Hepatitis B Virus (HBV) Infection

Chronic HBV infections (CHB) are a major global health concern, affecting 247 million individuals worldwide and causing 887,000 deaths annually. While there is an effective prophylactic vaccine available, 10-15% of individuals do not respond adequately to vaccination and are not protected against HBV infection.

Further exacerbating the prevalence of CHB is the high HBV vertical transmission rate. HBV-infected neonates and infants progress to CHB in nearly 90% of cases, whereas only 5% of HBV-infected adults progress to CHB. This simple fact, coupled with low vaccination rates, has resulted in areas of the world where CHB prevalence is greater than 8%.

CHB can lead to progressive liver dysfunction, cirrhosis, and in some cases hepatocellular carcinoma. There are multiple treatment options for CHB, including pegylated-IFNa and reverse-transcriptase inhibitors, but these treatments are rarely curative. Therefore, clinicians and researchers are now turning their focus towards HBV cure research, buoyed by the recent advent of a hepatitis C virus cure.

Multiple animal models of HBV infection have been utilized over the past four decades including the Peking duck, woodchuck, mouse, and chimpanzee. These models have contributed significantly to our understanding of virus-host interactions, but each have drawbacks that limit their utility for drug development. First, ducks and woodchucks are infected with species-specific hepatitis viruses that are related to HBV, but differ in genomic sequence, protein composition, and virion structure. In addition, both animals are outbred, ill-defined genetically, and scarcely used outside the HBV field, which consequentially limits the availability of important research reagents.  Second, because HBV does not infect mouse hepatocytes, current mouse models rely on artificial expression of HBV, either as a germline transgene or as a linear genome transferred by viral vectors, or on humanized livers that require significant immunomodulation to maintain. The relatively short lifespan of mice further detracts from the model, as liver dysfunction and fibrosis are generally gradual processes that can take years to manifest in humans. Finally, the NIH recently suspended all funding for chimpanzees in biomedical research, effectively ending the only physiologically relevant HBV animal model. Thus, development of a new non-human primate model that recapitulates HBV infection in humans is urgently needed.

Dr. Burwitz’s lab has built the first bona fide rhesus macaque model of HBV infection. This HBV model is emerging at an extremely important juncture, where efforts are now turning towards curative HBV therapies.

Transgenic non-human primates

The recent announcement that human twins were born in China following CRISPR/Cas9 editing of the CCR5 gene came as a major shock to the scientific community. While germline editing (permanent editing that is passed on to subsequent generations) holds significant promise for human health, there remain significant ethical and safety concerns surrounding germline editing of human embryos. Dr. Burwitz’s lab is studying the efficiency and adverse side effects of germline editing in the rhesus macaque model. These techniques, such as in vitro fertilization and embryo transfer to surrogates, are identical to those performed in human reproductive clinics and Dr. Burwitz’s research will shed light onto the safety and potential for human germline editing in the future.

Biography

Dr. Burwitz graduated from the University of Wisconsin - Madison in 2004 with a B.S. in molecular biology and psychology. He joined the Department of Cellular and Molecular Pathology at the Univeristy of Wisconsin - Madison in 2006 as a graduate student, and received his Ph.D. in 2010. In 2011, he joined VGTI as a staff scientist in the lab of Jonah Sacha, and in 2016 was promoted to research assistant professor.

