This is the resubmission of the competitive renewal of our RO1 that generated >63 publications over a 12-year funding period. Our goal is to assess the impact of dietary factors on chronic inflammation (INFL) profiles associated with cardiovascular disease (CVD) in treated and untreated SIV infections. As reported in other clinical conditions, diet plays a key role in modulating gut INFL, epithelial integrity and microbial translocation through shifts in microbiota metabolites, which may also induce excessive cell proliferation and activation or a skewed cell differentiation, resulting in a reduction of the immune cell subsets critical for gut health. Diet-induced changes in the host cellular fat and sugar metabolism may enhance SIV/HIV replication, reduce immune cell responses and promote cell senescence. Certain diets thus have the potential to enhance gut dysfunction during SIV/HIV infection. In addition to the impact on the gut, the diet-induced changes in microbiota may trigger changes in the adipose tissue that promote systemic INFL and induce liver damage that may associate abnormal clearance of microbial products, antiretroviral (ARV) metabolism and coagulation factor synthesis. Our hypothesis is therefore that, in the context of HIV/SIV, the diet?microbiota?metabolite axis has a critical impact on IA/INFL, response to ART and development of CVD. Long-term, perfectly controlled diet studies are very difficult to carry out in HIV+ infected subjects and can be confounded by numerous other factors (i.e., ART, age, alcohol, drugs, smoking, lack of physical activity) that may affect the same metabolic pathways. Our preliminary data show that administration of a high fat diet to SIV-infected NHPs induced alterations in the gut microbiota, MT, nonalcoholic fatty liver and increases in systemic IA/INFL, which altogether resulted in a significantly decreased survival. Based on these preliminary data and the rationales above, and as a logical continuation of the research from the previous funding periods, we designed this project, aimed at assessing the impact of major dietary components on the natural history of SIV infection and the development of SIV-related CVD in ART-nave NHPs and chronically infected NHPs on ART. In an NHP model developed in our lab, that faithfully reproduces the CVD described in HIV+ subjects, we will perform controlled studies to test the long term effects of multiple diets prior and after SIV infection, on or off ART. These experiments will establish the pathways impacted by each dietary component and cannot be performed in HIV+ subjects due to the difficulty to maintain strict diets, the risks associated with certain diets that can produce harm, and to the impossibility to perform extensive invasive sampling. Our goal is to develop a permanent drug-free, no risk adjuvant therapy for HIV+ subjects, to reduce residual INFL, improve immune function and decrease the CV comorbidities. If successful, these highly translational experiments may improve clinical management and survival of HIV+ patients, without the risk of adding new drug interactions in this heavily medicated population.

Public Health Relevance

This competitive renewal application is designed to continue our research aimed at understanding the role of chronic immune activation and inflammation in HIV infection and identify effective approaches to control them. We will assess the impact of the major dietary components (i.e., sugar, fat and fiber) on SIV pathogenesis and response to antiretroviral therapy. The impact of a Western Diet will be comparatively assessed in male vs female nonhuman primates infected with SIV. A dietary intervention will be tested with the aim to improve gut health during SIV/HIV infection. If successful, this research may result in a drug-free approach for the control of chronic immune activation and inflammation, the main drivers of disease progression, comorbidities and death in HIV- infected subjects.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Chen, Jue
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University of Pittsburgh
Schools of Medicine
United States
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Kleinman, Adam J; Sivanandham, Ranjit; Pandrea, Ivona et al. (2018) Regulatory T Cells As Potential Targets for HIV Cure Research. Front Immunol 9:734
Brocca-Cofano, Egidio; Xu, Cuiling; Wetzel, Katherine S et al. (2018) Marginal Effects of Systemic CCR5 Blockade with Maraviroc on Oral Simian Immunodeficiency Virus Transmission to Infant Macaques. J Virol 92:
Policicchio, Benjamin Bruno; Sette, Paola; Xu, Cuiling et al. (2018) Emergence of resistance mutations in simian immunodeficiency virus (SIV)-infected rhesus macaques receiving non-suppressive antiretroviral therapy (ART). PLoS One 13:e0190908
Policicchio, Benjamin B; Cardozo, Erwing Fabian; Sette, Paola et al. (2018) Dynamics of Simian Immunodeficiency Virus Two-Long-Terminal-Repeat Circles in the Presence and Absence of CD8+ Cells. J Virol 92:
Brocca-Cofano, Egidio; Kuhrt, David; Siewe, Basile et al. (2017) Pathogenic Correlates of Simian Immunodeficiency Virus-Associated B Cell Dysfunction. J Virol 91:
Wetzel, Katherine S; Yi, Yanjie; Elliott, Sarah T C et al. (2017) CXCR6-Mediated Simian Immunodeficiency Virus SIVagmSab Entry into Sabaeus African Green Monkey Lymphocytes Implicates Widespread Use of Non-CCR5 Pathways in Natural Host Infections. J Virol 91:
Schechter, Melissa E; Andrade, Bruno B; He, Tianyu et al. (2017) Inflammatory monocytes expressing tissue factor drive SIV and HIV coagulopathy. Sci Transl Med 9:
Policicchio, Benjamin B; Xu, Cuiling; Brocca-Cofano, Egidio et al. (2016) Multi-dose Romidepsin Reactivates Replication Competent SIV in Post-antiretroviral Rhesus Macaque Controllers. PLoS Pathog 12:e1005879
He, Tianyu; Brocca-Cofano, Egidio; Policicchio, Benjamin B et al. (2016) Cutting Edge: T Regulatory Cell Depletion Reactivates Latent Simian Immunodeficiency Virus (SIV) in Controller Macaques While Boosting SIV-Specific T Lymphocytes. J Immunol 197:4535-4539
Raehtz, Kevin; Pandrea, Ivona; Apetrei, Cristian (2016) The well-tempered SIV infection: Pathogenesis of SIV infection in natural hosts in the wild, with emphasis on virus transmission and early events post-infection that may contribute to protection from disease progression. Infect Genet Evol 46:308-323

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