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Dr. Rosen's Research Lab


 

Research Team

Hugo Rosen, MD (PI)

Lucy Golden, PhD

Susan Smyk-Pearson

Andy Mengshol, MD

 

Our laboratory is interested in the immune response to hepatitis C virus (HCV), particularly understanding the mechanisms associated with spontaneous or therapeutic-induced clearance versus viral persistence.  Although the focus of our lab has been primarily on the role of antigen-specific T cells, we are also characterizing the potential role of innate immunity (e.g., dendritic and natural killer cells). The central theme of our studies is to define why HCV causes diverse outcomes in exposed individuals and characterize the division of labor, i.e., role played by different components of the immune system.

chart

Figure 1.  Innate and adaptive immunity are likely central to determining outcome of infection with HCV (courtesy, Nick Valiante).

The balance between HCV and host immune response depends on multiple factors such as nature of the infecting virus, route of infection and initial viral burden, genetic background of the individual as well as the immune status of the infected host. The interplay between these parameters ultimately determines the spectrum of possible clinical outcomes associated with viral disease. The study of HCV infection is challenging because of the lack of a readily available animal model to study the causal relationship between the host immune response and the virus. Thus, a number of very well characterized, prospective human cohorts form the basis of our laboratory’s studies. These cohorts include patients with acute HCV infection, subjects with spontaneously resolved infection, patients with genotype 1 undergoing combination antiviral therapy (Virahep-C immunology ancillary), and chronic HCV liver transplant recipients.  Thus, the experimental systems used in the majority of our studies employ "natural" host-pathogen interactions with an experimental emphasis on identification, characterization, isolation and manipulation of specific immune cells.

Study Cohorts/Questions


Acute HCV infection:

Although chronic HCV infection is very common, it is rarely identified acutely, and patients usually seek medical attention only after chronic infection is established. The very nature of this infection has made it extraordinarily difficult to study the early disease course except in the subset of individuals (<15% of total) with definitive early symptoms and diagnosisfootnote. Thus, the incubation period (the time between infection and onset of symptoms), that phase of the disease with ongoing active replication prior to development of an effective host immune response, has not yet been characterized. It is likely that immunologic and virologic events occurring in the earliest stages of infection determine the eventual outcome, and our goal is to elucidate these mechanisms. To date, we have enrolled more than 60 acutely infected patients from 5 centers around the U.S.

  • Our approach has been to screen whole genome CD4+ and CD8+ T cell responses in conjunction with virologic analyses, as described in Tester et al., J Exp Med. 2005 Jun 6;201(11):1725-31. {PDF-1}
  • We have also characterized the function and phenotype of regulatory T cells (Tregs) in the setting of acute HCV, in order to determine whether the reported association with chronic HCV and increased circulating frequency of Tregs is causally linked to persistence.
  • As initiating effective T cell responses is dependent on natural killer (NK) and dentritic cell (DC) interactions, work is ongoing to define NK and DC function in the acute setting.

Human Liver Transplant Model

  • The human liver transplant model provides an important framework and clinically relevant construct to characterize HCV immunity for a number of important reasons: a subset of patients develop an accelerated natural history, acute graft infection induces innate and adaptive immune responses , opportunity to characterize the role of donor- and recipient-restricted, HCV-specific T cell responses {PDF-2}.

 To date, our work can be summarized as follows:

  • The presence of an HCV-specific CD4+ T cell response early after liver transplantation correlates with protection against development of severe recurrence
  • A prospective study is ongoing to determine whether antiviral intervention in patients with a relatively diminished HCV-specific CD4+ T cell response (but prior to histologic evidence of recurrence) improves outcome
  • Antiviral therapy leads to reconstitution of HCV-specific CD8+ T cells and these cells are clonotypically identical to intrahepatic lymphocytes present prior to transplant
  • The liver allograft can select naïve HCV-specific CD8+ T cells (Rosen HR, et al.,  J Immunology Cutting Edge 2004 Nov 1;173(9):5355-9. {PDF-3}), Figure 2.
    • These CTLs are recipient derived but donor restricted and express high avidity T cell receptors
    • Work is ongoing to define the immunotherapeutic potential of TCR redirection
  • Our preliminary data indicates that pre-transplant peripheral NK levels stratifies patients at risk of severe recurrence independently of viral levels, suggesting that control of HCV by NK cells at the early stage of re-infection is important in determining subsequent outcome

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Figure 2. HLA restriction of CTL clones. In the presence of cognate peptide (NS3 1406 epitope) and non-self HLA allele, CTLs produced IFN gamma but not in the presence of self HLA alleles.


Virahep-C study (Treatment Study)

We serve as the Immunology Ancillary of an NIH study specifically designed to understand the basis of racial differences with regards to antiviral responsiveness. In a large analysis of over 350 chronically infected patients, we found that HCV (but not CMV) specific responses were diminished in African Americans.

Currently, in this prospective cohort, we are characterizing the role of Tregs, the mechanisms mediating homeostatic proliferation of HCV-specific CD8+ T cells, as well as the contribution of natural killer and dendritic cells to treatment outcome.


Hepatitis C Center Grant

The theme of this center grant is to understand mechanisms of immune evasion in HCV infection. Dr. Rosen is the Program Director; Dr. Young Hahn (University of Virginia) and Dr. Stephen Polyak (University of Washington) are the co-investigators. The specific aims include:

  1. To examine the innate arm of the immune system to determine which of their effector functions are the most critical for control of HCV infection.

2.  To define how professional antigen presenting cells (APC) influence the ability of NK and T cells to mediate viral clearance.

3. To understand how the HCV core protein within or outside the cell regulates innate signaling pathways such as IRF, Stat-JAK, and iNOS. Does viral sequence and structural variation contribute to differential signaling?

4. To elucidate the underlying mechanisms of regulatory T cell development (e.g., antigen presentation by immature DCs, core/gC1qR engagement) and their role in establishing persistence.


Other Collaborative Efforts

  • Adjunct appointment, Integrated Program in Immunology, University of Colorado and National Jewish Hospital
  • Member, Colorado CFAR
  • Collaborative studies with Cliona O’Farrelly (Dublin), Michael Nishimura (University of Chicago), David Lewinsohn (Oregon Health & Science University), and David Nelson (University of Florida).

Footnotes

Hoofnagle JH. Acute Hepatitis C. 2000. Chapter In: Liang TJ, Hoofnagle JH (eds): Hepatitis C: Biomedical Research Reports; pp 71-83.