Lauer Laboratory: Immunology of Viral Infections in Humans

Overview

HCV is a unique model system to study human viral infections, not only because it is one of the most clinically relevant chronic viral infections with a worldwide pandemic affecting more than 170 million people, but also of the dichotomy in its clinical course: While 80% of subjects will develop a life-long chronic infection, about 20% of subjects with acute HCV infection will complete eradicate the virus, usually within the first 6 months after infection. Most other infections that are studied in humans are either universally acute (influenza) or they generally persist (HIV, EBV, CMV). In addition, we are able to obtain tissue for analysis from the exclusive site of HCV replication, the liver. This makes HCV a model system for human immunology that should allow unique insights into the determinants of viral control and viral persistence.

The lab is the primary site of a NIH-sponsored U19 HCV Collaborative Research Center “Immune Control and Evasion during Acute HCV Infection” (PI: Georg Lauer), and also a main project site in the U19 Collaborative Center for Human Immunology “Mechanisms of Immune Failure in Chronic Infection: Hepatitis C as a Key Paradigm”. Furthermore we are part of a Human Immunology Consortium “Optimizing Human T-Cell Responses to Prevent Chronic Infection” funded by the Dana Foundation and part of the Center for Inflammatory Bowel Disease at Massachusetts General Hospital.

Dr. Lauer has been interested in both clinical and scientific aspects of HCV for over 15 years, starting with his clinical training in Internal Medicine and Gastroenterology and laboratory work on HCV for his PhD in Medical Sciences in Germany. Since coming to the Massachusetts General Hospital as a postdoctoral fellow more than 10 years ago he has build, together with his colleague Arthur Kim several large research cohorts and research specimen repositories, including more than 800 subjects with acute and chronic HCV infection. The lab is mainly interested in the immunopathogenesis of hepatitis C virus (HCV) infection.

There are currently two major programs in the lab, one that focuses on the T-cell response during acute HCV infection, the other studying the T-cell response against HCV that persists in chronic HCV infection, especially in the liver:

In the first program, we are trying to understand the correlates of protection from persistent HCV infection as well as the mechanisms employed by the virus to circumvent immunological control. These studies aim to guide the development of preventative HCV vaccines. In our translational studies we are using samples from a cohort of over 200 patients with acute HCV infection, recruited locally, in the Massachusetts Prison System and through our long-term collaborators at the Istituto Oswaldo Cruz in Rio de Janeiro, Brazil. We have been at the forefront of comprehensively mapping and defining the CD8 and CD4 response in acute HCV infection, using ELISpot and extensive flow cytometry studies using class I and class II peptide multimers. We also have closely described the interaction between the T-cell response and viral evolution. Recently we have started ambitious new projects to introduce Systems Biology approaches into the studies of the HCV T-cell response. We are generating large sets of microarray data from HCV-specific T-cells in order to define the early mechanisms that are associated with successful or unsuccessful control of HCV.

Our second program is focused on responses that persist, but are obviously ineffective, in chronic HCV infection. By defining the mechanisms by which T-cells are rendered ineffective and potential avenues to restore viral control we hope to enable future immunotherapies for the treatment of established HCV infection. A main component of this effort is the study of T-cells derived from infected livers, the main site of HCV infection and replication. We are developing microscopy based assays that will characterize the network of infected hepatocytes, immune cells and stimulatory and inhibitory signals in-situ. We also analyze liver derived immune cells by flow cytometry and microarray analysis of defined T-cell populations.

Our key collaborators are:

• Todd Allen, PhD from the Ragon Institute of MGH, MIT and Harvard (HCV virology)
• Galit Alter, PhD from the Ragon Institute of MGH, MIT and Harvard (NK cell studies)
• Nick Haining, MD from the Dana Farber Cancer Institute and Harvard Medical School (Microarray analysis)
• Gordon Freeman, PhD from the Dana Farber Cancer Institute and Harvard Medical School (T-cell Inhibitory Molecules)
• Arthur Kim, MD from the Infectious Disease Division at MGH and Harvard (HCV cohorts and immunology)
• Paul Klenerman, MD from Oxford University (HCV Immunology)
• Mansun Law from the Scripps Research Institute (Antibodies)
• Lia Lewis-Ximenez, MD from the Oswaldo Cruz Institute, Rio de Janeiro, Brazil (Acute HCV and HBV cohorts)
• Joseph Misdraji, MD from the department of Pathology at MGH and Harvard (Liver Tissue)
• John Wherry, PhD from the University of Pennsylvania (Mouse models of viral infection/immunology)

Group Members

• Georg M. Lauer, MD PhD
• Lizeng Qin, MD PhD
• Donatella Ciuffreda, MD
• Daniela Kroy, MD
• Peter Foote, Research Technician
• Garrett Hauck, Research Technician
• Laura Reyor, Clinical Research Coordinator
• Michelle Tomlinson, Clinical Research Coordinator
• Helen Yang, Summer Student

