Uncontrolled inflammation generates significant morbidity and mortality in many non-infectious (e.g. inflammatory bowel disease) and infectious (e.g. HIV) diseases. The central focus of Dr. Estes’s research seeks to understand how immune response dysregulation leads to tissue pathology, disease progression, and in the context of infectious diseases, pathogen persistence with the goal to develop and test effective therapeutic strategies that prevent disease and restores immune function. Towards that end, we utilize non-human primate models of several highly relevant human diseases, with a strong emphasis on models of HIV infection and disease, to elucidate determinants of local and systemic inflammation and to test therapeutics that modulate the immune landscape, restore immune homeostasis, and reduce viral reservoirs. We capitalize on the full power of our pre-clinical models by performing cutting-edge in vivo and in situ tissue analyses, including our pioneering work with next-generation in situ hybridization and immunohistochemistry, to generate comprehensive characterizations of the host-pathogen interactions, including the cellular and inflammatory immune landscapes present within relevant tissue microenvironments. Our studies invite collaboration, and we work with academic, government and industry partners around the globe on a wide range of projects from intestinal dysbiosis to the distribution of Zika virus within the host.
Current projects in the laboratory include:
1. The contribution of GI tract epithelial barrier dysfunction and damage to local and systemic inflammation during HIV/SIV infection, and subsequent tissue pathology and viral reservoir persistence. Moreover, we are testing the therapeutic administration of novel immune modulating agents, in collaboration with industry partners, to target proinflammatory cytokines in order to restore GI tract immune homeostasis and mitigate pathology.
2. Characterization of the HIV/SIV reservoirs in pharmacologic “sanctuary” sites such as lymphoid tissue B cell follicles, gut associated lymphoid tissues, and the central nervous system, with a two-pronged goal of understanding the factors that contribute to HIV/SIV persistence and developing novel therapies to reduce the size of the reservoir as part of the broader HIV cure strategy.
3. Elucidating mechanisms controlling inflammatory bowel disease and intestinal fibrosis to identify original therapeutic targets, by utilizing the first nonhuman primate model of experimental acute and chronic colitis in conjunction with a novel, non-invasive MRI-based method for quantifying intestinal inflammation and disease progression.
4. The development of new, sensitive in vivo and in situ tissue visualization techniques to advance our understanding of pathogen persistence and tissue pathology.
Dr. Estes graduated from Brigham Young University with a B.S. in Microbiology and Molecular Biology in 1999. He continued his graduate education at Brigham Young University and obtained his Ph.D. in Immunology and HIV Pathogenesis in 2003 in the laboratory of Dr. Gregory Burton. From 2003 to 2007, he was a postdoctoral fellow in the laboratory of Dr. Ashley Haase in the Department of Microbiology at the University of Minnesota focusing on the in vivo immunopathology of lentiviral infections. Following postdoctoral training, Dr. Estes joined the AIDS and Cancer Virus Program at the Frederick National Laboratory for Cancer Research, and was a Principal Investigator of the Retroviral Immunopathology Section and Senior Principal Scientist and Head of the Tissue Analysis Core. Dr. Estes was appointed an Adjunct Professor in the School of Health and Biomedical Sciences in the College of Science, Engineering and Health at RMIT University in Melbourne, Australia in 2017. In 2017, Dr. Estes accepted a dual appointment as Professor within the Vaccine and Gene Therapy Institute (VGTI) and Chief of the Division of Pathobiology & Immunology in the Oregon National Primate Research Center (ONPRC) at OHSU.
- Kathleen Busman-Sahay, Ph.D.
- Chi Ngai Chan, Ph.D.
- Leslie Johnston, B.S.
- Michael Nekorchuk, Ph.D.
Areas of interest
- HIV/SIV immunopathology, reservoir persistence, inflammatory bowel disease, and lymphoid and intestinal fibrosis
- Ph.D., Brigham Young University, Provo Utah United States 2003
Ortiz AM, Flynn JK, DiNapoli SR, Vujkovic-Cvijin I, Starke CE, Lai SH, Long ME, Sortino O, Vinton CL, Mudd JC, Johnston L, Busman-Sahay K, Belkaid Y, Estes JD, Brenchley JM. Experimental microbial dysbiosis does not promote disease progression in SIV-infected macaques. Nat Med. 2018 Jul 30. doi: 10.1038/s41591-018-0132-5. [Epub ahead of print] PubMed PMID: 30061696.
