This proposal is directed to the molecular pathogenesis of infection by the human immunodeficiency virus (HIV) and in particular to the basis for its cardinal manifestation, the acquired immuno deficiency syndrome (AIDS). We describe longitudinal analyses of lymph node and bone marrow by in situ hybridization and cognate single cells methods to define the number and type of cells which harbor HIV, and the extent of virus gene expression vis-a-vis viral and regulatory genes and stage of disease. We think this analysis will provide support for a war of attrition hypothesis which accounts for the profound loss of T helper lymphocytes despite the relatively low frequency of cells in which viral RNA can be demonstrated. We also will look for a mutant virulent virus in the later stages of disease. If one is found we will characterize the genome of the virus for comparisons with earlier isolates with the aim of identifying viral genes with a critical role in pathogenesis.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (ZRG1-AARR-2 (01))
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Sharma, Opendra K
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University of Minnesota Twin Cities
Schools of Medicine
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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; Paiardini, Mirko; Engram, Jessica C et al. (2012) Critical role of CD4 T cells in maintaining lymphoid tissue structure for immune cell homeostasis and reconstitution. Blood 120:1856-67
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
Zeng, Ming; Haase, Ashley T (2012) Ex vivo Co-culture of Lymphoid Tissue Stromal Cells and T Cells. Bio Protoc 2:
Zeng, Ming; Southern, Peter J; Reilly, Cavan S et al. (2012) Lymphoid tissue damage in HIV-1 infection depletes naive T cells and limits T cell reconstitution after antiretroviral therapy. PLoS Pathog 8:e1002437
Zeng, Ming; Smith, Anthony J; Wietgrefe, Stephen W et al. (2011) Cumulative mechanisms of lymphoid tissue fibrosis and T cell depletion in HIV-1 and SIV infections. J Clin Invest 121:998-1008
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
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
Denton, Paul W; Estes, Jacob D; Sun, Zhifeng et al. (2008) Antiretroviral pre-exposure prophylaxis prevents vaginal transmission of HIV-1 in humanized BLT mice. PLoS Med 5:e16

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