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

20.   Gaiha GD, Rossin EJ, Urbach J, Landeros C, Collins DR, Nwonu C, Muzhingi I, Anahtar MN, Waring OM, Piechocka-Trocha A, Waring M, Worrall DP, Ghebremichael MS, Newman RM, Power KA, Allen TM, Chodosh J, Walker BD. Structural topology defines protective CD8(+) T cell epitopes in the HIV proteome. Science. 2019 May 3;364(6436):480-484.

Link to Full Text

Relevant Links

Laboratory Staff

Name: Kiera Clayton

Email: klclayton@partners.org

Bio: 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.

 

Name: David Collins

Email: drcollins@mgh.harvard.edu

Education: Ph.D., University of Michigan; B.S., University of Rochester

Hometown: Defreestville, New York

Bio: David joined the Walker lab as a Research Fellow in 2015. His research aims to elucidate molecular regulation of antiviral CD8+ T cell dysfunction in HIV-infected individuals. Outside of lab, David enjoys a quiet life with his feline overlords.

 

Name: Gaurav Gaiha

Email: ggaiha@mgh.harvard.edu

Education: D.Phil, Oxford University; M.D., Harvard Medical School (HST)

Hometown: Lake Forest, Illinois

Bio: Gaurav is an Instructor of Medicine at Harvard Medical School, Gastroenterologist at MGH and a Research Fellow in the Walker Lab. He is working on developing preventative and therapeutic T cell vaccines directed against structurally constrained regions of the HIV proteome. Using a novel approach known as structure-based network analysis, he has identified a set of viral targets within the virus that appear to be resistant to mutation due to their importance in maintaining the structural integrity of viral proteins. In collaboration with both academic and industry partners, he is now exploring a variety of vaccine delivery modalities to induce T cell responses directed against these targets in vivo. In his free time, he enjoys spending time with wife, daughter and labrador Charlie, and is an ardent supporter of all Chicago sports teams, most notably the Chicago Cubs.

 

Name: Xiaolong Li

Email: xiaolong@crystal.harvard.edu

Education: Ph.D., University of Science and Technology of China, Peking University, and Dana Farber Cancer Institute

Hometown: Anhui province of China, the hometown of Yellow Mountain

Bio: Xiaolong is a research fellow at the Dana-Farber Cancer Institute and the Ragon Institute. He is originally from China and received his Ph.D. in biochemistry and structural biology from the University of Science and Technology of China (USTC) in 2016. He began his graduate education at USTC (2011) then completed his Ph.D program at Peking University (2012-2014) and Dana-Farber Cancer Institute (2014-2016). He has a background in crystallography, biochemistry and molecular biology. He has experiences in biochemical and structural studies of receptor protein, kinase, antibody and axon guidance cue.  However, he has been focusing on structural studies of peptide-HLA (pHLA), TCR and pHLA/TCR complex for a long time. By determining protein structures, he is gaining insight into the molecular mechanism involved in HIV-1 elite controllers who have enhanced CTL responses and cross reactivity for the control of antigen mutations. In his free time, he enjoys hiking, biking and skiing.

 

Name: Itai Muzhingi

Email: imuzhingi@mgh.harvard.edu

Education: B.A. in Biochemistry and Biophysics, Amherst College

Hometown: Chitungwiza, Zimbabwe

Bio: Itai Muzhingi is a Research Technician in the Walker Lab working under Dr. Gaurav Gaiha. He is testing the efficacy of various HIV vaccines, studying the immunological effects of SNPs in HLA-B57 and screening for host factors that mediate Nef-induced HLA class I downregulation. In college, Itai elucidated a regulatory mechanism for acetyl-CoA synthetase expression in Vibrio cholerae. He is passionate about promoting African talent in the STEM fields. Itai enjoys listening to music and exploring anything that he considers to be truly novel.

 

Name: Zachary Racenet

Email: zracenet@mgh.harvard.edu

Education: B.S. in Biology, Castleton State University

Hometown: Danville, Vermont

Bio: Zachary returned to academia after spending a few years being a technician in industry in hopes of pursing a Ph.D. Originally from northern Vermont, he attended Castleton University and focused his studies on cellular metabolism. Despite beginning his studies outside the realm of immunology he is captivated by the responsiveness and complexity of the immune system as well as the subversive nature of viruses. He works with David Collins researching T-cell dysfunction. Zachary spends his free time pursuing fitness and learning about technology and electronics.

 

Name: Peter Shahinian

Email: pshahinian@mgh.harvard.edu

Education: B.S., B.A., Boston University; M3, Texas Tech University Health Sciences Center

Hometown: El Paso, Texas

Bio: Peter is a medical student from Texas Tech University who is doing a research year in the Walker Lab before returning to complete his fourth year of medical education. After graduation, he is planning on pursuing a residency in internal medicine. His current research interests are in understanding T-cell cross reactivity, engineering CAR-T cells, and manipulating the immune system in order to treat chronic disease. In his free time, he likes to tend to his indoor garden and digs through SoundCloud for the next up and coming hip-hop artist. He also thinks he’s good at playing the ukulele.

