Medical Student Research Fellowship for Summer 2003
Mentor: Geri Brown, M.D.
Department: Internal Medicine
Room number: F4.124
Mail Code: 9151
Phone number:214-648-7292
E-mail: gbrow1@mednet.swmed.edu
Project title: Project Title: Host Immune Responses Influencing the Chronicity
of Hepatitis C Viral Infection
Human subjects IRB approved project number (where applicable): VA 01-82
Animal subjects IRB approved project number (where applicable): N/A
Project Type (patient-based research, animal-based research, or basic research;
this characterization is only to permit a general classification for grouping
similar types of projects) Translational Research
Brief Description of Project:
Unlike infections by other human hepatitis viruses, Hepatitis C virus (HCV)
infection of healthy immunocompetent adults is persistent or prolonged in many
cases. In part, this undoubtedly relates to high ratesof variability in the
amino acid sequence in the hypervariable region (HVR) 1 of the HCV envelope
protein which both result from immune pressure and permit "escape"
from neutralizing antibodies. HCV appears to have evolved strategies to evade
human immune responses. Binding of the HCV core protein to the lymphotoxin $
receptor (LT$R) and interference with LT$R signaling has been reported. Thus,
interference with signaling through the LT$R or other members of the TNF family
of receptors is one possible mechanism whereby there is evasion of the human
immune responses. Preliminary studies in my lab, whereby RNA was isolated from
HCV positive patients's peripheral blood lymphocytes ( PBL)during an IFN"-2B
based treatment trial and utilized in a quantitative real time PCR based assay
(RT PCR) demonstrated that TNFR1 and LT$R levels increased between 6 and 12
months in responders of IFN" based therapy but not in nonresponders. These
results suggested that the virus was cleared and then the host immune response
induced an upregulation of these receptors on PBL. Hence, normal immune responses
could be restored when HCV was no longer present. Importantly, these receptors
were only upregulated after decreases in viral loads and noted only in the responders
to IFNa based therapy. We propose to study whether there is evidence of enhanced
expression in the liver of TNFR, LT$R or other members of the TNF family of
receptors during the clearance of chronic HCV infection with IFN" based
therapy. These studies will determined whether the final clearance of HCV from
infected hepatocytes is associated with upregulation of these receptors on either
the hepatocyte or the infiltrating immune cells after clearance of the virus.
Quantitative RT PCR assays for assessing levels of expression of these genes
have been developed for peripheral blood from patients with hepatitis C and
will be used to assess expression in liver biopsy specimens from patients with
chronic hepatitis C or with other forms of liver disease. Fluorescinated antibodies
will also be used to determined the level of the TNF receptor family protein
expression in HCV infected versus control liver specimens.
Previous Research Activities or Publications with Medical Students:
Summer Research Mentor to a MS0, Zhi Mao 5/00-8/00
awarded an outstanding presentation at the 39th Medical Student Research Forum,
UT Southwestern Medical Center at Dallas 1/23/01
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