Walker

Bruce Walker, MD

Lab Info:

Principal Investigator: Bruce Walker, MD

Office/Location: 400TS 870

Phone: (857) 268-7073

Email: bwalker@partners.org | Assistant: Gaby Berger gberger1@partners.org

Category: Group Leaders, Members

The Walker laboratory focuses on mechanisms of immune control in HIV infection, focusing in particular on persons who control HIV infection spontaneously without the need for medication. Through an international collaboration now funded by the Gates Foundation, more than 1500 persons who control HIV infection to less than 2000 RNA Copies/ml without the need for antiviral medications have been recruited, and immunologic, virologic and host genetic mechanisms accounting for this remarkable phenotype are being investigated. Our results,  published in Science, indicate that the major genetic determinants of HIV control affect the nature of the peptide-HLA binding. We are currently focusing our research efforts on this interaction and how it impacts the inductive and effector phases of the CD8 T cell response.

 

Other projects currently underway are building on a observation that the antiviral efficacy of CTL varies dramatically among different epitopes and different restricting HLA alleles, in an attempt to define the major antiviral effector functions and apply these to vaccine development. At the same time, efforts are underway to define the subset of CD8 T cell responses that exert the strongest antiviral effect, and to define those responses that are simply passengers and fail to contribute to immune control.

 

In addition to these efforts in Boston, a major effort is underway at our laboratory at the Nelson Mandela School of Medicine at the University of KwaZulu-Natal, South Africa, where a major population based effort is underway to define evolution of clade C virus infection under immune selection pressure, and to define predictable pathways to immune escape. We have established a mechanism for recruitment of persons with acute HIV infection by screening persons who test antibody negative at VCT (now HCT) sites in KZN. We anticipate an expanding collaboration with persons at the Ithembalebantu Clinic in Umlazi to accelerate these studies, which will include examination of tissue biopsies.

 

Persons interested in joining this lab should have a strong background in immunology and/or molecular biology, a strong interest in working on immune responses in humans, and an ability to work relatively independently. The lab is highly collaborative with other labs within the Ragon Institute and outside, and thus seeks people who are committed to scientific collaboration. Please visit the Training Programs page for information about how to apply.

 

 

Important Accomplishments

  • Identification of strong circulating HIV-specific cytotoxic T lymphocytes in infected persons.
  • Identification of HIV-specific CD4 T cells and their association with immune control of HIV.
  • Identification of immunoregulatory pathways that turn HIV-specific immune responses off in vivo.
  • Demonstration of the superior antiviral efficacy of Gag-specific CD8 T cell responses.

Present Areas of Investigation

  • Define the relative antiviral efficacy of epitope-specific CTL responses in infected persons
  • Define the predicatable pathways to immune escape in infected persons
  • Define the mechanisms that underlie effective cell killing
  • Define the mechanisms of spontaneous control of HIV infection using a genome wide association scan.

Selected Publications

1.   Walker BD, Chakrabarti S, Moss B, Paradis TJ, Flynn T, Durno AG, Blumberg RS, Kaplan JC, Hirsch MS, Schooley RT. HIV-specific cytotoxic T lymphocytes in seropositive individuals. Nature. 1987; 328(6128):345-348.

Link to PubMed

2.   Walker BD, Flexner C, Paradis TJ, Fuller T, Hirsch MS, Schooley RT, Moss B.  HIV-1 reverse transcriptase is a target for cytotoxic T lymphocytes in infected individuals.  Science 1988; 240:64-66.

Link to PubMed

3.   Yang OO, Kalams SA, Trocha A, Cao H, Luster A, Johnson RP, Walker BD.  Suppression of human immunodeficiency virus type 1 replication by CD8+ cells: Evidence for HLA class I-restricted triggering of cytolytic and noncytolytic mechanisms.  J Virol 1997; 71:3120-3128.

