Dendritic cells (DC) and monocytes/macrophages (Mo/M?) are innate immune cells that play a critical role in the host response to viral infection b mediating antiviral activity and inducing adaptive immune responses. However, in human immunodeficiency virus (HIV) infection of humans this relationship between DC, Mo/M? and virus control is not clear, as generalized immune activation that is a central feature of progression to AIDS may be driven by an overactive innate immune response to infection. Hence, a central unanswered question in HIV pathogenesis is whether the DC and Mo/M? response to infection is desirable or detrimental. This represents a critical impediment to progress in the field, as we do not know if therapeutic strategies should be aimed at blocking or promoting innate immunity. In this proposal we will address this central question in simian immunodeficiency virus (SIV) infection of rhesus macaques, which models HIV infection of humans. We will prospectively study the DC and Mo/M? response in SIVmac251-infected macaques with controlled infection vs. normal or rapid progression and compare this to macaques infected with SIVmac251 and treated with antiretroviral therapy or infected with attenuated SIVmac239?nef. With this full spectrum of outcomes of infection we will be able to put into context the relevance of the DC and Mo/M? response to AIDS pathogenesis. In addition, we will use a novel humanized antibody specific for one subset of DC, the plasmacytoid DC, to deplete these cells at the time of infection or during the chronic phase. This will, for the first time, allow us to directly determine the contribution of plasmacytoid DC to virs control and chronic immune activation. These hypothesis-driven studies will further define the role of DC and Mo/M? in HIV infection and provide direction for development of therapeutics targeting innate immunity.

Public Health Relevance

HIV infection continues to be a leading cause of morbidity and mortality in the United States and the world. This research focuses on the role of essential innate immune cells - dendritic cells, monocytes and macrophages - in virus control and AIDS pathogenesis. Addressing this issue is central to determining whether the innate response is beneficial or harmful, which in turn will inform the design of therapeutic strategies to either enhance or inhibit the response in HIV- infected individuals. The work therefore has considerable public health significance, including the potential to impact development of novel therapies to combat HIV infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI071777-07
Application #
8473151
Study Section
Special Emphasis Panel (ZRG1-AARR-E (02))
Program Officer
Sharma, Opendra K
Project Start
2012-05-23
Project End
2017-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
7
Fiscal Year
2013
Total Cost
$640,225
Indirect Cost
$203,415
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Public Health
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Swan, Zachary D; Wonderlich, Elizabeth R; Barratt-Boyes, Simon M (2016) Macrophage accumulation in gut mucosa differentiates AIDS from chronic SIV infection in rhesus macaques. Eur J Immunol 46:446-54
Wonderlich, Elizabeth R; Wu, Wen-Chi; Normolle, Daniel P et al. (2015) Macrophages and Myeloid Dendritic Cells Lose T Cell-Stimulating Function in Simian Immunodeficiency Virus Infection Associated with Diminished IL-12 and IFN-α Production. J Immunol 195:3284-92
Wijewardana, Viskam; Bouwer, Anthea L; Brown, Kevin N et al. (2014) Accumulation of functionally immature myeloid dendritic cells in lymph nodes of rhesus macaques with acute pathogenic simian immunodeficiency virus infection. Immunology 143:146-54
Kader, Muhamuda; Smith, Amanda P; Guiducci, Cristiana et al. (2013) Blocking TLR7- and TLR9-mediated IFN-α production by plasmacytoid dendritic cells does not diminish immune activation in early SIV infection. PLoS Pathog 9:e1003530
Wonderlich, Elizabeth R; Wijewardana, Viskam; Liu, Xiangdong et al. (2013) Virus-encoded TLR ligands reveal divergent functional responses of mononuclear phagocytes in pathogenic simian immunodeficiency virus infection. J Immunol 190:2188-98
Wonderlich, Elizabeth R; Barratt-Boyes, Simon M (2013) SIV infection of rhesus macaques differentially impacts mononuclear phagocyte responses to virus-derived TLR agonists. J Med Primatol 42:247-53
Malzahn, Jessica; Shen, Chengli; Caruso, Lori et al. (2012) Effect of early anti-retroviral therapy on the pathogenic changes in mucosal tissues of SIV infected rhesus macaques. Virol J 9:269
Wonderlich, Elizabeth R; Barratt-Boyes, Simon M (2012) A dendrite in every pie: myeloid dendritic cells in HIV and SIV infection. Virulence 3:647-53
Barratt-Boyes, S M; Wijewardana, V (2011) A divergent myeloid dendritic cell response at virus set-point predicts disease outcome in SIV-infected rhesus macaques. J Med Primatol 40:206-13
Wonderlich, Elizabeth R; Kader, Muhamuda; Wijewardana, Viskam et al. (2011) Dissecting the role of dendritic cells in simian immunodeficiency virus infection and AIDS. Immunol Res 50:228-34

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