Immune clearance of highly pathogenic SIV infection.
Immune clearance of highly pathogenic SIV infection.
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人类和猿猴免疫缺陷病毒（HIV、SIV）的既定感染被认为是永久性的，即使是最有效的免疫反应和抗逆转录病毒疗法（ART）也只能控制但不能清除这些感染。维持这些感染的残留病毒是否容易被清除，对于未来数百万艾滋病毒感染者的管理至关重要。我们最近报道，约 50% 的恒河猴 (RM) 接种了表达 SIV 蛋白的恒河猴巨细胞病毒 (RhCMV/SIV) 载体，表现出对高致病性 SIVmac239 感染的持久、无病毒血症控制。在这里，我们证明，无论攻击途径如何，RhCMV/SIV 载体引发的免疫反应在明显的淋巴和血行病毒传播后控制 SIVmac239，并且具有复制能力的 SIV 在多个位点持续数周至数月。然而，随着时间的推移，受保护的 RM 失去了 SIV 感染的迹象，显示出使用超灵敏测定法始终缺乏可测量的血浆或组织相关病毒，并且 T 细胞对疫苗中未包含的 SIV 决定簇的反应性丧失。对攻击后 69-172 周尸检的 RhCMV/SIV 载体保护的 RM 组织进行广泛的超灵敏 RT-PCR 和 PCR 分析，未在背景中检测到 SIV RNA 或 DNA，并且通过组织的广泛共培养分析或通过将 6000 万个血淋巴细胞过继转移至初始 RM，在这些 RM 中未检测到具有复制能力的 SIV。这些数据为逐步清除致病性慢病毒感染提供了令人信服的证据，并表明一些慢病毒储存库可能容易受到 CMV 载体引发和维持的持续效应记忆 T 细胞介导的免疫监视的影响。
Established infections with the human and simian immunodeficiency viruses (HIV, SIV) are thought to be permanent with even the most effective immune responses and anti-retroviral therapies (ART) only able to control, but not clear, these infections. Whether the residual virus that maintains these infections is vulnerable to clearance is a question of central importance to the future management of millions of HIV-infected individuals. We recently reported that ~50% of rhesus macaques (RM) vaccinated with SIV protein-expressing Rhesus Cytomegalovirus (RhCMV/SIV) vectors manifest durable, aviremic control of infection with highly pathogenic SIVmac239. Here, we demonstrate that regardless of route of challenge, RhCMV/SIV vector-elicited immune responses control SIVmac239 after demonstrable lymphatic and hematogenous viral dissemination, and that replication-competent SIV persists in multiple sites for weeks to months. However, over time, protected RM lost signs of SIV infection, showing a consistent lack of measurable plasma or tissue-associated virus using ultrasensitive assays, and loss of T cell reactivity to SIV determinants not in the vaccine. Extensive ultrasensitive RT-PCR and PCR analysis of tissues from RhCMV/SIV vector-protected RM necropsied 69–172 weeks after challenge did not detect SIV RNA or DNA over background, and replication-competent SIV was not detected in these RM by extensive co-culture analysis of tissues or by adoptive transfer of 60 million hematolymphoid cells to naïve RM. These data provide compelling evidence for progressive clearance of a pathogenic lentiviral infection, and suggest that some lentiviral reservoirs may be susceptible to the continuous effector memory T cell-mediated immune surveillance elicited and maintained by CMV vectors.
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