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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL061960-01
Application #
2764073
Study Section
Special Emphasis Panel (ZHL1-CSR-R (S1))
Project Start
1998-09-20
Project End
1999-08-31
Budget Start
1998-09-20
Budget End
1999-08-31
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
201373169
City
New York
State
NY
Country
United States
Zip Code
10065
Lago, P M; Boechat, N; Migueis, D P et al. (2012) Interleukin-10 and interferon-gamma patterns during tuberculosis treatment: possible association with recurrence. Int J Tuberc Lung Dis 16:656-9
Perez-Sweeney, Beatriz; DeSalle, Rob; Ho, John L (2010) An introduction to a novel population genetic approach for HIV characterization. Infect Genet Evol 10:1155-64
Ho, John L; Lapa e Silva, Jose Roberto (2010) Promotion of a down-modulated lung immune state may be a strategy by M. tuberculosis to foster active disease and persistence. Discov Med 9:34-41
Almeida, Alexandre S; Lago, Patricia M; Boechat, Neio et al. (2009) Tuberculosis is associated with a down-modulatory lung immune response that impairs Th1-type immunity. J Immunol 183:718-31
Lazzarini, Luiz Claudio Oliveira; Huard, Richard C; Boechat, Neio L et al. (2007) Discovery of a novel Mycobacterium tuberculosis lineage that is a major cause of tuberculosis in Rio de Janeiro, Brazil. J Clin Microbiol 45:3891-902
Huard, Richard C; Fabre, Michel; de Haas, Petra et al. (2006) Novel genetic polymorphisms that further delineate the phylogeny of the Mycobacterium tuberculosis complex. J Bacteriol 188:4271-87
Bonecini-Almeida, M Gloria; Ho, John L; Boechat, Neio et al. (2004) Down-modulation of lung immune responses by interleukin-10 and transforming growth factor beta (TGF-beta) and analysis of TGF-beta receptors I and II in active tuberculosis. Infect Immun 72:2628-34
Huard, Richard C; Chitale, Sadhana; Leung, Mary et al. (2003) The Mycobacterium tuberculosis complex-restricted gene cfp32 encodes an expressed protein that is detectable in tuberculosis patients and is positively correlated with pulmonary interleukin-10. Infect Immun 71:6871-83
Huard, Richard C; de Oliveira Lazzarini, Luiz Claudio; Butler, W Ray et al. (2003) PCR-based method to differentiate the subspecies of the Mycobacterium tuberculosis complex on the basis of genomic deletions. J Clin Microbiol 41:1637-50