Understanding The Interface Between Human Granzymes and Hepatitis C Virus (HCV)

Felipe Andrade, M.D., Ph.D.

Johns Hopkins University School of Medicine

Division of Rheumatology
Funded in December, 2008: $400000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY .

LAY SUMMARY

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Understanding The Interface Between Immune T Cells and Hepatitis C Virus Infection

Dr. Felipe Andrade’s research is designed to identify the pathways used by immune T cells to attack hepatitis C virus (HCV).

Chronic HCV infection can lead to fatal liver cirrhosis or cancer.  About three percent of the world’s population is infected with HCV.  The infection is chronic in two-thirds of affected people, while in the other third the immune system spontaneously clears the infection.  Scientists do not yet know what accounts for this difference in response.  Growing evidence suggests, however, that adaptive immune “cytotoxic” T cells activated specifically to attack this virus are essential for spontaneous resolution of acute HCV infection and for long-term protection from persistent infection.  Just how these T cells confer total protection is not yet understood.  Research suggests that a dominant role is played by “granzymes”, which cytotoxic immune T cells release into virally-infected cells to induce the cells’ death and stop the spreading of the virus.  

Dr. Andrade and his colleagues discovered that granzymes and essential viral proteins are involved in an intricate dance.  Granzymes inhibit essential viral proteins, and some proteins encoded by viruses can inhibit human granzymes. Dr. Andrade now hypothesizes that the outcome of this interaction between granzymes and the viral-encoded proteins is a key determinant of whether the virus is cleared or becomes a chronic infection. 

He will test this hypothesis by determining whether: 1) HCV encodes proteins that inhibit human granzymes; 2) the virally-encoded proteins are targets of human granzymes; and 3) certain combinations of the five different types of human granzymes function synergistically with one another to outflank these viral defenses and restrain the virus’ destructive effects and replication.  If the findings support this hypothesis, they could lead to methods to strengthen the functions of the specific combination of granzymes that most effectively curtail viral replication.

ABSTRACT

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Understanding The Interface Between Human Granzymes and Hepatitis C Virus (HCV)

Cytotoxic cells are a key factor governing the outcome of acute hepatitis C in humans and chimpanzees, and there is a consensus view that this response may define chronic infection vs. spontaneous resolution.

Although cytotoxic cells use multiple mechanisms to exert their antiviral activity, the release of granzymes into infected target cells is considered a dominant player in the cellular immune response against viruses and other intracellular pathogens.  Interestingly, the recent findings that viruses can block granzyme activities, and that granzymes can directly target viral proteins suggest that the efficient clearance of viruses may be an integrated function, affected by viral and host factors at the granzyme-virus interface.  These factors include (1) susceptibility of viral proteins to cleavage by specific granzymes, (2) presence of granzyme inhibitors, and (3) expression and access of distinct granzymes to infected target cells.

There is a great need for further understanding of the direct role of granzymes in the control of human viruses through the identification of viral substrates and inhibitors for these proteases.  In addition, since different populations of cytotoxic lymphocytes express distinct subsets of granzymes, this information may guide the identification of cytotoxic cells with potential granzyme combinations that may naturally inactivate hepatitis C virus (HCV).  Thus, the proposed studies are designed to identify novel antiviral pathways used by human cytotoxic lymphocytes to target HCV.  We will dissect whether HCV encodes inhibitors against human granzymes, identify whether HCV-encoded proteins are cleaved and inactivated by granzymes, and define how different protease specificities of the various granzymes might converge to restrain HCV infection. 

To search for these granzyme-HCV interactions, we will apply our significant expertise in defining viral inhibitors and substrates for all five human granzymes in HCV-expressing target cells using infectious and replicon systems from different strains of HCV.  Defining whether and how granzymes interact with HCV, and the consequences of these interactions (viral resistance vs. viral clearance) is potentially critical to the understanding of mechanistic pathways in HCV pathogenesis.

INVESTIGATOR BIOGRAPHIES

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Felipe Andrade, M.D., Ph.D.

Felipe Andrade, M.D., Ph.D., is Assistant Professor of Medicine in the Division of Rheumatology at Johns Hopkins University School of Medicine.  Following receipt of his medical degree from the National University in Mexico City in 1990, he trained in internal medicine at the National Medical Center, and in rheumatology at the National Institute of Nutrition, in Mexico City.  Awarded a Fulbright Scholarship in 1995, he then earned a Ph.D. in immunology at Hopkins and became an instructor in the rheumatology division.  Following a brief faculty appointment back at the National Institute of Nutrition, he returned to Hopkins to pursue human immune research. 

Dr Andrade’s broad interests are in the mechanisms of autoimmune rheumatic diseases, an interest sparked by his clinical training in these diseases. During his early career, he acquired significant expertise in pathways of cell death, particularly those induced by human cytotoxic lymphocytes. His interest in the interaction of viruses and the cytotoxic lymphocyte granule pathway was sparked by the recognition that viruses likely evolved strategies to prevent cytotoxic lymphocyte-induced death, and that elucidating such mechanisms could provide important insights into the operation and regulation of this important immune effector pathway –– both in infection as well as in autoimmunity.

His ongoing studies focus on the role of cytotoxic lymphocyte granule pathways in virus clearance as well as in the pathogenesis of various human autoimmune rheumatic diseases, including systemic lupus erythematosus and rheumatoid arthritis. He believes that understanding the cytotoxic lymphocyte granule pathway from both sides of the tantalizing infection-autoimmunity interface will provide unique insights into the pathogenesis of multiple inflammatory and infectious diseases that cause great morbidity worldwide.