 

Name: Nishant Kumar Singh

Email: nsingh0@mgh.harvard.edu

Education: Ph.D., University of Notre Dame

Hometown: Jamshedpur, India

Bio: Nishant Singh is a joint Research Fellow in the Walker Lab and the Birnbaum Lab at Koch Institute at MIT. He received his Ph.D. in Biochemistry at the University of Notre Dame in 2019. At Notre Dame, he worked for Dr. Brian Baker, where he conducted structural and biophysical characterization of T cell receptor (TCR) variants with the goal to better understand the factors that govern antigen specificity and TCR mediated signaling in T cells. Since joining the Walker Lab, he has been working on defining the role of TCR recognition and signaling in immune control of HIV infection, using a unique, well-pedigreed bank of human samples. In general, he is interested in understanding the transcriptional and immunologic profiles of T cell responses in HIV infected individuals and recipients of candidate vaccines. In his free time, he likes to read books, run by the river and spend time with friends.

 

Name: Heather Stuart

Email: hastuart@mgh.harvard.edu

Education: Honors B.S. in Pharmaceutical Sciences, University of Rhode Island

Hometown: Warren, Rhode Island

Bio: Heather is a Research Technician in the Walker Lab working under Kiera Clayton. Her undergraduate studies focused on pharmaceutical science. She previously worked as a research associate intern in a pharmaceutical compounding lab. Her research interests shifted from pharmaceuticals to immunology after completing her senior honors project on EBV’s role in cancer. She plans to pursue a Ph.D. in immunology. In her free time, she enjoys taking care of her pet mice and her aquariums.

 

Name: Alicja Trocha

Email: atrocha@partners.org

Education: DVM, Polish Agriculture University

Hometown: Gdansk, Poland

Bio: Alicja Trocha is a Senior Laboratory Manager who has worked for Dr. Bruce Walker for many years. She started that journey when the Walker Lab had only handful of members and was embarking on the great expedition to become one of the most recognized leaders in HIV and Immunology research. Trained as veterinarian in Poland, she thought that this job would be the starting point of becoming one in America. Instead, it turned out to be a dream come true. Working alongside a world-class visionary and true leader, the job became incredibly fulfilling in its mission to make an everlasting imprint on the future. Starting as lab technician, she became an expert of growing, cultivating and establishing CD8 T-cells, and now the Walker Lab can call itself the world’s largest repository of HIV CD8 T cells. Over the many years, she has participated in numerous exciting and exceptional projects and was a part of the personal journeys of many Postdocs, Research Fellows and Technicians. In recent years, the move to the 400 Technology Square building brought a considerable expansion in space and research potential with the addition of many new members, and her role has grown to help manage that progress and minimize the obstacles. In her free time, Alicja enjoys nature walks, biking, a good book, and new adventures.

 

Name: Onyinyechi Ukaire (Ukay)

Email: oukaire@mgh.harvard.edu

Education: B.S. in Biochemistry and Computer Science, Tufts University

Hometown: Abuja, Nigeria

Bio: After graduating in May 2018, Ukay joined Bruce Walker’s lab as a research technician in bioinformatics under the mentorships of Adrienne Yanez and Jonathan Urbach. By applying computational techniques, Ukay organizes, analyzes and visualizes gene expression data from RNA sequencing of HIV-specific CD4+ and CD8+ T cells. He has developed his own informatics pipelines, which he will deploy again for future projects. In his free time, he enjoys stepping out of his comfort zone to do something new. Recently, he cooked butter chicken and ramen; surprisingly, they both turned out well and their pictures ended up on Instagram. Importantly, he loves A Song of Ice and Fire by George R.R. Martin and wrote predictions on events that would unfold. For current news, please see oukaire.com.

 

Name: Jonathan Urbach

Email: jurbach@mgh.harvard.edu

Education: A.B., Cornell University; Ph.D., Harvard University

Hometown: Annapolis, Maryland

Bio: Jonathan is a bioinformatics specialist, who joined the Walker lab in May 2017. Jonathan completed his Ph.D. in Chemistry in the laboratory of Jack Szostak, then worked 15 years as a bioinformatician in the lab of Fred Ausubel studying innate immunity. His main research focus is on the transcriptional changes that occur in CTLs of elite and viremic HIV controllers leading up to the loss of control. He’s also interested in how structural information can be used to predict amino acid mutational tolerance in proteins and predict optimal epitopes for vaccines to elicit cellular immune responses. In his spare time, he runs the Ragon Bioinformatics Working Group and listens to loud music.

 

Name: Alonso Villasmil Ocando

Email: avillasmilocando@mgh.harvard.edu

Education: B.A. in Biology, Williams College

Hometown: Orlando, Florida

Bio: Alonso is a Research Technician in the Walker Lab. As an HHMI EXROP fellow in the Walker Lab during the summer of 2017, he worked on understanding the transcriptional regulation of T cell trafficking and lymph node dynamics. After graduating from Williams College with a B.A. in Biology, he rejoined the lab and is currently investigating CAR T cell therapies against HIV. Outside of lab, Alonso enjoys walks along the Esplanade, dancing, and planning his next travel adventures.

 

Name: Adrienne Yanez

Email: adrienneg_yanez@dfci.harvard.edu      

Education: B.S. University of Notre Dame; Ph.D. Harvard University

Hometown: Lake Station, Indiana

Bio: Adrienne is a Research Fellow in the Walker Lab. Her thesis work focused on the mechanism of miRNA-mediated translational repression and the global regulation of miRNA activity by translation initiation factors in melanoma. She is working to identify and manipulate gene regulatory networks that control HIV-specific CD4+ T cell functions in HIV infection. In her spare time, she enjoys playing outside and performing as a background extra in exclusive Ragon film productions.

 

 

Former Laboratory Members