and epithelial cell lines. Moreover, the T4 gene is expressed in the brain as well as in lymphocytes, providing an explanation for the dual neurotropic and lymphotropic character of the virus. In this manner, a T-lymphocyte surface protein thought to be important in mediating effector cell-target cell interactions has been exploited by a human lymphotropic virus to target the AIDS virus specifically to populations of T4+ cells

The surface glycoproteins T4 and T8 define different functional subsets of T lymphocytes and may act as recognition molecules mediating appropriate interactions between the T cell and its target. Previously we employed gene transfer and subtractive hybridization to isolate a T8 cDNA; now we have isolated and sequenced a cDNA clone encoding the T4 molecule. The deduced protein sequence reveals that T4 is an integral membrane protein that shares significant amino acid and structural homologies with members of the immunoglobulin supergene family. The overall structure of T4 consists of an N-terminal variable (V)-like domain, a joining (J)-like region, a third extracellular domain, a membrane-spanning region homologous to class II MHC beta-chains, and a highly charged cytoplasmic domain. Comparison of the protein sequences deduced from the T4 and T8 cDNAs reveals structural similarities consistent with their postulated role as recognition molecules, as well as differences suggesting that the two proteins recognize different structures on the target cell

The T cell surface glycoproteins T4 and T8 are thought to mediate efficient cell-cell interactions in the immune system and in this way may be responsible for the appropriate targeting of subpopulations of T cells. We have used gene transfer combined with subtractive hybridization to isolate both cDNA and functional genomic clones encoding the T8 protein. The sequence of the cDNA reveals that T8 is a transmembrane protein with an N-terminal domain which shares significant homology to immunoglobulin variable region light chains. This immunoglobulin-like structure is likely to be important in the function of T8 during differentiation and in the course of the immune response

The study of immune phenomena dependent on the major histocompatibility complex (MHC) would be greatly simplified by the use of MHC antigen-containing liposomes in various functional systems. Towards this end, we have constructed unilamellar phosphatidylcholine liposomes containing H-2 and Ia antigens. These molecules were not simply trapped within the aqueous compartment of the liposome as assessed by their accessibility to papain digestion. They were shown to be integrally inserted in the liposome bilayer because they could not be dissociated from the liposome with high salt and EDTA concentrations but could be solubilized by detergent. A sensitive radioimmunoassay showed that the Ia molecules were antigenically active in the liposome environment. Both Ia and H-2 antigens could be immunoprecipitated from detergent-solubilized liposomes. By comparing liposome-associated Ia activity in the presence and absence of detergent and by showing accessibility of the Ia antigens to papain, it was concluded that the majority of Ia antigens were exposed on the external surface of the liposome. These results suggest that the orientation of MHC antigens in liposomes closely parallels their natural orientation in the cell membrane