HIV is tropic for the helper-inducer (OKT4/Leu-3) subset of T lymphocytes. Recent experiments investigating the basis of this tropism have demonstrated a specific binding of the viral 120K envelope protein to T4 molecules on the surface of helper T-cells. As the T4 glycoprotein is expressed predominately on the helper- inducer subpopulation of T-cells, this specific binding is likely to be a major determining factor in the selective lymphotropism of HIV and the T4 glycoprotein may function as the main or sole component of the viral receptor on T-cells. The acquired immune deficiency syndrome (AIDS) is frequently complicated by a clinically distinct encephalopathy which has been termed the AIDS dementia complex. Viral studies on brain tissue from AIDS patients indicate that this syndrome probably results from a direct HIV infection of the brain and thus, that this virus may also be tropic from cells in the central nervous system. The basis for this tropism is presently unknown and the major goal of the proposed research is to establish the role that the T4 glycoprotein plays in the neurotropism of HIV and the pathogenesis of AIDS dementia. Northern blot hybridization analysis has detected two distinct T4 messages in human brain. One is 3.2 kb in length and identical in sequence to the T4 message synthesized by helper-inducer T-cells. The other is 2.0 kb in length and its relationship to the 3.2 kb message is presently unknown. Nuclease protection and cDNA cloning experiments will be performed to establish the structure of the 2.0 kb T4 message. In addition, the ability of the protein encoded by the 2.0 kb message to function as a receptor for HIV will be tested in transfection experiments and antibody blocking assays. Potential targets for HIV infection in the brain will be identified by performing in situ hybridizations to establish the cell type distribution of the 3.2 and 2.0 kb T4 messages in brain. Experiments are also proposed to generate an animal model for studies on the pathogenesis of AIDS and AIDS dementia. The animal is a transgenic mouse that appropriately expresses T4, the receptor for HIV, in T-cells, macrophages, and the brain.
| Blum, M D; Wong, G T; Higgins, K M et al. (1993) Reconstitution of the subclass-specific expression of CD4 in thymocytes and peripheral T cells of transgenic mice: identification of a human CD4 enhancer. J Exp Med 177:1343-58 |
