Highly active anti-retroviral therapy (HAART) has reduced mortality and morbidity from HIV infection. However, there is significant variability in the CD4+ T cell response to HAART with up to 25% of patients naive to anti-retroviral therapy having a clinically insignificant rise in peripheral CD4+ T cell count. Our preliminary data suggest a mechanism of chronic inflammation from HIV replication may be responsible for this variability by disruption of the reticular network and collagen formation in the T cell zone (TZ) of lymphatic tissues (LT), a unique niche where the pool of naive T cells is maintained, antigen presented, and proliferation occurs. Functionally this might cause abnormalities of cellular migration, T cell homeostasis, and lack of diffusion of cytokines and other signaling molecules. These observations have led us to form the hypothesis that ongoing rounds of HIV-1 replication in LT causes a progressive and destructive inflammatory reaction that alters the architecture and function of the TZ, the extent of which is directly related to the potential for successful restoration of the CD4+ T cell population with HAART. Our studies will determine if measurement of collagen as a function of architectural damage in the TZ more accurately predicts the change in CD4+ T cell count with ART than commonly used predictors (baseline CD4+ T cell count or plasma HIV RNA) and if the damage is reversible. We will complete functional studies to determine the kinetics of CD4+ T cell repopulation in both peripheral and lymphatic tissues by measuring the relative proportions of naive, memory, and effector CD4+ T cells in peripheral and LT at each time point to determine if there are reciprocal changes in these phenotypes in peripheral blood and LT that suggest redistribution as a mechanism for immune reconstitution. Through these studies we wish to elucidate the mechanism(s) for incomplete immune reconstitution.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI054232-04
Application #
7002677
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Plaeger, Susan F
Project Start
2003-07-01
Project End
2007-12-31
Budget Start
2006-01-01
Budget End
2006-12-31
Support Year
4
Fiscal Year
2006
Total Cost
$482,607
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Estes, Jacob D; Reilly, Cavan; Trubey, Charles M et al. (2015) Antifibrotic therapy in simian immunodeficiency virus infection preserves CD4+ T-cell populations and improves immune reconstitution with antiretroviral therapy. J Infect Dis 211:744-54
Zeng, Ming; Haase, Ashley T; Schacker, Timothy W (2012) Lymphoid tissue structure and HIV-1 infection: life or death for T cells. Trends Immunol 33:306-14
Schacker, Timothy W; Bosch, Ronald J; Bennett, Kara et al. (2010) Measurement of naive CD4 cells reliably predicts potential for immune reconstitution in HIV. J Acquir Immune Defic Syndr 54:59-62
Estes, Jacob D; Haase, Ashley T; Schacker, Timothy W (2008) The role of collagen deposition in depleting CD4+ T cells and limiting reconstitution in HIV-1 and SIV infections through damage to the secondary lymphoid organ niche. Semin Immunol 20:181-6
Brenchley, J M; Knox, K S; Asher, A I et al. (2008) High frequencies of polyfunctional HIV-specific T cells are associated with preservation of mucosal CD4 T cells in bronchoalveolar lavage. Mucosal Immunol 1:49-58
Brenchley, Jason M; Paiardini, Mirko; Knox, Kenneth S et al. (2008) Differential Th17 CD4 T-cell depletion in pathogenic and nonpathogenic lentiviral infections. Blood 112:2826-35
Estes, Jacob; Baker, Jason V; Brenchley, Jason M et al. (2008) Collagen deposition limits immune reconstitution in the gut. J Infect Dis 198:456-64
Estes, Jacob D; Wietgrefe, Stephen; Schacker, Timothy et al. (2007) Simian immunodeficiency virus-induced lymphatic tissue fibrosis is mediated by transforming growth factor beta 1-positive regulatory T cells and begins in early infection. J Infect Dis 195:551-61
Skarda, David E; Taylor, Jodie H; Chipman, Jeffrey G et al. (2007) Inguinal lymph node biopsy in patients infected with the human immunodeficiency virus is safe. Surg Infect (Larchmt) 8:173-8
Schacker, Timothy W; Brenchley, Jason M; Beilman, Gregory J et al. (2006) Lymphatic tissue fibrosis is associated with reduced numbers of naive CD4+ T cells in human immunodeficiency virus type 1 infection. Clin Vaccine Immunol 13:556-60

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