Hepatocyte Apoptosis in Hepatitis C/HIV Co-Infection
Abstract & Commentary
By Dean L. Winslow, MD, FACP
Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center; Clinical Professor of Medicine, Stanford University School of Medicine
Dr. Winslow is a consultant for Bayer Diagnostics, and is on the speaker's bureau for GlaxoSmithKline and Pfizer.
This article originally appeared in the October 2006 issue of Infectious Disease Alert. It was edited by Stan Deresinski, MD, FACP, and peer reviewed by Connie Price, MD. Dr. Deresinski is Clinical Professor of Medicine, Stanford University; Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center, and Dr. Price is Assistant Professor, University of Colorado School of Medicine. Dr. Deresinski serves on the speaker's bureau for Merck, Pharmacia, GlaxoSmithKline, Pfizer, Bayer, and Wyeth, and does research for Merck. Dr. Price reports no financial relationship relevant to this field of study.
Synopsis: Hepatocytes exposed in vitro to Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV) envelope proteins and undergo apoptosis as a result of cell surface binding of the proteins. The studies indicate that HCV/HIV envelope proteins induce hepatocyte apoptosis by activating a novel downstream STAT1 signaling pathway.
Source: Balasubramanian A, et al. Signal Transducer and Activator of Transcription Factor 1 Mediates Apoptosis Induced by Hepatitis C Virus and HIV Envelope Proteins in Hepatocytes. J Infect Dis. 2006;194:670-681.
This interesting paper from Groopman's laboratory at Beth Israel in Boston, reports the results of some elegant experiments designed to elucidate potential mechanisms, accounting for the innocent bystander hepatocyte apoptosis previously observed as a result of binding of HCV and HIV proteins.1-3 Activation of STAT1 by HCV-E2 and HIV-gp120 proteins was demonstrated in HepG2 cells by DNA binding using a label-specific probe in gel shift assays. HepG2 cells were also transiently transfected with various luciferase-containing constructs. Chemiluminescence detection showed a 2.6-fold increase in luciferase activity in the HCV-E2/HIV-gp120-costimulated cells in cells transfected with the pGAS-TA-Luc vector, compared with unstimulated transfected cells. No change, however, was detected in the transfected cells stimulated with HCV-E2 or HIV-gp120 alone.
Another set of experiments demonstrated tyrosine and serine phosphorylation of STAT1 induced by HCV-E2/HIV-gp120. Phosphorylation of STAT1 had previously been shown to result in dimerization of this protein and translocation to the nucleus, resulting in transcription of target genes. Additional experiments using both Western blotting and immunoprecipitation assays demonstrated that tyrosine phosphorylation of STAT1 was mediated by Lyn kinase. Another set of experiments demonstrated that p38 mitogen-activated protein (MAP) kinase was also involved in STAT1 tyrosine phosphorylation. A series of elegant experiments using both an inhibitor of PKCdelta and PKCdelta single-stranded inhibitory (si) RNA can mediate STAT1 serine phosphorylation after HCV-E2/HIV-gp120 costimulation. Mechanistic experiments demonstrated that STAT1 contributes to FasL-mediated apoptosis in the presence of HCV/HIV envelope protein costimulation, as well as STAT1 enhancement of mitochondrial apoptotic pathways associated with cytochrome c leakage. Finally, STAT1 mediation of caspase 3 activation in HCV-E2/HIV-gp120-induced apoptosis was demonstrated.
While modern antiretroviral therapy has been responsible for a dramatic decrease in the mortality rate of HIV over the last 10 years, increasing evidence points to the relatively greater burden of chronic liver disease due to HCV as a cause of morbidity and mortality in HIV patients. It is also generally universally accepted that the severity and rate of progression of HCV-associated chronic liver disease are greatly increased in HIV infected patients.
One of the things that I have always loved about the subspecialty of infectious diseases is the close relationship between the laboratory and the bedside. The last 140 years have shown steady progress in the understanding of the complex interface between the pathogen and the host. This particular paper caught my attention because, in a series of elegant experiments that tease out the effects of how HCV and HIV envelope proteins contribute to apoptotic hepatocyte death, it demonstrates mechanisms responsible for a clinically important phenomenon. While my personal opinion remains that real progress in treatment of HCV will be made with the development of small molecule inhibitors of viral-specific processes (such HCV protease or helicase), the demonstration of the importance of these STAT1-mediated signaling events suggest another route for development of therapeutic strategies for HCV/HIV coinfection.
It may be of interest to know a little about the senior author of this paper, Dr. Jerome Groopman, who is a Professor of Medicine at Harvard and a hematologist/oncologist by training. Many years ago when I was doing basic research in HIV, I would see Jerry at various meetings and we would occasionally talk about science or life. I was always impressed with his wisdom and kindness, which clearly went to the core of his being. Many years later, I read a review in the New York Times of his first book written for lay people, "The Measure of Our Days," published in 1997, which details the spiritual lives of several patients as they reach the end of their physical lives. His 2000 book, "Second Opinions: Stories of Intuition and Choice in the Changing World of Medicine" is excellent as well. These 2 books were later used as the takeoff for the television series, "Gideon's Crossing." Jerry is a wonderful example of that kind of person who is an excellent scientist, doctor, husband, and father, and someone who combines all of that with a deep spiritual awareness.
- Munshi M, et al. Hepatitis C and Human Immunodeficiency Virus Envelope Proteins Cooperatively Induce Hepatocytic Apoptosis via an Innocent Bystander Mechanism. J Infect Dis. 2003;188:1192-1204.
- Hesselgesser J, et al. Neuronal Apoptosis Induced by HIV-1 gp 120 and the Chemokine SDF-1alpha is Mediated by the Chemokine Receptor CXCR4. Curr Biol. 1998;8:595-598.
- Berndt C, et al. CXCR4 and CD4 Mediate a Rapid CD95-Independent Cell Death in CD4+ T Cells. Proc Natl Acad Sci USA. 1998;95:12556-12561.