AASLD2018[531]CAD是宿主因子和抗病毒靶标 Hdv感染

StephenW

s 531
CAD Is a Host Factor and Antiviral Target for
Hdv Infection
Eloi R. Verrier1, Amélie Weiss2, Charlotte Bach1, Laura
Heydmann1, Arnaud Kopp2, Houssein El Saghire3, Patrick
Pessaux4, Thomas Garcia5, Patrick Pale5, Mirjam B. Zeisel4,
Camille Sureau6, Catherine Schuster1, Laurent Brino2 and
Thomas F. Baumert7, (1)Inserm U1110, Institut De Recherches
Sur Les Maladies Virales Et Hépatiques, Université De
Strasbourg, 3 Rue Koeberlé, F-67000 Strasbourg, France,
(2)Igbmc, (3)Inserm, U1110, Institut De Recherche Sur
Les Maladies Virales Et Hépatiques, Strasbourg, France;
Université De Strasbourg, Strasbourg, France, (4)I, (5)Institut
De Chimie, Université De Strasbourg, (6)Ints, (7)Institut
Hospitalo-Universitaire, Pôle Hépato-Digestif, Hôpitaux
Universitaires De Strasbourg, Strasbourg, France
Background: Hepatitis D virus (HDV) is a circular RNA
virus co-infecting hepatocytes with hepatitis B virus. Chronic
hepatitis D results in severe liver disease and an increased
risk of liver cancer. Efficient therapeutic approaches against
HDV are absent. Methods: Here, we combined RNAi lossof-
function (7500 druggable genes) and small molecule (1200
FDA-approved drugs) screens to uncover host-dependency
factors for HDV infection. Results: The loss-of-function
screen identified 191 host factor candidates for HDV infection.
Validation studies identified CAD, encoding a trifunctional
enzyme playing a key role in pyrimidine biosynthesis as
a HDV key host factor. Interestingly, ESR1, encoding the
estrogen receptor 1, a regulator of CAD expression, was also
a candidate from the primary screen. In parallel, Fulvestrant,
an ESR1 antagonist was identified in the small molecule
screen as an efficient inhibitor of HDV infection associated
with a decrease in CAD expression. Kinetic assays revealed
that ESR1/CAD pathway mediates the early steps of HDV
replication. Robust antiviral activity of the CAD inhibitor
PALA in both cell lines and primary human hepatocytes
confirmed the role of CAD as antiviral target. Conclusion:
The discovery of HDV host-dependency factors elucidates
the pathogenesis of viral disease biology and opens the door
to novel therapeutic strategies for HDV cure.

StephenW

s 531
CAD是宿主因子和抗病毒靶标
Hdv感染
Eloi R. Verrier1，AmélieWeiss2，Charlotte Bach1，Laura
Heydmann1，Arnaud Kopp2，Houssein El Saghire3，Patrick
Pessaux4，Thomas Garcia5，Patrick Pale5，Mirjam B. Zeisel4，
Camille Sureau6，Catherine Schuster1，Laurent Brino2和
Thomas F. Baumert7，（1）Inserm U1110，Institut De Recherches
Sur Les Maladies ViralesEtHépatiques，UniversitéDe
斯特拉斯堡，3 RueKoeberlé，F-67000斯特拉斯堡，法国，
（2）Igbmc，（3）Inserm，U1110，Institut De Recherche Sur
Les Maladies ViralesEtHépatiques，法国斯特拉斯堡;
斯特拉斯堡大学，法国斯特拉斯堡，（4）I，（5）Institut
De Chimie，UniversitéDeStrasbourg，（6）Ints，（7）Institut
Hospitalo-Universitaire，PôleHépato-Digestif，Hôpitaux
Universitaires De斯特拉斯堡，史特拉斯堡，法国
背景：丁型肝炎病毒（HDV）是一种环状RNA
病毒与乙型肝炎病毒共感染肝细胞。慢性
丁型肝炎导致严重的肝脏疾病并且增加
患肝癌的风险。有效的治疗方法
HDV不存在。方法：在这里，我们结合RNAi损失 -
功能（7500药物基因）和小分子（1200
FDA批准的药物筛选以揭示宿主依赖性
HDV感染的因素。结果：失去功能
筛选鉴定了195个HDV感染的宿主因子候选物。
验证研究确定CAD，编码三官能
酶在嘧啶生物合成中发挥关键作用
HDV密钥主机因素。有趣的是，ESR1编码了
雌激素受体1，也是CAD表达的调节因子
来自主屏幕的候选人。与此同时，Fulvestrant，
在小分子中鉴定出ESR1拮抗剂
筛选作为HDV感染相关的有效抑制剂
随着CAD表达的减少。动力学分析显示
ESR1 / CAD途径介导HDV的早期步骤
复制。 CAD抑制剂具有强大的抗病毒活性
PALA在细胞系和原代人肝细胞中
确认了CAD作为抗病毒靶标的作用。结论：
HDV宿主依赖因子的发现阐明了这一点
病毒性疾病生物学的发病机制和打开了大门
HDV治疗的新型治疗策略。