HIV-1 infection and AIDS remain a major worldwide public health problem, and efforts toward understanding how the virus causes immunodeficiency and toward developing novel therapies are still required, despite the advent of highly active antiretroviral therapy (HAART). Increased homing of T cells to lymphoid tissues (LTs) during HIV-1 infection, with loss through direct infection/killing or bystander killing, has been proposed as one mechanism contributing to the development of immunodeficiency. In addition, increased homing of CD4+ T cells and its amelioration following HAART have been demonstrated in HIV-1- infected patients. The causes and consequences of altered homing of leukocytes to LTs are not fully understood and these issues constitute a major focus of this proposal. A comprehensive understanding of the mechanisms that lead to changes in homing to LTs will identify possible targets for immunotherapy. Our overall hypothesis for these studies is that alterations in chemokine expression in LTs contribute to the development of immunodeficiency during HIV-1 infection. Using the SIV/macaque model system, we have made initial observations regarding the alteration of chemokine expression in lymph nodes (LNs) and spleen, but comprehensive analyses are required to fully understand the magnitude of alterations and their causes and consequences. Based on our initial findings we have proposed a model for type 1, IFN-y-driven positive feedback loops that sustain the ongoing recruitment of type 1 T cells into LTs. However, this model has not been addressed experimentally and we propose to do exactly this by therapeutically modulating the recruitment of cells into LTs during SIV infection.
The Specific Aims of this proposal are to: (1) Define alterations in the networks of chemokines in macaque LTs during pathogenic SIV infection; (2) Determine the biochemical properties of inflammatory and homeostatic macaque chemokines that could be involved in HIV/SIV immunopathogenesis; and (3) Determine the virologic and immunologic effects of systemic treatment of SIV infected macaques with chemokine receptor antagonists.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI060422-04
Application #
7384468
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Embry, Alan C
Project Start
2005-03-01
Project End
2010-02-28
Budget Start
2008-03-01
Budget End
2009-02-28
Support Year
4
Fiscal Year
2008
Total Cost
$496,823
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Public Health
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Gopal, Radha; Monin, Leticia; Torres, Diana et al. (2013) S100A8/A9 proteins mediate neutrophilic inflammation and lung pathology during tuberculosis. Am J Respir Crit Care Med 188:1137-46
Gopal, R; Rangel-Moreno, J; Slight, S et al. (2013) Interleukin-17-dependent CXCL13 mediates mucosal vaccine-induced immunity against tuberculosis. Mucosal Immunol 6:972-84
Lucero, Carissa M; Fallert Junecko, Beth; Klamar, Cynthia R et al. (2013) Macaque paneth cells express lymphoid chemokine CXCL13 and other antimicrobial peptides not previously described as expressed in intestinal crypts. Clin Vaccine Immunol 20:1320-8
Slight, Samantha R; Rangel-Moreno, Javier; Gopal, Radha et al. (2013) CXCR5? T helper cells mediate protective immunity against tuberculosis. J Clin Invest 123:712-26
Qin, Shulin; Junecko, Beth A F; Lucero, Carissa M et al. (2013) Simian immunodeficiency virus infection potently modulates chemokine networks and immune environments in hilar lymph nodes of cynomolgus macaques. J Acquir Immune Defic Syndr 63:428-37
Qin, Shulin; Alcorn, John F; Craigo, Jodi K et al. (2011) Epigallocatechin-3-gallate reduces airway inflammation in mice through binding to proinflammatory chemokines and inhibiting inflammatory cell recruitment. J Immunol 186:3693-700
Qin, Shulin; Fallert Junecko, Beth A; Trichel, Anita M et al. (2010) Simian immunodeficiency virus infection alters chemokine networks in lung tissues of cynomolgus macaques: association with Pneumocystis carinii infection. Am J Pathol 177:1274-85
Qi, Yanjun; Dhiman, Harpreet K; Bhola, Neil et al. (2009) Systematic prediction of human membrane receptor interactions. Proteomics 9:5243-55
Reinhart, Todd A; Qin, Shulin; Sui, Yongjun (2009) Multiple roles for chemokines in the pathogenesis of SIV infection. Curr HIV Res 7:73-82
Verzijl, Dennis; Storelli, Stefania; Scholten, Danny J et al. (2008) Noncompetitive antagonism and inverse agonism as mechanism of action of nonpeptidergic antagonists at primate and rodent CXCR3 chemokine receptors. J Pharmacol Exp Ther 325:544-55

Showing the most recent 10 out of 15 publications