Link to PubMed

4.   Goulder PJ, Brander, C, Tang Y, Tremblay C, Colbert RA, Addo MA, Rosenberg ES, Nguyen T, Allen R, Trocha A, Altfeld M, He S, Bunce M, Funkhouser R, Pelton SI, Burchett SK, McIntosh K, Korber BTM, Walker BD.  Evolution and transmission of stable CTL escape mutations in HIV infection.  Nature.  2001; 412(6844):334-338.

Link to PubMed

5.   Rosenberg ES, Billingsley JM, Caliendo AM, Boswell SL, Sax P, Kalams SA, Walker BD.  Vigorous HIV-1-specific CD4+ T cell responses correlate with control of viremia.  Science 1997; 278:1447-1450.

Link to PubMed

6.   Kaufmann DE, Lichterfeld M, Altfeld M, Addo MM, Johnston MN, Lee PK, Wagner BS, Kalife ET, Strick D, Rosenberg ES, Walker BD. Limited Durability of Viral Control following Treated Acute HIV Infection. PLoS Med. 2004 Nov;1(2):e36. Epub 2004 Oct 26.

Link to PubMed

7.   Altfeld M, Allen TM, Yu XG, Johnston MN, Agrawal D, Korber BT, Montefiori DC, O’Connor DH, Davis BT, Lee PK, Maier EL, Harlow J, Goulder PJR, Brander C, Rosenberg ES, Walker BD. HIV superinfection despite broad CD8+ T-cell responses containing replication of the primary virus. Nature.  2002 Nov 28; 420:434-439.

Link to PubMed

8.   Day C.L., Kaufmann D.E., Kiepiela P., Brown JA., Moodley ES., Reddy S., Mackey EW., Miller J.D., Leslie A.J., DePierres C., Mncube Z., Duraiswamy J., Zhu B., Eichbaum Q., Altfeld M., Wherry E.J., Coovadia H.M., Goulder P.J., Klenerman P., Ahmed R., Freeman GJ., Walker B.D. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression.  Nature.  2006 Sep 21; 443(7109):350-354.

Link to PubMed

9.   Kaufmann DE, Kavanagh DG, Pereyra F, Zaunders JJ, Mackey EW, Miura T, Palmer S, Brockman M, Rathod A, Piechocka-Trocha A, Baker B, Zhu B, Le Gall S, Waring MT, Ahern R, Moss K, Kelleher AD, Coffin JM, Freeman GJ, Rosenberg ES, Walker BD. Upregulation of CTLA-4 by HIV-specific CD4 (+) T cells correlates with disease progression and defines a reversible immune dysfunction. Nat Immunol. 2007 Nov; 8(11):1246-1254.

Link to PubMed

10.   Gaiha G, McKim KJ, Woods M,  Pertel T, Rohrbach J, Barteneva N, Chin CR, Liu D, Soghoian DZ, Cesa K, Wilton S, Waring MT, Chicoine A, Doering T, Wherry J, Kaufmann, D, Lichterfeld M, Brass AL  & Walker BD.  Dysfunctional HIV-specific CD8+ T cell proliferation is associated with increased caspase-8 activity and mediated by necroptosis.  Immunity 41(6): 1001-1012.

Link to PubMed

11.   Chen H, Ndhlovu ZM, Liu D, Porter LC, Fang JW, Darko S, Brockman MA, Miura T, Brumme ZL, Schneidewind A, Piechocka-Trocha A, Cesa KT, Sela J, Cung TD, Toth I, Pereyra F, Yu XG, Douek DC, Kaufmann DE, Allen TM, Walker BD. TCR clonotypes modulate the protective effect of HLA class I molecules in HIV-1 infection. Nat Immunol. 2012 Jun 10; 13(7):691-700.

Link to PubMed

12.   Pereyra F, Jia X, McLaren PJ, Telenti A, De Bakker P, Walker BD et al. The Major Genetic Determinants of HIV-1 Control Affect HLA Class I Peptide Presentation; The International HIV Controller Study. Science 2010 Dec 10; 330(6010):1551-1557.

