The immunodeficiency inducing lentiviruses HIV-1 and SIV replicate in numerous tissues throughout the host, with early unchecked replication during the final stages of disease. The lung has been demonstrated in our previous studies to serve as a critical site of viral replication during the transition from clinical latency to AIDS in the SIV/macaque model of HIV-1 infection and disease induction in humans. This proposal outlines an experimental plan to comprehensively characterize the virologic and immunologic outcomes of infection in rhesus macaque lung tissues by SIV during the acute, clinically latent, and terminal stages of disease. Our hypothesis is that there are very specific virologic and immunologic events that occur in the lung immediately preceding the transition from clinical latency to AIDS, and we will seek to identify these events. For these in vivo analyses, cohorts of rhesus macaques will be inoculated intravenously with SlVdeltaB670 or biological and molecular clones derived therefrom, and in situ hybridization and immunohistochemical staining will be utilized to identify the numbers, locations, and types of productively infected cells in multiple parts of the lungs, in comparison to lymphoid tissues. In parallel, characterization of the composition of the lymphocytic and monocytic subsets will be performed. For these studies, lung tissue will be disaggregated and single cell suspensions generated to allow flow cytometric analyses of surface immunophenotype, in vitro killing analyses of SIV-specific cytotoxic T cell activities, and PCR/ heteroduplex mobility analyses of the T cell receptor Vbeta repertoire. In all experiments, investigations of lung tissues will be performed in comparison to bronchoalveolar lavage (BAL) cells, as the majority of existing data regarding the effects of HIV-1 on the immunologic environment in the lung are from BAL. These investigations will provide insight into the mechanisms by which primate lentiviruses alter the immunologic environment within the lung, leading to susceptibility to respiratory infections as well as systemic immunodeficiency.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL062056-05S1
Application #
6662441
Study Section
Special Emphasis Panel (ZHL1 (S2))
Program Officer
Colombini-Hatch, Sandra
Project Start
1998-09-30
Project End
2003-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
5
Fiscal Year
2002
Total Cost
$75,000
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Public Health
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Fallert, Beth A; Poveda, Sandra; Schaefer, Todd M et al. (2008) Virologic and immunologic events in hilar lymph nodes during simian immunodeficiency virus infection: development of polarized inflammation. J Acquir Immune Defic Syndr 47:16-26
Schaefer, Todd M; Fuller, Craig L; Basu, Shrabani et al. (2006) Increased expression of interferon-inducible genes in macaque lung tissues during simian immunodeficiency virus infection. Microbes Infect 8:1839-50
Sanghavi, Sonali K; Reinhart, Todd A (2005) Increased expression of TLR3 in lymph nodes during simian immunodeficiency virus infection: implications for inflammation and immunodeficiency. J Immunol 175:5314-23
Sanghavi, Sonali K; Shankarappa, Raj; Reinhart, Todd A (2004) Genetic analysis of Toll/Interleukin-1 Receptor (TIR) domain sequences from rhesus macaque Toll-like receptors (TLRs) 1-10 reveals high homology to human TLR/TIR sequences. Immunogenetics 56:667-74
Sarkar, Surojit; Kalia, Vandana; Murphey-Corb, Michael et al. (2003) Expression of IFN-gamma induced CXCR3 agonist chemokines and compartmentalization of CXCR3+ cells in the periphery and lymph nodes of rhesus macaques during simian immunodeficiency virus infection and acquired immunodeficiency syndrome. J Med Primatol 32:247-64
Choi, Yang Kyu; Whelton, Kelly M; Mlechick, Brandy et al. (2003) Productive infection of dendritic cells by simian immunodeficiency virus in macaque intestinal tissues. J Pathol 201:616-28
Choi, Yang Kyu; Fallert, Beth A; Murphey-Corb, Michael A et al. (2003) Simian immunodeficiency virus dramatically alters expression of homeostatic chemokines and dendritic cell markers during infection in vivo. Blood 101:1684-91
Croix, Denise A; Board, Kathryn; Capuano 3rd, Saverio et al. (2002) Alterations in T lymphocyte profiles of bronchoalveolar lavage fluid from SIV- and Pneumocystis carinii-coinfected rhesus macaques. AIDS Res Hum Retroviruses 18:391-401
Reinhart, Todd A; Fallert, Beth A; Pfeifer, Melanie E et al. (2002) Increased expression of the inflammatory chemokine CXC chemokine ligand 9/monokine induced by interferon-gamma in lymphoid tissues of rhesus macaques during simian immunodeficiency virus infection and acquired immunodeficiency syndrome. Blood 99:3119-28
Schaefer, Todd M; Bell, Ian; Pfeifer, Melanie E et al. (2002) The conserved process of TCR/CD3 complex down-modulation by SIV Nef is mediated by the central core, not endocytic motifs. Virology 302:106-22

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