forARRA years 1-2funding The goals of this project are to define how HIV-1 interacts with pDC and to elucidate the role of pDC cells in HIV-1 replication and pathogenesis. As the major sensor of viral infections, altered pDC level/activity may playa critical role during HIV-1 disease progression. However, the role of pDC cells in F-IIV infection and pathogenesis is poorly understood, mainly due to the lack of robust in vivo models. The DKO-hu I-4SC model is ideal for this purpose. With a stable functional human immune system, functional pDC cells are developed in normal proportion in all lymphoid organs in DKO-hu mice. HIV-1 establishes persistent infection, with immune hyperactivation and depletion of human CD4 T cells. We have also shown that, during HIV-1 infection, PDC cells are productively infected, activated, depleted and functionally impaired in DKO-hu HSC mice. HIV-1 with the pathogenic R3A Env also efficiently activates PDC in vitro, correlated with its high binding affinity to CD4 receptor and coreceptors. Based on our preliminary findings and reports from Sly-infected monkeys or HIV- infected patients, postulate that HIV-1 intimately interacts with PDC cells, and chronic engaging of PDC during persistent HIV infection wifl deplete or impair PDC activity. The reduced or altered PDC activity contributes to chronic HIV infection, hyperimmune activation and AIDS progression. The following modified specific aims are proposed to test these hypotheses. First, we wil iinvestigate the Induced by HIV infection, by genetically analyzing the candidate signaling pathways (SA2a). Third, we will proliferation and survival of pOC cells during early and late-chronic HIV-1 pDC activation with genetic approaches. In addition, we will also define the signaling defects in pOC cells Second, we will define the role of each relevant receptor (CD4, CCR5, CXCR4, BDCA2, TLR7 and TLR9) in pDC activation with specific inhibitors and with genetic approaches. In addition, we will also purify pDC cells from mock- or HIV-infected DKO-hu mice to identify genes that are deregulated by HIV infection. We will define the signaling defects in pDC cells induced by HIV infection, by genetically analyzing the candidate signaling pathways. Third, we will study if stimulation or inhibition of pDC activation with the agonistic or antagonistic ligands of TLR7/TLR9 before or during HIV infection will affect HIV replication and immuno-pathogenesis. In addition, we will treat DKO-hu mice with the pDC-specific mAb conjugated with the Saporin toxin, which specifically depletes pDC, to test the role of pDC during infection. We will thus focus on the most fundamental questions of pDC cells in HIV pathogenesis. Elucidation of the mechanism by which HIV-1 interacts with pDC cells and their role in HIV-1 infection and AIDS pathogenesis will facilitate not only our understanding of pDC biology in HIV pathogenesis, but also development of novel therapeutic strategies.

Public Health Relevance

This project will investigate the role of PDC cells in HIV-1 infection and pathogenesis in vivo. Elucidation of the mechanism by which HIV-1 interacts with pDC cells and their role in HIV-1 infection and AIDS pathogenesis will facilitate not only our understanding of pDC biology in HIV pathogenesis, but also development of novel therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI080432-04
Application #
8288315
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Sharma, Opendra K
Project Start
2009-07-22
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$366,300
Indirect Cost
$118,800
Name
University of North Carolina Chapel Hill
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Bot, Ilze; Daissormont, Isabelle T M N; Zernecke, Alma et al. (2014) CXCR4 blockade induces atherosclerosis by affecting neutrophil function. J Mol Cell Cardiol 74:44-52
Guo, Haitao; Gao, Jianmei; Taxman, Debra J et al. (2014) HIV-1 infection induces interleukin-1? production via TLR8 protein-dependent and NLRP3 inflammasome mechanisms in human monocytes. J Biol Chem 289:21716-26
Liu, Su-Yang; Aliyari, Roghiyh; Chikere, Kelechi et al. (2013) Interferon-inducible cholesterol-25-hydroxylase broadly inhibits viral entry by production of 25-hydroxycholesterol. Immunity 38:92-105
Zhang, Liguo; Jiang, Qi; Li, Guangming et al. (2011) Efficient infection, activation, and impairment of pDCs in the BM and peripheral lymphoid organs during early HIV-1 infection in humanized rag2ýýý/ýýýýý Cýýý/ýýý mice in vivo. Blood 117:6184-92
Washburn, Michael L; Bility, Moses T; Zhang, Liguo et al. (2011) A humanized mouse model to study hepatitis C virus infection, immune response, and liver disease. Gastroenterology 140:1334-44
West, John A; Gregory, Sean M; Sivaraman, Vijay et al. (2011) Activation of plasmacytoid dendritic cells by Kaposi's sarcoma-associated herpesvirus. J Virol 85:895-904
Johnson, Soren M; Torrice, Chad D; Bell, Jessica F et al. (2010) Mitigation of hematologic radiation toxicity in mice through pharmacological quiescence induced by CDK4/6 inhibition. J Clin Invest 120:2528-36