Chen Christopher Y, Winer Benjamin Y, Chavez Deborah, Guerra Bernadette, Brasky Kathleen M, Eng Stacey, Salas Eduardo, Tam Danny, Simmons Joe H, Abee Christian R, Delaney William E, Ploss Alexander, Lanford Robert E, Voitenleitner Christian
Southwest National Primate Research Center Texas Biomedical Research Institute San Antonio TX.
Department of Molecular Biology Princeton University Princeton NJ.
Hepatol Commun. 2020 Jan 3;4(3):371-386. doi: 10.1002/hep4.1471. eCollection 2020 Mar.
Development of curative therapies for chronic hepatitis B virus (HBV) infection will likely require new animal models. Here, we evaluate HBV infection in squirrel monkeys based on the high-sequence homology of the HBV receptor, Na+/taurocholate co-transporting peptide (NTCP), between humans and squirrel monkeys. HBV PreS1 peptide was examined for binding human and squirrel monkey NTCP. Immunodeficient , , , (FNRG) mice engrafted with human or squirrel monkey hepatocytes were challenged with HBV or Woolly Monkey HBV (WMHBV). In addition, adult squirrel monkeys were inoculated with HBV, WMHBV, adeno-associated virus containing an infectious genome of HBV (AAV-HBV), and AAV-WMHBV. Finally, neonate squirrel monkeys were assessed for the potential of chronic infection with WMHBV. PreS1 peptide efficiently bound to human and squirrel monkey NTCP but not to mouse or capuchin NTCP. FNRG mice engrafted with squirrel monkey hepatocytes were susceptible to infection by WMHBV but not human HBV. Similarly, adult squirrel monkeys could be infected with WMHBV but not human HBV, whereas chimeric mice engrafted with human hepatocytes were susceptible to HBV but not WMHBV. Infection of squirrel monkeys with AAV-WMHBV yielded maximum viremia of 10 genomes/mL with detectable virus for up to 8 months. Notably, covalently closed circular DNA was detected in the liver of these animals. Infection of neonates with WMHBV led to detectable viremia for up to 6 months. : Adult and neonate squirrel monkeys exhibited prolonged WMHBV viremia lasting 6-8 months. This is greater than twice the duration of viremia achieved in other nonhuman primates and suggests that squirrel monkeys may be a suitable model for testing HBV therapeutics.
开发针对慢性乙型肝炎病毒（HBV）感染的治愈性疗法可能需要新的动物模型。在此，我们基于人类和松鼠猴之间HBV受体——牛磺胆酸钠共转运多肽（NTCP）的高度序列同源性，评估松鼠猴中的HBV感染情况。检测了HBV前S1肽与人类和松鼠猴NTCP的结合情况。用人或松鼠猴肝细胞移植的免疫缺陷FNRG小鼠分别用HBV或绒毛猴HBV（WMHBV）进行攻击。此外，成年松鼠猴接种了HBV、WMHBV、含有HBV感染性基因组的腺相关病毒（AAV-HBV）和AAV-WMHBV。最后，评估新生松鼠猴慢性感染WMHBV的可能性。前S1肽能有效结合人类和松鼠猴的NTCP，但不结合小鼠或卷尾猴的NTCP。移植了松鼠猴肝细胞的FNRG小鼠易受WMHBV感染，但不易受人类HBV感染。同样，成年松鼠猴可被WMHBV感染，但不能被人类HBV感染，而移植了人类肝细胞的嵌合小鼠易受HBV感染，但不易受WMHBV感染。用AAV-WMHBV感染松鼠猴后，最大病毒血症水平为10个基因组/毫升，可检测到病毒长达8个月。值得注意的是，在这些动物的肝脏中检测到了共价闭合环状DNA。用WMHBV感染新生动物后，可检测到病毒血症长达6个月。结论：成年和新生松鼠猴表现出持续6 - 8个月之久的WMHBV病毒血症。这比其他非人灵长类动物实现的病毒血症持续时间长两倍多，表明松鼠猴可能是测试HBV治疗方法的合适模型。