Marshall VA, Labo N, Hao XP, Holdridge B, Thompson M, Miley W, Brands C, Coalter V, Kiser R, Anver M, Golubeva Y, Warner A, Jaffe ES, Piatak M Jr, Wong SW, Ohlen C, MacAllister R, Smedley J, Deleage C, Del Prete GQ, Lifson JD, Estes JD, Whitby D. Gammaherpesvirus infection and malignant disease in rhesus macaques experimentally infected with SIV or SHIV. PLoS Pathog. 2018 Jul 12;14(7):e1007130. doi: 10.1371/journal.ppat.1007130. eCollection 2018 Jul. PubMed PMID: 30001436; PubMed Central PMCID: PMC6042791.
Estes JD, Wong SW, Brenchley JM. Nonhuman primate models of human viral infections. Nat Rev Immunol. 2018 Jun;18(6):390-404. doi: 10.1038/s41577-018-0005-7. Review. PubMed PMID: 29556017; PubMed Central PMCID: PMC5970954.
Peterson CW, Wang J, Deleage C, Reddy S, Kaur J, Polacino P, Reik A, Huang ML, Jerome KR, Hu SL, Holmes MC, Estes JD, Kiem HP. Differential impact of transplantation on peripheral and tissue-associated viral reservoirs: Implications for HIV gene therapy. PLoS Pathog. 2018 Apr 19;14(4):e1006956. doi: 10.1371/journal.ppat.1006956. eCollection 2018 Apr. PubMed PMID: 29672640; PubMed Central PMCID: PMC5908070.
Estes JD, LeGrand R, Petrovas C. Visualizing the Immune System: Providing Key Insights into HIV/SIV Infections. Front Immunol. 2018 Mar 2;9:423. doi: 10.3389/fimmu.2018.00423. eCollection 2018. Review. PubMed PMID: 29552017; PubMed Central PMCID: PMC5840205.
Deleage C, Chan CN, Busman-Sahay K, Estes JD. Next-generation in situ hybridization approaches to define and quantify HIV and SIV reservoirs in tissue microenvironments. Retrovirology. 2018 Jan 9;15(1):4. doi: 10.1186/s12977-017-0387-9. Review. PubMed PMID: 29316956; PubMed Central PMCID: PMC5761108.
Estes JD, Kityo C, Ssali F, Swainson L, Makamdop KN, Del Prete GQ, Deeks SG, Luciw PA, Chipman JG, Beilman GJ, Hoskuldsson T, Khoruts A, Anderson J, Deleage C, Jasurda J, Schmidt TE, Hafertepe M, Callisto SP, Pearson H, Reimann T, Schuster J, Schoephoerster J, Southern P, Perkey K, Shang L, Wietgrefe SW, Fletcher CV, Lifson JD, Douek DC, McCune JM, Haase AT, Schacker TW. Defining total-body AIDS-virus burden with implications for curative strategies. Nat Med. 2017 Nov;23(11):1271-1276. doi: 10.1038/nm.4411. Epub 2017 Oct 2. PubMed PMID: 28967921; PubMed Central PMCID: PMC5831193.
McGary CS, Deleage C, Harper J, Micci L, Ribeiro SP, Paganini S, Kuri-Cervantes L, Benne C, Ryan ES, Balderas R, Jean S, Easley K, Marconi V, Silvestri G, Estes JD, Sekaly RP, Paiardini M. CTLA-4(+)PD-1(-) Memory CD4(+) T Cells Critically Contribute to Viral Persistence in Antiretroviral Therapy-Suppressed, SIV-Infected Rhesus Macaques. Immunity. 2017 Oct 17;47(4):776-788.e5. doi: 10.1016/j.immuni.2017.09.018. PubMed PMID: 29045906; PubMed Central PMCID: PMC5679306.
Petrovas C, Ferrando-Martinez S, Gerner MY, Casazza JP, Pegu A, Deleage C, Cooper A, Hataye J, Andrews S, Ambrozak D, Del Río Estrada PM, Boritz E, Paris R, Moysi E, Boswell KL, Ruiz-Mateos E, Vagios I, Leal M, Ablanedo-Terrazas Y, Rivero A, Gonzalez-Hernandez LA, McDermott AB, Moir S, Reyes-Terán G, Docobo F, Pantaleo G, Douek DC, Betts MR, Estes JD, Germain RN, Mascola JR, Koup RA. Follicular CD8 T cells accumulate in HIV infection and can kill infected cells in vitro via bispecific antibodies. Sci Transl Med. 2017 Jan 18;9(373). pii: eaag2285. doi: 10.1126/scitranslmed.aag2285. PubMed PMID: 28100833; PubMed Central PMCID: PMC5497679.
Osuna CE, Lim SY, Deleage C, Griffin BD, Stein D, Schroeder LT, Omange RW, Best K, Luo M, Hraber PT, Andersen-Elyard H, Ojeda EF, Huang S, Vanlandingham DL, Higgs S, Perelson AS, Estes JD, Safronetz D, Lewis MG, Whitney JB. Zika viral dynamics and shedding in rhesus and cynomolgus macaques. Nat Med. 2016 Dec;22(12):1448-1455. doi: 10.1038/nm.4206. Epub 2016 Oct 3. Erratum in: Nat Med. 2017 Feb 7;23 (2):264. PubMed PMID: 27694931; PubMed Central PMCID: PMC5293594.
