In contrast to HIV-1 infection of humans and SIV infection of rhesus macaques (RMs), which are almost invariably associated with AIDS, natural lentiviral infections of African primates, such as SIVsmm infection of sooty mangabeys (SM), are typically non-pathogenic. The mechanisms underlying this non-pathogenic phenotype remain largely unknown;however, we have previously shown that a key feature of nonpathogenic SIV infection is the absence of chronic, generalized immune activation in the context of low cellular immune responses to the virus. As the HIV-associated immune activation (IA) is thought to be a key factor in the pathogenesis of AIDS, we proposed that the lack of IA protects SIV-infected SMs from disease progression. In further studies, we observed that SM-derived plasmacytoid dendritic cells (pDCs) produce significantly lower levels of type 1 interferon (IFNs) in response to toll-like receptor (TLR)-7 or -9 stimulation than human or RM-derived pDCs. These findings led us to hypothesize that a blunted type 1 IFN responses to TLR-7/9 stimulation mediated by SIV or its products protects SIV-infected SMs from developing the generalized immune activation associated with pathogenic HIV/SIV infections.
The aim of this project is to directly test this hypothesis by treating naturally SIV-infected SMs with IFN-a and TLR-7/-9 stimulation, as well as treating SIV-infected RMs with anti-IFN-a antibody and TLR-7/-9 inhibitors. These interventions will allow us to determine whether and to what extent differences in the level of pDCs responsiveness to TLR-7/-9 stimulation and/or IFN-a production between RMs and SMs are responsible for the striking differences in the level of immune activation observed in these two species after SIV infection. The results of these studies will improve our understanding of the mechanisms underlying the lack of disease in SIV-infected SMs and determine whether targeting TLR-7/9 activation and/or IFN-a production are promising targets for therapeutic interventions aimed at reducing the HIV-associated chronic immune activation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI076174-05
Application #
8377459
Study Section
Special Emphasis Panel (ZAI1-PRJ-A)
Project Start
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$652,495
Indirect Cost
$81,243
Name
Case Western Reserve University
Department
Type
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Freeman, Michael L; Morris, Stephen R; Lederman, Michael M (2017) CD161 Expression on Mucosa-Associated Invariant T Cells is Reduced in HIV-Infected Subjects Undergoing Antiretroviral Therapy Who Do Not Recover CD4+ T Cells. Pathog Immun 2:335-351
Siewe, Basile; Nipper, Allison J; Sohn, Haewon et al. (2017) FcRL4 Expression Identifies a Pro-inflammatory B Cell Subset in Viremic HIV-Infected Subjects. Front Immunol 8:1339
Siedner, Mark J; Kim, June-Ho; Nakku, Ruth Sentongo et al. (2016) HIV infection and arterial stiffness among older-adults taking antiretroviral therapy in rural Uganda. AIDS 30:667-70
McGinty, Tara; Mirmonsef, Paria; Mallon, Patrick W G et al. (2016) Does systemic inflammation and immune activation contribute to fracture risk in HIV? Curr Opin HIV AIDS 11:253-60
Shive, Carey L; Clagett, Brian; McCausland, Marie R et al. (2016) Inflammation Perturbs the IL-7 Axis, Promoting Senescence and Exhaustion that Broadly Characterize Immune Failure in Treated HIV Infection. J Acquir Immune Defic Syndr 71:483-92
Fu, P; Hughes, J; Zeng, G et al. (2016) A comparative investigation of methods for longitudinal data with limits of detection through a case study. Stat Methods Med Res 25:153-66
Luo, Zhenwu; Ma, Lei; Zhang, Lumin et al. (2016) Key differences in B cell activation patterns and immune correlates among treated HIV-infected patients versus healthy controls following influenza vaccination. Vaccine 34:1945-55
Pandiyan, Pushpa; Younes, Souheil-Antoine; Ribeiro, Susan Pereira et al. (2016) Mucosal Regulatory T Cells and T Helper 17 Cells in HIV-Associated Immune Activation. Front Immunol 7:228
Siedner, Mark J; Kim, June-Ho; Nakku, Ruth Sentongo et al. (2016) Persistent Immune Activation and Carotid Atherosclerosis in HIV-Infected Ugandans Receiving Antiretroviral Therapy. J Infect Dis 213:370-8
Mudd, Joseph C; Panigrahi, Soumya; Kyi, Benjamin et al. (2016) Inflammatory Function of CX3CR1+ CD8+ T Cells in Treated HIV Infection Is Modulated by Platelet Interactions. J Infect Dis 214:1808-1816

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