Publications

1. Lauer GM, Walker BD. Hepatitis C virus infection. N Engl J Med 2001 Jul 5;345(1):41-52.
2. Lauer GM, Nguyen TN, Day CL, Robbins GK, Flynn T, McGowan K, Rosenberg ES, Lucas M, Klenerman P, Chung RT, Walker BD. Human immunodeficiency virus type 1-hepatitis C virus coinfection: intraindividual comparison of cellular immune responses against two persistent viruses. J Virol. 2002 Mar;76(6):2817-26. PMC135971
3. Lauer GM, Ouchi K, Chung RT, Nguyen TN, Day CL, Purkis DR, Reiser M, Kim AY, Lucas M, Klenerman P, Walker BD. Comprehensive analysis of CD8(+)-T-Cell responses against hepatitis C virus reveals multiple unpredicted specificities. J Virol. 2002 Jun;76(12):6104-13. PMC136241
4. Lauer GM, Barnes E, Lucas M, Timm J, Ouchi K, Kim AY, Day CL, Robbins GK, Casson, DR, Reiser M, Dusheiko G, Allen TM, Chung RT, Walker BD and Klenerman P. High resolution analysis of cellular immune responses in resolved and persistent hepatitis C virus infection. Gastroenterology. 2004 Sep;127(3):924-36.
5. Timm J, Lauer, GM*, Kavanagh DG, Sheridan I, Kim AY, Lucas M, Pillay T, Ouchi K, Reyor LL, Schulze zur Wiesch J, Gandhi RT, Chung RT, Klenerman P, Walker BD, Allen TM. CTL epitope escape and reversion in acute HCV infection. J Exp Med. 2004 Dec 20;200(12):1593-604. PCM2212005 *co- first author
6. Lauer GM, Lucas M, Timm J, Ouchi K, Kim AY, Day CL, Wiesch JS, Paranhos-Baccala G, Sheridan I, Casson DR, Reiser M, Gandhi RT, Li B, Allen TM, Chung RT, Klenerman P, Walker BD. Full-breadth analysis of CD8+ T-cell responses in acute hepatitis C virus infection and early therapy. J Virol. 2005 Oct;79(20):12979-88. PCM1235828
7. McGovern BH, Wurcel A, Kim AY, Schulze zur Wiesch AJ, Bica I, Zaman T, Timm J, Walker BD, Lauer GM. Acute hepatitis C in incarcerated injection drug users. Clin Infect Dis. 2006 Jun 15;42(12):1663-70. Epub 2006 May 11.
8. Kim AY, Zur Wiesch JS, Kuntzen T, Timm J, Kaufmann DE, Duncan JE, Jones AM, Wurcel AG, Davis BT, Gandhi RT, Robbins GK, Allen TM, Chung RT, Lauer GM, Walker BD. Impaired hepatitis C virus-specific T cell responses and recurrent hepatitis C virus in HIV coinfection. PLoS Med. 2006 Dec;3(12):e492. PCM1705826
9. Schulze Zur Wiesch J, Lauer GM, Timm J, Kuntzen T, Neukamm M, Berical A, Jones AM, Nolan BE, Longworth SA, Kasprowicz V, McMahon C, Wurcel A, Lohse AW, Lewis-Ximenez LL, Chung RT, Kim AY, Allen TM, Walker BD. Immunologic evidence for lack of heterologous protection following resolution of HCV in patients with non genotype 1 infection. Blood. 2007 Sep 1;110(5):1559-69. PCM1975840
10. Kuntzen T, Timm J, Berical A, Lewis-Ximenez LL, Jones A, Nolan B, Schulze Zur Wiesch J, Li B, Schneidewind A, Kim A, Chung RT, Lauer GM, Allen TM. Viral Sequence Evolution in Acute HCV Infection. J Virol. 2007 Nov;81(21):11658-68. PCM2168804
11. Northfield JW, Kasprowicz V, Lucas M, Kersting N, Bengsch B, Kim A, Philips RE, Walker B, Thimme R, Lauer G, Klenerman P. CD161 expression on HCV-specific CD8+ T-cells suggests a distinct pathway of T-cell differentiation. Hepatology. 2008;47(2):396-406.
12. Kasprowicz V, Ward SM, Turner A, Grammatikos A, Nolan B, Lewis-Ximenez L, Sharp C, Woodfruff J, Fleming V, Sims S, Walker BD, Lauer GM, Klenerman P. Defining the directionality and quality of CD8+ T cell heterologous immunity in hepatitis C virus infection. J Clin Invest. 2008;118(3):1143-53. PMC2214846
13. Kasprowicz V, Schulze Zur Wiesch J, Kuntzen T, Nolan BE, Longworth S, Berical A, Blum J, McMahon C, Reyor LL, Elias N, Kwok WW, McGovern BG, Freeman G, Chung RT, Klenerman P, Lewis-Ximenez L, Walker BD, Allen TM, Kim AY, Lauer GM. High PD-1 expression on HCV-specific CD8+ and CD4+ T cells during acute Hepatitis C irrespective of clinical outcome. J Virol. 2008; 82: 3154-3160. PMC2258997
14. Kasprowicz V, Kang YH, Lucas M, Schulze zur Wiesch J, Kuntzen T, Fleming V, Nolan BE, Longworth S, Berical A, Bengsch B, Thimme R, Lewis-Ximenez L, Allen TM, Kim AY, Klenerman P, Lauer GM. Hepatitis C virus (HCV) sequence variation induces an HCV-specific T-cell phenotype analogous to spontaneous resolution. J Virol. 2010 Feb;84(3):1656-63. Epub 2009 Nov 11. PMC2812309
15. Lewis-Ximenez LL, Lauer GM, Schulze Zur Wiesch J, de Sousa PS, Ginuino CF, Paranhos-Baccalá G, Ulmer H, Pfeiffer KP, Goebel G, Pereira JL, Mendes de Oliveira J, Yoshida CF, Lampe E, Velloso CE, Alves Pinto M, Coelho HS, Almeida AJ, Fernandes CA, Kim AY, Strasak AM. Prospective follow-up of patients with acute hepatitis C virus infection in Brazil. Clin Infect Dis. 2010 May 1;50(9):1222-30. PMCID: pending