Link to PubMed

13.   Miura T, Brockman MA, Brumme ZL, Brumme CJ, Pereyra F, Trocha A, Block BL, Schneidewind A, Allen TM, Heckerman D, Walker BD. HLA-associated alterations in replication capacity of chimeric NL4-3 viruses carrying gag-protease from elite controllers of human immunodeficiency virus type 1. J Virol. 2009 Jan; 83(1):140-149.

Link to PubMed

14.   Ferguson AL, Mann JK, Omarjee S, Ndung’u T, Walker BD, Chakraborty AK. Translating HIV Sequences into Quantitative Fitness Landscapes Predicts Viral Vulnerabilities for Rational Immunogen Design. Immunity. 2013 Mar 21; 38(3):606-617.

Link to PubMed

15.   Park RJ, Wang T, Koundakjian D, Hultquist JF, Lamothe-Molina P, Monel B, Schumann K, Yu H, Krupzcak KM, Garcia-Beltran W, Piechocka-Trocha A, Krogan NJ, Marson A, Sabatini DM, Lander ES, Hacohen N, Walker BD. A genome-wide CRISPR screen identifies a restricted set of HIV host dependency factors. Nat Genet. 2017;49(2):193-203.

Link to PubMed

16.   Kiepiela P, Leslie AJ, Honeyborne I, Ramduth D, Thobakgale C, Chetty S, Rathnavalu P, … Bunce M, Barber LD, Szinger J, Day C, Klenerman P, Mullins J, Korber B, Coovadia HM, Walker BD, Goulder PJ. Dominant influence of HLA-B in mediating the potential co-evolution of HIV and HLA. Nature. 2004;432(7018):769-775.

Link to PubMed

17.   Kiepiela P, Ngumbela K, Thobakgale C, Ramduth D, Honeyborne I, Moodley E, Reddy S, … 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. Nat Med. 2007 Jan;13(1):46-53.

Link to PubMed

18.   Radebe M, Gounder K, Mokgoro M, Ndhlovu ZM, Mncube Z, Mkhize L, van der Stok M, Jaggernath M, Walker BD, Ndung’u T. Broad and persistent Gag-specific CD8+ T-cell responses are associated with viral control but rarely drive viral escape during primary HIV-1 infection. AIDS. 2015;29(1):23-33.

Link to PubMed

19.   Ndhlovu ZM, Kamya P, Mewalal N, Kløverpris HN, Nkosi T, Pretorius K, Laher F, Ogunshola F… Chakraborty A, Dong K, Ndung’u T, Walker BD. Magnitude and Kinetics of CD8(+) T Cell Activation during Hyperacute HIV Infection Impact Viral Set Point. Immunity. 2015 Sep 15; 43(3):591-604.

Link to PubMed

Relevant Links

Laboratory Staff

kiera
Kiera Clayton | klclayton@partners.org
Kiera Clayton is a Postdoctoral Fellow who joined the Walker Lab in December of 2014. Her work focuses on understanding how co-inhibitory pathways play a role in modulating HIV-specific responses and their impact on protective T cell memory formation during HIV infection. She obtained an Honors BS in Biochemistry followed by her PhD in Immunology, both from the University of Toronto in Canada. During her PhD, she studied the co-inhibitory molecule, Tim-3, and characterized its function and regulation in human CD8+ T cells. In her free time, she enjoys running, skiing, wine tasting, and jazz.

