AIDS and Cancer Virus Program, National Cancer Institute, Frederick, Maryland, USA.
J Virol. 2012 Mar;86(6):3152-66. doi: 10.1128/JVI.06886-11. Epub 2012 Jan 11.
Although xenotropic murine leukemia virus-related virus (XMRV) has been previously linked to prostate cancer and myalgic encephalomyelitis/chronic fatigue syndrome, recent data indicate that results interpreted as evidence of human XMRV infection reflect laboratory contamination rather than authentic in vivo infection. Nevertheless, XMRV is a retrovirus of undefined pathogenic potential that is able to replicate in human cells. Here we describe a comprehensive analysis of two male pigtailed macaques (Macaca nemestrina) experimentally infected with XMRV. Following intravenous inoculation with >10(10) RNA copy equivalents of XMRV, viral replication was limited and transient, peaking at ≤2,200 viral RNA (vRNA) copies/ml plasma and becoming undetectable by 4 weeks postinfection, though viral DNA (vDNA) in peripheral blood mononuclear cells remained detectable through 119 days of follow-up. Similarly, vRNA was not detectable in lymph nodes by in situ hybridization despite detectable vDNA. Sequencing of cell-associated vDNA revealed extensive G-to-A hypermutation, suggestive of APOBEC-mediated viral restriction. Consistent with limited viral replication, we found transient upregulation of type I interferon responses that returned to baseline by 2 weeks postinfection, no detectable cellular immune responses, and limited or no spread to prostate tissue. Antibody responses, including neutralizing antibodies, however, were detectable by 2 weeks postinfection and maintained throughout the study. Both animals were healthy for the duration of follow-up. These findings indicate that XMRV replication and spread were limited in pigtailed macaques, predominantly by APOBEC-mediated hypermutation. Given that human APOBEC proteins restrict XMRV infection in vitro, human XMRV infection, if it occurred, would be expected to be characterized by similarly limited viral replication and spread.
虽然嗜异鼠白血病病毒相关病毒（XMRV）先前与前列腺癌和肌痛性脑脊髓炎/慢性疲劳综合征有关，但最近的数据表明，被解释为人类 XMRV 感染证据的结果反映了实验室污染而不是真实的体内感染。尽管如此，XMRV 是一种潜在致病性不明的逆转录病毒，能够在人类细胞中复制。在这里，我们描述了对两只经实验感染 XMRV 的雄性长尾猕猴（Macaca nemestrina）的综合分析。静脉内接种超过 10(10)个 RNA 拷贝等价物的 XMRV 后，病毒复制受到限制且短暂，在感染后 4 周时达到峰值，病毒 RNA（vRNA）血浆拷贝数≤2,200，尽管外周血单个核细胞中的病毒 DNA（vDNA）在 119 天的随访中仍可检测到。同样，尽管可检测到 vDNA，但通过原位杂交在淋巴结中未检测到 vRNA。细胞相关 vDNA 的测序显示广泛的 G 到 A 超突变，提示 APOBEC 介导的病毒限制。与有限的病毒复制一致，我们发现 I 型干扰素反应短暂上调，在感染后 2 周时恢复到基线，未检测到细胞免疫反应，并且向前列腺组织的扩散有限或没有。然而，在感染后 2 周时即可检测到抗体反应，包括中和抗体，并在整个研究过程中维持。在随访期间，两只动物均健康。这些发现表明，XMRV 在长尾猕猴中的复制和传播受到限制，主要是由 APOBEC 介导的超突变。鉴于人类 APOBEC 蛋白在体外限制 XMRV 感染，如果发生人类 XMRV 感染，预计其特征将是类似的有限病毒复制和传播。