- "B cell follicle sanctuary permits persistent productive simian immunodeficiency virus infection in elite controllers" Nature Medicine 2015
- "Erratum" Nature October 30 2014
- "Molecularly tagged simian immunodeficiency virus SIVmac239 synthetic swarm for tracking independent infection events" Journal of Virology 2014
- "Immune clearance of highly pathogenic SIV infection" Nature 2013
- "Premature induction of an immunosuppressive regulatory T cell response during acute simian immunodeficiency virus infection" Journal of Infectious Diseases March 1 2006
- "Reduced inflammation and lymphoid tissue immunopathology in rhesus macaques receiving anti-tumor necrosis factor treatment during primary simian immunodeficiency virus infection" Journal of Infectious Diseases 2013
- "Effect of suberoylanilide hydroxamic acid (SAHA) Administration on the residual virus pool in a model of combination antiretroviral therapy-mediated suppression in SIVmac239-Infected Indian rhesus macaques" Antimicrobial Agents and Chemotherapy November 1 2014
- "Restricted replication of xenotropic murine leukemia virus-related virus in pigtailed macaques" Journal of Virology March 2012
- "Elevated Plasma Viral Loads in Romidepsin-Treated Simian Immunodeficiency Virus-Infected Rhesus Macaques on Suppressive Combination Antiretroviral Therapy" Antimicrobial Agents and Chemotherapy March 1 2016
- "Effect of anti-IL-15 administration on T Cell and NK cell homeostasis in rhesus macaques" Journal of Immunology August 15 2016
- "Microbial Translocation and Inflammation Occur in Hyperacute Immunodeficiency Virus Infection and Compromise Host Control of Virus Replication" PLoS Pathogens December 7 2016
- "Distribution, persistence, and efficacy of adoptively transferred central and effector memory-derived autologous simian immunodeficiency virus-specific CD8+ T cell clones in rhesus macaques during acute infection" Journal of Immunology January 1 2010
- "An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist" New England Journal of Medicine June 4 2009
- "Gut epithelial barrier and systemic inflammation during chronic HIV infection" AIDS January 1 2015
- "Maintenance of Intestinal Th17 Cells and Reduced Microbial Translocation in SIV-infected Rhesus Macaques Treated with Interleukin (IL)-21" PLoS Pathogens July 1 2013
- "Intrarectal transmission, systemic infection, and CD4+ T cell depletion in humanized mice infected with HIV-1" Journal of Experimental Medicine April 16 2007
- "Experimental colitis in SIV-uninfected rhesus macaques recapitulates important features of pathogenic SIV infection" Nature Communications August 18 2015
- "Peak SIV replication in resting memory CD4+ T cells depletes gut lamina propria CD4+ T cells" Nature April 28 2005
- "Zika viral dynamics and shedding in rhesus and cynomolgus macaques" Nature Medicine December 1 2016
- "Inflammatory cytokines drive CD4+ t-cell cycling and impaired responsiveness to interleukin 7" Journal of Infectious Diseases August 15 2014
- "Administration of interleukin-7 increases CD4 T cells in idiopathic CD4 lymphocytopenia" Blood February 25 2016
- "CXCR5+ follicular cytotoxic T cells control viral infection in B cell follicles" Nature Immunology September 20 2016
- "Downregulation of robust acute type I interferon responses distinguishes nonpathogenic simian immunodeficiency virus (SIV) infection of natural hosts from pathogenic SIV infection of rhesus macaques" Journal of Virology August 1 2010
- "Decreases in Colonic and Systemic Inflammation in Chronic HIV Infection after IL-7 Administration" PLoS Pathogens January 1 2014
- "Large number of rebounding/founder HIV variants emerge from multifocal infection in lymphatic tissues after treatment interruption" Proceedings of the National Academy of Sciences of the United States of America March 10 2015
- "Interleukin-21 combined with ART reduces inflammation and viral reservoir in SIV-infected macaques" Journal of Clinical Investigation December 1 2015
- "Collagen deposition limits immune reconstitution in the gut" Journal of Infectious Diseases August 15 2008
- "Enhancing immune responses to limit chronic immune activation during SIV" Journal of Clinical Investigation May 1 2012
- "Follicular dendritic cells and human immunodeficiency virus type 1 transcription in CD4+ T cells" Journal of Virology January 1 2009
- "Increased intestinal permeability correlates with sigmoid mucosa alpha-synuclein staining and endotoxin exposure markers in early Parkinson's disease" PLoS One December 1 2011