Major Areas of Research
- HIV disease pathogenesis
- The HIV reservoir
- Immune repertoire analysis and vaccine correlates
The Human Immunology Section (HIS) studies the processes that determine the course of human diseases in which the immune system plays a central role in their pathogenesis and outcome. Our overriding philosophy is to address questions of human disease directly in humans. We try to avoid the constraints of hypothesis-driven or circumstantial evidence-based approaches, while using state-of-the art technologies to measure as many aspects of the diseased system as possible and thus use the knowledge gained to initiate clinical studies of new therapeutic and vaccine approaches.
Our studies of HIV explore the cellular and molecular mechanisms by which the virus is acquired and disease progression is maintained, with an emphasis on host genetic and microbiological factors that render an individual vulnerable to infection. We explore the relationships among target cell types and availability as the reservoir for HIV, systemic inflammation, lymphoid tissue architecture, the gastrointestinal mucosal barrier and the individual's 'pathogen burden' in determining the rate of disease progression, particularly during treatment with antiretroviral drugs. As route of exposure to HIV is a critical determinant of acquisition, we thus study cohorts of both men and women to adopt a truly trans-gender approach.
Another major aspect of our work is to explore immune receptor repertoire diversity in infectious disease and cancer. T cell and B cell receptor repertoires, which begin to develop in the fetus, endow the immune system with a prerogative for the specific recognition of antigens, and immunological memory is the direct consequence of that entitlement.
Critical to the development of vaccines and other immunological interventions is a deep understanding of the evolution of these antigen-specific repertoires at the level of the receptor-epitope interface. To pursue these studies, we have pioneered methods for next-generation sequencing and bioinformatic analysis of T cell and B cell receptor repertoires. While much of the laboratory's bench work is, by definition, science-based, our bioinformatic analyses which make up an increasingly greater proportion of the laboratory's work incorporate a more art-based approach in order to convey large and complex datasets in accessible graphical formats.
Dr. Douek studied medicine at the Universities of Oxford and London, receiving academic scholarships from both institutions. He then practiced internal medicine and became a Member of the Royal College of Physicians (London) in 1993. He was awarded a Wellcome Trust Clinical Graduate Training Fellowship to pursue a Ph.D. in immunology at the University of London, which he earned in 1997. He completed his postdoctoral work at the Rockefeller University and the University of Texas Southwestern Medical Center, Dallas, where he was named assistant professor in infectious diseases (2000). While a postdoctoral fellow with Dr. Richard Koup, he developed the “TREC assay” to measure thymic output in humans. Dr. Douek was appointed to a tenure-track position in the Vaccine Research Center (VRC) Laboratory of Immunology in November 2000. Dr. Douek brought impressive academic credentials, training, and experience to the VRC and is internationally recognized in the fields of basic immunology, HIV, and transplantation biology. He was converted to a tenured senior investigator position in February 2007, the year in which he was presented with the World AIDS Day Award. He serves as chief of the Human Immunology Section at the VRC.
Boritz EA, Darko S, Swaszek L, Wolf G, Wells D, Wu X, Henry AR, Laboune F, Hu J, Ambrozak D, Hughes MS, Hoh R, Casazza JP, Vostal A, Bunis D, Nganou-Makamdop K, Lee JS, Migueles SA, Koup RA, Connors M, Moir S, Schacker T, Maldarelli F, Hughes SH, Deeks SG, Douek DC. Multiple Origins of Virus Persistence during Natural Control of HIV Infection. Cell. 2016 Aug 11;166(4):1004-15. doi: 10.1016/j.cell.2016.06.039.
Sandler NG, Bosinger SE, Estes JD, Zhu RTR, Tharp GK, Boritz E, Levin D, Wijeyesinghe S, Nganou Makamdop K, del Prete GQ, Hill BJ, Timmer JK, Reiss E, Yarden G, Darko S, Contijoch E, Todd JP, Silvestri G, Nason M, Norgren RB Jr., Keele BF, Rao S, Langer JA, Lifson JD, Schreiber G and Douek DC. Type I IFN responses in rhesus macaques prevent SIV infection and slow disease progression.Nature 511:601-605 (2014).
Milner JD, Brenchley JM, Laurence A, Freeman AF, Hill BJ, Elias KM, Kanno Y, Spalding C, Elloumi HZ, Paulson ML, Davis J, Hsu A, Asher AI, O'Shea J, Holland SM, Paul WE, Douek DC. Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature. 2008 Apr 10;452(7188):773-6.
Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, Rao S, Kazzaz Z, Bornstein E, Lambotte O, Altmann D, Blazar BR, Rodriguez B, Teixeira-Johnson L, Landay A, Martin JN, Hecht FM, Picker LJ, Lederman MM, Deeks SG, Douek DC. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med. 2006 Dec;12(12):1365-71.
Douek DC, Brenchley JM, Betts MR, Ambrozak DR, Hill BJ, Okamoto Y, Casazza JP, Kuruppu J, Kunstman K, Wolinsky S, Grossman Z, Dybul M, Oxenius A, Price DA, Connors M, Koup RA. HIV preferentially infects HIV-specific CD4+ T cells. Nature. 2002 May 2;417(6884):95-8.
Douek DC, McFarland RD, Keiser PH, Gage EA, Massey JM, Haynes BF, Polis MA, Haase AT, Feinberg MB, Sullivan JL, Jamieson BD, Zack JA, Picker LJ, Koup RA. Changes in thymic function with age and during the treatment of HIV infection. Nature. 1998 Dec 17;396(6712):690-5.