Collins,David

David Collins | drcollins@mgh.harvard.edu
David joined the Walker lab as a postdoctoral fellow in August 2015. His research aims to better define the hallmarks of effective memory CTL responses and to identify mechanisms of immune failure in a cohort of progressors who previously maintained durable HIV control. David is originally from upstate New York and holds a B.S. in microbiology from University of Rochester and a Ph.D. in microbiology and immunology from University of Michigan, where his thesis research elucidated the roles of Vpr and macrophage infection in HIV pathogenesis. Outside of lab David enjoys volunteering at animal shelters, playing tennis, and occasionally sleeping.

guarav
Gaurav Gaiha
I am originally from Chicago, IL. I completed by BS in Biochemistry and BA in Economics from the University of Illinois in 2003. I subsequently obtained a PhD in Biochemistry with a focus in HIV immunology at Oxford University working in the MRC Immunochemistry Unit and in collaboration with the MRC Human Immunology Unit. After Oxford, I moved onto the Health Sciences and Technology (HST) program at Harvard Medical School to complete my MD, which I completed with Magna Cum Laude honors based on work I completed at the Ragon Institute of MGH, MIT and Harvard in the lab of Prof. Bruce Walker. I am now a 2nd-year Internal Medicine Resident at Massachusetts General Hospital and continue to pursue active projects in the lab.My research interests are focused on understanding the properties that define successful and dysfunctional HIV-specific CD8+ T cell responses in patients with divergent clinical outcomes using transcriptional profiling and shRNA knockdown technology. I am also working on a novel network analysis platform to identify critical areas of mutational constraint within the HIV proteome and ultimately hope to parlay this work into novel T-cell based vaccine designs.”

 

Nwonu,Chioma

Chioma Anthonia Nwonu | cnwonu@mgh.harvard.edu
Chioma joined the Walker laboratory in September 2015 as a research technician under the direction of Srinika Ranasinghe. She attended Smith College where she majored in Biochemistry with a strong background in molecular biology. She previously worked in a laboratory at Smith College that studies the molecular biology of lymphatic filariasis, a neglected tropical disease. She hopes to pursue a career in medicine and clinical research. Chioma is from Nigeria and enjoys cooking traditional Nigerian dishes.

ryan_park
Ryan Park | rjpark@partners.org
Ryan is an MD student at Harvard Medical School. He received a B.S. and an M.S. in Molecular Biophysics and Biochemistry from Yale University in 2012. He is in the Harvard-MIT Health Sciences & Technology (HST) program and joined the Walker lab in January 2013 for his thesis project. He’s originally from Los Angeles but has also lived in Chicago, Fort Worth, and Seoul. In the lab, he is trying to understand the mechanism for the differential function of CD8+ T cell clones from Elite Controllers and Chronic Progressors. In his dwindling time outside of the lab and classroom, he enjoys cooking, playing the saxophone, and reading and dreaming about fast cars.

alicja
Alicja Piechocka-Trocha | atrocha@partners.org
Alicja is a Senior Laboratory Manager for the Ragon Institute and has been working for Dr. Bruce Walker for the last 24 years. Trained as a veterinarian from Polish Agriculture University in Olsztyn, she began to perform research, and despite all odds, she truly learned to love it. The aspect of teaching and educating future aspiring scientist as well as cultivating all habits of safe and meticulous lab work in young students and fellows has become a professional journey for her. What they learn with Alicja they will apply in their new endeavors. When not at work she enjoys reading books, long nature walks and skiing.

Adrienne
Adrienne Yanez | adrienneg_yanez@dfci.harvard.edu

Adrienne joined the Porichis lab as a research fellow in March 2015. She is working to identify and manipulate gene regulatory networks that improve HIV-specific CD4 T-cell responses to HIV infection. She received her Ph.D. from Harvard University, where she studied global regulation of miRNA activity by translation initiation factors in melanoma.  In her spare time, she enjoys playing outside, exploring her surroundings, and gazing into empty centrifuges (see picture above).

 

 

 

 

 

 

Joshua Lengieza | jlengieza@partners.org

Josh joined the Walker lab in May 2016 as a research technician working under Kiera Clayton. He graduated from MCPHS University with a B.S. in Medical and Molecular Biology. During his undergraduate studies, he worked on nociceptors involvement in immune responses. Outside of the lab Josh enjoys biking, going to the beach and reading.

 

 

Former Laboratory Members