Dendritic cells (DC) are professional antigen-presenting cells that are critical in the innate and acquired immune response to pathogens. DC exist as two major subsets in humans and nonhuman primates, being classical or myeloid DC (mDC) and plasmacytoid DC (pDC). mDC and pDC are lost from the circulation in human immunodeficiency virus type 1 (HIV)-infected individuals, which is thought to be due to recruitment of circulating cells to lymphoid tissues and is associated with progression to disease. The proposed recruitment of pDC to lymph nodes has been used to explain the increased expression of IFN-a in lymph nodes in HIV- infected individuals, which in turn has been linked to TNF-related apoptosis-inducing ligand (TRAIL)-mediated CD4+ T cell apoptosis. However, the effects of infection on DC subsets in lymphoid tissues remain largely unexplored. Using the rhesus macaque/simian immunodeficiency virus (SIV) model, we have shown that DC numbers are increased in lymph nodes at the peak of viremia, consistent with recruitment through inflammation. However, during simian AIDS, DC are depleted from blood, peripheral and mesenteric lymph nodes and spleen, and are reduced in density in skin. These data suggest a highly dynamic process of DC recruitment to and subsequent loss from lymphoid tissues during SIV infection. Our proposal aims to build on these novel findings, focusing in particular on the mechanism(s) of DC loss. Our preliminary data indicate that lymph node DC in monkeys with AIDS are activated and prone to spontaneous death in culture. We hypothesize that DC loss from lymphoid tissues during pathogenic SIV infection is primarily mediated by factors relating to chronic inflammation and activation. To test this hypothesis we will comprehensively analyze DC subsets in blood and tissues after intravaginal inoculation of rhesus macaques with SIVmac251. We will administer antiretroviral therapy (ART) in a subset of animals, which will aid in dissecting the mechanism of cell loss by reducing immune activation. We will (1) Determine DC kinetics and activation and the relationship to tissue inflammation in SIV infection;(2) Determine the role of direct infection in DC loss in SIV infection;(3) Determine the role of apoptosis in DC loss during SIV infection and (4) Determine the capacity for pDC and mDC to produce IFN-a and Th1-stimulating cytokines during SIV infection. These studies will greatly advance our understanding of complex DC biology in HIV infection.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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AIDS Immunology and Pathogenesis Study Section (AIP)
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Embry, Alan C
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University of Pittsburgh
Internal Medicine/Medicine
Schools of Public Health
United States
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Swan, Zachary D; Bouwer, Anthea L; Wonderlich, Elizabeth R et al. (2017) Persistent accumulation of gut macrophages with impaired phagocytic function correlates with SIV disease progression in macaques. Eur J Immunol 47:1925-1935
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-? 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-? 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

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