Selected publications

• Burwitz BJ, Wettengel JM, Mück-Häusl MA, Ringelhan M, Ko C, Festag MM, Hammond KB, Northrup M, Bimber BN, Jacob T, Reed JS, Norris R, Park B, Moller-Tank S, Esser K, Greene JM, Wu HL, Abdulhaqq S, Webb G, Sutton WF, Klug A, Swanson T, Legasse AW, Vu TQ, Asokan A, Haigwood NL, Protzer U, Sacha JB. Hepatocytic expression of human sodium-taurocholate cotransportingpolypeptide enables hepatitis B virus infection of macaques. Nat Commun. 2017 Dec 15;8(1):2146. doi: 10.1038/s41467-017-01953-y. PMID: 29247188
• Greene JM, Lhost JJ, Hines PJ, Scarlotta M, Burwitz BJ, Budde ML, Dudley DM, Pham N, Cain B, Mac Nair CE, Weiker MK, O'Connor SL, Friedrich TC, O'Connor DH. Adoptive transfer of lymphocytes isolated from simian immunodeficiency virus SIVmac239Δnef vaccinated macaques does not affect acute-phase viral loads but may reduce chronic-phase viral loads in major histocompatibility complex-matched recipients. Journal of Virology. 2013 Jul: 87(13):7382-92. PMCID: PMC3700297.
• O'Connor SL, Lhost JJ, Becker EA, Detmer AM, Johnson RC, Macnair CE, Wiseman RW, Karl JA, Greene JM, Burwitz BJ, Bimber BN, Lank SM, Tuscher JJ, Mee ET, Rose NJ, Desrosiers RC, Hughes AL, Friedrich TC, Carrington M, O'Connor DH. MHC heterozygote advantage in simian immunodeficiency virus-infected Mauritian cynomolugs macaques. Science Translational Medicine. 2010 Mar 10: 2(22):22ra18. PMCID: PMC2865159.
• Burwitz BJ, Pendley CJ, Greene JM, Detmer AM, Lhost JJ, Karl JA, Piaskowski SM, Rudersdorf RA, Wallace LT, Bimber BN, Loffredo JT, Cox DG, Bardet W, Hildebrand W, Wiseman RW, O'Connor SL, O'Connor DH. Mauritian cynomolgus macaques share two exceptionally common major histocompatibility complex class I alleles that restrict simian immunodeficiency virus-specific CD8+ T cells. Journal of Virology. 2009 Jun: 83(12):6011-9. PMCID: PMC2687399.
• Burwitz BJ, Greene JM, O'Connor DH. Pirate primates in uncharted waters: lymphocyte transfers in unrelated, MHC-matched macaques. Current HIV Research. 2009 Jan: 7(1):51-6. PMCID: PMC4509675.
• Greene JM, Burwitz BJ, Blasky AJ, Mattila TL, Hong JJ, Rakasz EG, Wiseman RW, Hasekrug KJ, Skinner PJ, O'Connor SL, O'Connor DH. Allogeneic lymphocytes persist and traffic in feral MHC-matched mauritian cynomolgus macaques. PLoS One. 2008 Jun 11:3(6):e2384.PMCID: PMC2408966.
• Hansen SG, Wu HL, Burwitz BJ, Hughes CM, Hammond KB, Ventura AB, Reed JS, Gilbride RM, Ainslie E, Morrow DW, Ford JC, Selseth AN, Pathak R, Malouli D, Legasse AW, Axthelm MK, Nelson JA, Früh K, Lopez CA, Korber BT, Gnanakaran S, Picker LJ, Sacha JB. Broadly targeted CD8+ T cell responses restricted by major histocompatibility complex-E. Science. 2016 Feb 12:351(6274):714-20. PMCID: PMC4769032.
• Hansen SG, Piatak M, Ventura AB, Hughes CM, Gilbride RM, Ford JC, Burwitz BJ, Planer SL, TurnerJM, Legasse AW, Axthelm MK, Edlefsen PT, Nelson JA, Früh K, Estes JD, Sacha JB, Lifson JD, Picker LJ. Immune clearance of highly pathogenic SIV infection. Nature. 2013 Oct 3: 502(7469):100-4. PMCID: PMC3849456.
• Hansen SG, Sacha JB, Hughes CM, Ford JC, Burwitz BJ, Scholz I, Gilbride RM, Gilliam AN, Lewis MS, Ventura AB, Xu G, Malouli D, Richards R, Whizin N, Reed JS, Hammond KB, Fischer M, Turner JM, Legasse AW, Axthelm MK, Edlefsen PT, Nelson JA, Lifson JD, Früh K, Picker LJ. Cytomegalovirus Vectors Violate CD8+ T Cell Epitope Recognition Paradigms. Science. 2013 May 24: 340(6135):1237874. PMCID: PMC3816976.