description) Despite antiretroviral therapy, break-through HIV-viremia occurs, a process that is associated with immune activation and inflammation. Recent data indicate that vascular endothelia is a crucial site for inflammation and HIV infection. HIV infection is associated with leukocyte recruitment and adhesion on endothelia; thus, increased leukocyte recruitment may enhance HIV and vice versa. We hypothesize that HIV infection initiates a series of inflammatory events through the vascular endothelium to cause endothelium dysfunction, retarded wound healing, and HIV replication. Infected endothelia may upregulate adhesion molecules to promote leukocyte recruitment, increased release of chemokines to aid leukocyte transmigration through endothelium, and amplify the whole inflammatory responses. In addition, soluble proteins of HIV may similarly activate an array of endothelial cell genes to synergize with this inflammatory response. We speculate that the global effect of these inflammatory reactions subsequent to HIV infection causes endothelial cell dysfunction. Our studies showed a crucial role of inflammatory signals in upregulating HIV replication, and vascular endothelium in inflammation, recruitment of leukocytes and homing of hematopoietic cells. Utilizing lipophosphoglycan (LPG) of Leishmania as a molecular tool, we found that LPG selectively suppressed cytokine genes expression, endothelia activation (e.g., adhesion molecules, chemokine (MCP-1), chemokine receptor (CXCR4), and HIV production through blockage of NfkB- and Tat -dependent mechanisms. We therefore propose to study 1) cell activating effect of HIV proteins or virions and HIV-bearing leukocytes in terms of up-regulating the expression of adhesion molecules, MCP-1 and CXCR4, 2) the role of leukocyte adhesion upon their co-receptor on endothelium in amplifying endothelial dysfunction, 3) specificity for these processes in regulating endothelial cell gene transcription, and 4) to utilize a unique molecular tool (LPG) to uncouple HIV replication from host activation, and suppress endothelial dysfunction.
The specific aims are to: 1) characterize HIV induced endothelial cell dysfunction, 2) delineate mechanisms to suppress HIV activation, and 3) characterize and determine molecular events in leukocytes and endothelial cell interactions in HIV infection. Findings from this proposal identifying mechanisms in HIV mediated endothelial cell dysfunction, and mechanisms to interrupt viral replication without affecting host immune gene expression will likely translate into novel targets to develop new therapies.
