The long term objective of this application is to understand how HIV evades the immune response and establishes a chronic infection. Insights into how this occurs may lead to new strategies to augment the ability of the immune response to eradicate the virus. One way that HIV avoids immune recognition is by reducing cell surface levels of major histocompatibility complex class I molecules (MHC-I), thereby protecting HIV-infected cells from recognition by cytotoxic T lymphocytes (CTLs). In addition, we have found that the capacity of cells to process and present antigens varies depending on the MHC-I haplotype and the cell type that is infected. Thus, we will pursue the following aims: (1) We will demonstrate that antigen presenting cells (APCs) and individual MHC-I molecules have unique pathways of antigen processing and presentation that (2) affect their responsiveness to Nef and recognition by CTLs. In addition, we will demonstrate that (3) HIV evades the immune response by remaining latent in long-lived progenitors of these cell types, which can serve as inducible reservoirs of HIV infection in vivo. To accomplish these goals we will use biochemical and cell biological methods to define the trafficking pathways of individual MHC-I molecules in normal and HIV- infected cells. We will also perform studies using patient samples to characterize the capacity of myeloid precursors to support HIV infection in vivo. This proposal is relevant to the mission of NIH in that it seeks to understand basic mechanisms of how HIV establishes a chronic infection. This work has the potential to have a significant impact on public health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI051192-07
Application #
7739497
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Embry, Alan C
Project Start
2001-12-01
Project End
2011-11-30
Budget Start
2009-12-01
Budget End
2010-11-30
Support Year
7
Fiscal Year
2010
Total Cost
$395,129
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Collins, David R; Lubow, Jay; Lukic, Zana et al. (2015) Vpr Promotes Macrophage-Dependent HIV-1 Infection of CD4+ T Lymphocytes. PLoS Pathog 11:e1005054
Collins, David R; Collins, Kathleen L (2014) HIV-1 accessory proteins adapt cellular adaptors to facilitate immune evasion. PLoS Pathog 10:e1003851
Mashiba, Michael; Collins, David R; Terry, Valeri H et al. (2014) Vpr overcomes macrophage-specific restriction of HIV-1 Env expression and virion production. Cell Host Microbe 16:722-35
Kulpa, Deanna A; Del Cid, Natasha; Peterson, Kirsten A et al. (2013) Adaptor protein 1 promotes cross-presentation through the same tyrosine signal in major histocompatibility complex class I as that targeted by HIV-1. J Virol 87:8085-98
Mashiba, Mike; Collins, Kathleen L (2013) Molecular mechanisms of HIV immune evasion of the innate immune response in myeloid cells. Viruses 5:1-14
Mashiba, Mike; Collins, Kathleen L (2012) Molecular mechanisms of HIV immune evasion of the innate immune response in myeloid cells. Viruses 5:1-14
Carter, Christoph C; McNamara, Lucy A; Onafuwa-Nuga, Adewunmi et al. (2011) HIV-1 utilizes the CXCR4 chemokine receptor to infect multipotent hematopoietic stem and progenitor cells. Cell Host Microbe 9:223-234
Wonderlich, Elizabeth R; Leonard, Jolie A; Collins, Kathleen L (2011) HIV immune evasion disruption of antigen presentation by the HIV Nef protein. Adv Virus Res 80:103-27
McNamara, Lucy A; Collins, Kathleen L (2011) Hematopoietic stem/precursor cells as HIV reservoirs. Curr Opin HIV AIDS 6:43-8
Norman, Jason M; Mashiba, Michael; McNamara, Lucy A et al. (2011) The antiviral factor APOBEC3G enhances the recognition of HIV-infected primary T cells by natural killer cells. Nat Immunol 12:975-83

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