A Recombinant Rhesus Monkey Rhadinovirus Deleted of Glycoprotein L Establishes Persistent Infection of Rhesus Macaques and Elicits Conventional T Cell Responses
A Recombinant Rhesus Monkey Rhadinovirus Deleted of Glycoprotein L Establishes Persistent Infection of Rhesus Macaques and Elicits Conventional T Cell Responses
复制标题
删除糖蛋白 L 的重组恒河猴鼻病毒可建立恒河猴的持续感染并引发常规 T 细胞反应
DOI：
10.1128/jvi.01093-19
复制
发表时间：
2020
影响因子：
5.4
通讯作者：
Desrosiers RC
中科院分区：
文献类型：
--
作者：
Hahn AS;Bischof GF;Großkopf AK;Shin YC;Domingues A;Gonzalez-Nieto L;Rakasz EG;Watkins DI;Ensser A;Martins MA;Desrosiers RC
在糖蛋白L(Gl)缺失突变的背景下，构建了表达SIVmac239 Gag蛋白的具有复制能力的重组猕猴RRV株。Gl基因的缺失使病毒从Eph家族受体上解靶。静脉接种两只Mamu-A*01+RRV-naive恒河猴后，评价该gl-Gag重组RRV感染、维持和诱导免疫应答的能力。这两只猴子都产生了抗RRV抗体反应，通过实时荧光聚合酶链式反应(Real-time PCR)对外周血单个核细胞(PBMC)中RRV DNA的定量检测显示，其水平与感染重组gl+RRV的猴子相似。分选的CD3+、CD20+和CD14+PBMC亚群中RRV DNA水平的比较表明，CD20+亚群被gl-阴性RRV感染。这与在体外转化的B细胞株的结果相反，在体外转化的B细胞系中，gl基因的缺失导致传染性显著降低。在20 周期间，主要组织相容性复合体I类(MHC-I)四聚体染色记录了GAG特异性CD8+T细胞反应。疫苗诱导的主要针对MAMU-A*01限制性Gag181-189CM9表位的CD8+T细胞应答可被MHC-I提呈阻断所抑制。我们的结果表明，gl和与Eph家族受体的相互作用对于大剂量静脉感染后B细胞室的定植是必不可少的，这表明存在替代受体。此外，GL-RRV引起的细胞免疫反应主要是典型的。重要的卡波西肉瘤相关疱疹病毒(KSHV)与撒哈拉以南非洲的大量疾病负担有关，通常与人类免疫缺陷病毒(HIV)感染有关。相关的恒河猴流行性感冒病毒(RRV)已显示出用猴免疫缺陷病毒(SIV)的抗原免疫猴子的潜力。SIV是HIV的猕猴模型。KSHV和RRV通过病毒Gh/Gl糖蛋白复合体与Eph家族的细胞受体结合。我们现在已经获得了一个表达SIV Gag抗原而不表达gl的重组RRV。该重组RRV通过静脉途径感染，在B细胞室持续感染，并对SIV Gag抗原产生强烈的免疫应答。这些结果反对gl和Eph家族受体在RRVin活体感染B细胞中的作用，并对KSHV减毒活疫苗或疫苗载体的开发具有指导意义。
A replication-competent, recombinant strain of rhesus monkey rhadinovirus (RRV) expressing the Gag protein of SIVmac239 was constructed in the context of a glycoprotein L (gL) deletion mutation. Deletion of gL detargets the virus from Eph family receptors. The ability of this gL-minus Gag recombinant RRV to infect, persist, and elicit immune responses was evaluated after intravenous inoculation of twoMamu-A*01+RRV-naive rhesus monkeys. Both monkeys responded with an anti-RRV antibody response, and quantitation of RRV DNA in peripheral blood mononuclear cells (PBMC) by real-time PCR revealed levels similar to those in monkeys infected with recombinant gL+RRV. Comparison of RRV DNA levels in sorted CD3+versus CD20+versus CD14+PBMC subpopulations indicated infection of the CD20+subpopulation by the gL-minus RRV. This contrasts with results obtained with transformed B cell linesin vitro, in which deletion of gL resulted in markedly reduced infectivity. Over a period of 20 weeks, Gag-specific CD8+T cell responses were documented by major histocompatibility complex class I (MHC-I) tetramer staining. Vaccine-induced CD8+T cell responses, which were predominantly directed against the Mamu-A*01-restricted Gag181-189CM9 epitope, could be inhibited by blockade of MHC-I presentation. Our results indicate that gL and the interaction with Eph family receptors are dispensable for the colonization of the B cell compartment following high-dose infection by the intravenous route, which suggests the existence of alternative receptors. Further, gL-minus RRV elicits cellular immune responses that are predominantly canonical in nature.IMPORTANCEKaposi’s sarcoma-associated herpesvirus (KSHV) is associated with a substantial disease burden in sub-Saharan Africa, often in the context of human immunodeficiency virus (HIV) infection. The related rhesus monkey rhadinovirus (RRV) has shown potential as a vector to immunize monkeys with antigens from simian immunodeficiency virus (SIV), the macaque model for HIV. KSHV and RRV engage cellular receptors from the Eph family via the viral gH/gL glycoprotein complex. We have now generated a recombinant RRV that expresses the SIV Gag antigen and does not express gL. This recombinant RRV was infectious by the intravenous route, established persistent infection in the B cell compartment, and elicited strong immune responses to the SIV Gag antigen. These results argue against a role for gL and Eph family receptors in B cell infection by RRVin vivoand have implications for the development of a live-attenuated KSHV vaccine or vaccine vector.
登录
查看更多内容
DOI：
10.1073/pnas.0509201102
发表时间：
2005-12-13
影响因子：
11.1
作者：
Wang, D;Shenk, T
通讯作者：
Shenk, T
恒河猴鼻病毒：KSHV 研究模型。
影响因子：
--
作者：
Christine M. O'Connor;D. Kedes
通讯作者：
D. Kedes
影响因子：
1.2
作者：
Gonzalez-Nieto, Lucas;Domingues, Aline;Martins, Mauricio A.
通讯作者：
Martins, Mauricio A.
影响因子：
4.4
作者：
Todd M. Allen;J. Sidney;M. del Guercio;R. Glickman;G. Lensmeyer;D. Wiebe;R. Demars;C. Pauza;R. Johnson;A. Sette;D. Watkins
通讯作者：
Todd M. Allen;J. Sidney;M. del Guercio;R. Glickman;G. Lensmeyer;D. Wiebe;R. Demars;C. Pauza;R. Johnson;A. Sette;D. Watkins
具有 B 细胞（骨髓来源）特征的连续淋巴细胞系，缺乏 Epstein-Barr 病毒基因组，源自三种人类淋巴瘤。
DOI：
--
发表时间：
1974
影响因子：
11.1
作者：
G. Klein;T. Lindahl;M. Jondal;W. Leibold;J. Menezes;K. Nilsson;C. Sundström
通讯作者：
C. Sundström