Virology
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Bruce D. Walker, M.D.

Professor of Medicine;

Ragon Institute of MGH, MIT, and Harvard
Mass General Hospital-East
149 13th Street, Room 5212D
Charlestown, MA 02129
Tel: 617-724-8332
Fax: 617-726-4691
e-mail: bwalker@partners.org
Tel: 617-724-8332
Fax: 617-726-4691
e-mail: bwalker@partners.org
6 postdoctoral fellows, 1 pre-doctoral students

 

 Bruce Walker

     Our laboratory focuses on the cellular immune response to human viral pathogens, particularly HIV-1 and hepatitis C virus (HCV). , Numerous studies in murine models of viral infection have shown a protective role for virus-specific CTL and virus-specific T helper cell responses. We have been investigating the role of these cells in chronic human viral infections, and are particularly interested in translational studies,focusing in particular on translating questions at the bedside to the lab, and answers from the lab back to the bedside. A number of areas are being targeted, including:

Immune control of acute viral infections:  For both HIV and HCV infection, we have established cohorts of persons with acute infection who we have studied longitudinally to determine the virologic and immunologic factors that influence different disease outcomes.  Studies focus on the earliest targets of the cellular immune response, the mechanisms of immune control, host genetic factors that influence adaptive immune responses, and the role of specific effector cells in viral containment in the critical early phases of infection.  The cases of acute HIV infection are recruited locally, and those with acute HCV infection come from a collaboration in Brazil.

Viral evolution under immune selection pressure:  These studies are based on persons with acute and chronic infection, with the goal of determining the pathways to immune escape and the effects of selection pressure at a population level.  The studies focus in part on a cohort of HIV infected Zulu patients in South Africa, where we have built a state of the art basic science research facility that allows us to conduct detailed virology and immunology studies on site. Past students have conducted parts of their studies at this site in Africa.   In addition, a collaboration with the Broad Institute in Cambridge is dramatically increasing our sequencing capacity by bringing the automated approaches from the Human Genome Project to the HIV field.

Antigen processing and immunodominance:  The immune system has the potential ability to target multiple epitopes, but repeatedly selects the same few for recognition.  These studies based on detailed examination of the antigen processing pathway, are designed to determine the factors that influence immunodominance and are focused on application to vaccine efforts. 

Elite Control of HIV:  We have assembled a cohort of over 600 persons who are able to control HIV without the need for medications.  Those who maintain viral loads of less than 50 RNA copies/ml are termed elite controllers, and a major focus is on defining the mechanisms of this remarkable outcome. 

References:  

  • Bhattacharya, T., M. Daniels, D. Heckerman, B. Foley, N. Frahm, C. Kadie, J. Carlson, K. Yusim, B. McMahon, B. Gaschen, S. Mallal, J.I. Mullins, D.C. Nickle, J. Herbeck, C. Rousseau, G.H. Learn, T. Miura, C. Brander, B. Walker, and B. Korber. 2007. Founder effects in the assessment of HIV polymorphisms and HLA allele associations. Science 315:1583-1586.       Kim, A.Y., J. Schulze zur Wiesch, T. Kuntzen, J. Timm, D.E. Kaufmann, J.E. Duncan, A.M. Jones, A.G. Wurcel, B.T. Davis, R.T. Gandhi, G.K. Robbins, T.M. Allen, R.T. Chung, G.M. Lauer, and B.D. Walker. 2006. Impaired hepatitis C virus-specific T cell responses and recurrent hepatitis C virus in HIV coinfection. PLoS Med 3:e492.
  • Kiepiela, P., K. Ngumbela, C. Thobakgale, D. Ramduth, I. Honeyborne, E. Moodley, S. Reddy, C. de Pierres, Z. Mncube, N. Mkhwanazi, K. Bishop, M. van der Stok, K. Nair, N. Khan, H. Crawford, R. Payne, A. Leslie, J. Prado, A. Prendergast, J. Frater, N. McCarthy, C. Brander, G.H. Learn, D. Nickle, C. Rousseau, H. Coovadia, J.I. Mullins, D. Heckerman, B.D. Walker, and P. Goulder. 2007. CD8+ T-cell responses to different HIV proteins have discordant associations with viral load. Nat Med 13:46-53.
  • Day, C.L., D.E. Kaufmann, P. Kiepiela, J.A. Brown, E.S. Moodley, S. Reddy, E.W. Mackey, J.D. Miller, A.J. Leslie, C. DePierres, Z. Mncube, J. Duraiswamy, B. Zhu, Q. Eichbaum, M. Altfeld, E.J. Wherry, H.M. Coovadia, P.J. Goulder, P. Klenerman, R. Ahmed, G.J. Freeman, and B.D. Walker. 2006. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443:350-354.
  • Allen, T.M., M. Altfeld, S.C. Geer, E.T. Kalife, C. Moore, M. O'Sullivan K, I. Desouza, M.E. Feeney, R.L. Eldridge, E.L. Maier, D.E. Kaufmann, M.P. Lahaie, L. Reyor, G. Tanzi, M.N. Johnston, C. Brander, R. Draenert, J.K. Rockstroh, H. Jessen, E.S. Rosenberg, S.A. Mallal, and B.D. Walker. 2005. Selective escape from CD8+ T-cell responses represents a major driving force of human immunodeficiency virus type 1 (HIV-1) sequence diversity and reveals constraints on HIV-1 evolution. J Virol 79:13239-13249.
  • Allen, T.M., M. Altfeld, X.G. Yu, K.M. O'Sullivan, M. Lichterfeld, S. Le Gall, M. John, B.R. Mothe, P.K. Lee, E.T. Kalife, D.E. Cohen, K.A. Freedberg, D.A. Strick, M.N. Johnston, A. Sette, E.S. Rosenberg, S.A. Mallal, P.J. Goulder, C. Brander, and B.D. Walker. 2004. Selection, transmission, and reversion of an antigen-processing cytotoxic T-lymphocyte escape mutation in human immunodeficiency virus type 1 infection. J Virol 78:7069-7078.