Bruce D. Walker, M.D.
Ragon Institute of MGH, MIT, and Harvard
AIDS Research Center, Rm. 5212D
149 13th Street
Charlestown, MA 02129
Our laboratory focuses on the cellular immune response to human viral pathogens, particularly HIV-1. 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: 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 major focus of these studies is now on a new cohort of high risk uninfected women in KwaZulu Natal, South Africa, who are being screened twice weekly for viral RNA to identify incident infections. Both pre and post infection samples are available from these persons, and investigations include not just peripheral blood but also tissue studies.
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 role of TCR diversity in contributing to immune containment. Our recent studies indicate that specific TCR clonotypes modulate the protective effects of HLA class I alleles, and explain the clinical observation that possessing a protective HLA class I allele such as B*27 or B*57 is not in itself predictive of immune containment. Efforts are underway to understand induction of highly cross reactive and highly functional CTL responses, in part using cohorts in Boston and in part cohorts in South Africa, where we maintain a vibrant research operation.
Elite Control of HIV: We have assembled a cohort of over 600 persons who are able to control HIV to undetectable levels 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.
1. Day CL, Kaufmann DE, Kiepiela P, Brown JA, Moodley ES, Reddy S, Mackey EW, Miller JD, Leslie AJ, DePierres C, Mncube Z, Duraiswamy J, Zhu B, Eichbaum Q, Altfeld M, Wherry EJ, Coovadia HM, Goulder PJ, Klenerman P, Ahmed R, Freeman GJ, Walker BD. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature. 2006;443(7109):350-4.
2. Kiepiela P, Ngumbela K, Thobakgale C, Ramduth D, Honeyborne I, Moodley E, Reddy S, de Pierres C, Mncube Z, Mkhwanazi N, Bishop K, van der Stok M, Nair K, Khan N, Crawford H, Payne R, Leslie A, Prado J, Prendergast A, Frater J, McCarthy N, Brander C, Learn GH, Nickle D, Rousseau C, Coovadia H, Mullins JI, Heckerman D, Walker BD, Goulder P. CD8+ T-cell responses to different HIV proteins have discordant associations with viral load. Nature medicine. 2007;13(1):46-53.
3. Dahirel V, Shekhar K, Pereyra F, Miura T, Artyomov M, Talsania S, Allen TM, Altfeld M, Carrington M, Irvine DJ, Walker BD, Chakraborty AK. Coordinate linkage of HIV evolution reveals regions of immunological vulnerability. Proceedings of the National Academy of Sciences of the United States of America. 2011;108(28):11530-5. Epub 2011/06/22.
4. Radebe M, Nair K, Chonco F, Bishop K, Wright JK, van der Stok M, Bassett IV, Mncube Z, Altfeld M, Walker BD, Ndung'u T. Limited Immunogenicity of HIV CD8+ T-Cell Epitopes in Acute Clade C Virus Infection. The Journal of infectious diseases. 2011;204(5):768-76. Epub 2011/08/17.
5. Chen H, Ndhlovu ZM, Walker B. TCR clonotypes modulate the protective effect of HLA class I alleles. Nature immunology. In press.
Last Update: 6/11/2012