Gammaretroviruses in Biologics

摘要：使用猪组织或细胞的临床试验正在进行中。由于所有猪的基因组中都携带猪内源性逆转录病毒（PERV），因此这些异种移植手术存在接触和传播PERV的风险。我们之前的研究表明，PERV的激活发生在猪原代外周血单个核细胞（PBMC）暴露于有丝分裂剂后。我们现在已经证明，猪血浆也携带传染性PERV，这是从4只NIH迷你猪的血浆中分离出来的。然后，我们将该分析扩展到从猪血浆中提取的许可生物制剂Hyate:C（猪因子VIII）。临床许多Hyate:C对PERV RNA序列和病毒酶呈阳性。然而，对6批Hyate:C进行的传染性试验未能检测到感染性PERV，这表明临床材料只保留了灭活病毒的片段。这些研究的结果强调了两个重要的观点：1)从血浆中分离出传染性PERV，证实了PERV在猪体内的一些隔室中表达，这突出了猪异种移植受体暴露于PERV的可能性；2)对Hyate:C的分析强调了在动物源性产品的生产中需要采用强大的病毒灭活和去除方法。

Summary: Clinical trials using porcine tissues or cells are underway. Since all pigs carry in their genome porcine endogenous retroviruses (PERV), these xenotransplantation procedures carry the risk of exposure to and transmission of PERV. We previously showed that activation of PERV occurs after exposure of pig primary peripheral blood mononuclear cells (PBMC) to mitogenic agents. We now have shown that porcine plasma also carries infectious PERV that was isolated from plasma four out of four NIH mini pigs. We then extended this analysis to a licensed biologic derived from porcine plasma, Hyate:C (porcine factor VIII). Clinical lots of Hyate:C were positive for PERV RNA sequences and for a viral enzyme. However, infectivity assays performed on six lots of Hyate:C failed to detect infectious PERV, demonstrating that the clinical material only retained fragments of inactivated virus. The results from these studies highlight two important points: 1) isolation of infectious PERV from plasma confirms that PERV is expressed in vivo in some pig compartments, highlighting the potential for exposure to PERV in porcine xenotransplantation recipients; 2)the analysis of Hyate:C underscores the need for incorporating robust viral inactivation and removal methods in the manufacture of products derived from animal sources.