The AIDs-retroviruses (HTLV-III, LAV, and ARV) have shown a tropism for selectively infecting the T-lymphocyte subpopulation identified by the monoclonal antibodies OKT4 or Leu-3a. This specificity is mediated at least in part by the association of the virus with the T4 antigen expressed on the surface of these cells. The structures on the virus which bind to this antigen, and cellular factors which regulate the expression of the T4 molecule and influence cytopathic effects which follow viral infection remain to be determined. This proposal will investigate the interaction of HTLV-III with T4 cells in three areas. 1) Efforts will be made to identify the viral-associated determinants which are required for binding to T4 lymphocytes. Preliminary observations have suggested that the virus may selectively incorporate HLC class II (DR) determinants during budding from the cell surface. The possibility that DR antigens of cellular origin are utilized by the virion during infection of the T4 cell will be further investigated. In addition, monoclonal anti-T4 antibodies which inhibit viral binding will be used to produce anti-idiotypes as a strategy for identifying the structures on the virion which bind to T4. 2) Factors which regulate the expression of the T4 antigen and cellular receptors for HTLV-III will be evaluated. This proposal will further explore the findings that phorbol esters modulate both the expression of the T4 molecule and reduce the susceptability of T4 cells to HTLV-III infection. Possible interactions between viral penetration/infection and the activation protein kinase-C will be investigated, in addition to findings that phorbol esters alter the ability of T4 cell lines which are stably infected with HTLV-III to support viral production. 3) Recent findings have indicated that in addition to cell death, AIDS retroviruses may also produce a non-cytotoxic, persistent infection of normal peripheral blood T4 lymphocytes. This has suggested that a range of biological consequences may occur following HTLV-III infection. Cytopathic effects of HTLV-III infection will be evaluated in T4 cell lines specifically responsive to antigen, alloantigen or mitogen. Efforts will be made to determine host factors which influence cytotoxicity following infection, and functional consequences for the T4 cell when non-cytotoxic infection occurs.
| Hoxie, J A; Rackowski, J L; Haggarty, B S et al. (1988) T4 endocytosis and phosphorylation induced by phorbol esters but not by mitogen or HIV infection. J Immunol 140:786-95 |
| Gonzalez-Scarano, F; Waxham, M N; Ross, A M et al. (1987) Sequence similarities between human immunodeficiency virus gp41 and paramyxovirus fusion proteins. AIDS Res Hum Retroviruses 3:245-52 |
| Hoxie, J A; Fitzharris, T P; Youngbar, P R et al. (1987) Nonrandom association of cellular antigens with HTLV-III virions. Hum Immunol 18:39-52 |
| Hoxie, J A; Alpers, J D; Rackowski, J L et al. (1986) Alterations in T4 (CD4) protein and mRNA synthesis in cells infected with HIV. Science 234:1123-7 |
