Memory CD4+ T lymphocytes are preferred targets for HIV-1. However, memory T cells are normally inefficiently recruited to lymphoid organs, where HIV-1 replication mostly occurs in the early stages of disease. Recent studies from several laboratories, including our own, identified cyclophilins, a group of highly abundant cellular proteins mostly known as receptors for immunosuppressive drug, cyclosporin A, as potential regulators of leukocyte trafficking. Importantly, one of the cyclophilins, cyclophilin B (CypB), has been shown to induce chemotaxis and specific adhesion of memory CD4+ T cells to the extracellular matrix. Our studies identified CD147 as a cellular receptor for both CypA and CypB. We now propose to investigate the role of cyclophilin-CD147 interaction as a regulator of CD4+ T cell recruitment to HIV-infected lymphoid tissue. Our working hypothesis is that interaction of CypB or CypA (secreted by live cells or released from dead cells) with CD147 on memory CD4+ T cells attracts these cells to lymphoid organs, thus supplying new targets for the virus. To test this hypothesis, we propose the following Specific Aims:
Specific Aim 1. To analyze CD147 expression on T lymphocytes and cyclophilin production by lymphoid tissue.
Specific Aim 2. To determine the role of cyclophilin-CD147 interaction in T cell recruitment to lymphoid organs. The feasibility studies proposed in this application represent a high degree of innovation because they explore a novel factor in HIV pathogenesis. Therefore, the R03 mechanism appears highly appropriate. If proven, this hypothesis will serve as a foundation for a new research program, which might suggest novel approaches to treatment of HIV-1 infection.
| Yurchenko, Vyacheslav; Constant, Stephanie; Bukrinsky, Michael (2006) Dealing with the family: CD147 interactions with cyclophilins. Immunology 117:301-9 |
