Berry Neil, Ham Claire, Alden Jack, Clarke Sean, Stebbings Richard, Stott Jim, Ferguson Deborah, Almond Neil
1Division of Virology, NIBSC, South Mimms, Potters Bar, Hertfordshire EN6 3QG, UK.
2Divison of Biotherapeutics, NIBSC, South Mimms, Potters Bar, Hertfordshire EN6 3QG, UK.
J Gen Virol. 2015 Jul;96(Pt 7):1918-29. doi: 10.1099/vir.0.000135. Epub 2015 Apr 1.
Vaccination with live attenuated simian immunodeficiency virus (SIV) in non-human primate species provides a means of characterizing the protective processes of retroviral superinfection and may lead to novel advances of human immunodeficiency virus (HIV)/AIDS vaccine design. The minimally attenuated SIVmacC8 vaccine has been demonstrated to elicit early potent protection against pathogenic rechallenge with genetically diverse viral isolates in cynomolgus macaques (Macaca fascicularis). In this study, we have characterized further the biological breadth of this vaccine protection by assessing the ability of both the nef-disrupted SIVmacC8 and its nef-intact counterpart SIVmacJ5 viruses to prevent superinfection with the macrophage/neurotropic SIVmac239/17E-Fr (SIVmac17E-Fr) isolate. Inoculation with either SIVmacC8 or SIVmacJ5 and subsequent detailed characterization of the viral replication kinetics revealed a wide range of virus-host outcomes. Both nef-disrupted and nef-intact immunizing viruses were able to prevent establishment of SIVmac17E-Fr in peripheral blood and secondary lymphoid tissues. Differences in virus kinetics, indicative of an active process, identified uncontrolled replication in one macaque which although able to prevent SIVmac17E-Fr superinfection led to extensive neuropathological complications. The ability to prevent a biologically heterologous, CD4-independent/CCR5+ viral isolate and the macrophage-tropic SIVmac316 strain from establishing infection supports the hypothesis that direct target cell blocking is unlikely to be a central feature of live lentivirus vaccination. These data provide further evidence to demonstrate that inoculation of a live retroviral vaccine can deliver broad spectrum protection against both macrophage-tropic as well as lymphocytotropic viruses. These data add to our knowledge of live attenuated SIV vaccines but further highlight potential safety concerns of vaccinating with a live retrovirus.
用减毒活猴免疫缺陷病毒（SIV）对非人灵长类动物进行疫苗接种，为研究逆转录病毒重复感染的保护机制提供了一种方法，并且可能会推动人类免疫缺陷病毒（HIV）/艾滋病疫苗设计取得新进展。已证明，最低限度减毒的SIVmacC8疫苗能在食蟹猴（猕猴属）中引发早期强效保护，抵御基因多样的病毒分离株的致病性再次攻击。在本研究中，我们通过评估缺失nef基因的SIVmacC8及其完整nef基因的对应病毒SIVmacJ5预防巨噬细胞/嗜神经SIVmac239/17E-Fr（SIVmac17E-Fr）分离株重复感染的能力，进一步明确了这种疫苗保护的生物学广度。接种SIVmacC8或SIVmacJ5并随后详细表征病毒复制动力学，揭示了广泛的病毒-宿主结果。缺失nef基因和完整nef基因的免疫病毒均能阻止SIVmac17E-Fr在外周血和二级淋巴组织中定植。病毒动力学的差异表明存在一个活跃过程，在一只猕猴中发现了不受控制的复制，尽管它能够预防SIVmac17E-Fr重复感染，但却导致了广泛的神经病理并发症。预防生物学上异源的、不依赖CD4/CCR5+的病毒分离株以及巨噬细胞嗜性的SIVmac316毒株建立感染的能力支持了这样一种假说，即直接的靶细胞阻断不太可能是减毒活慢病毒疫苗接种的核心特征。这些数据提供了进一步的证据，证明接种减毒活逆转录病毒疫苗可提供针对巨噬细胞嗜性病毒和淋巴细胞嗜性病毒的广谱保护。这些数据增加了我们对减毒活SIV疫苗 的了解，但进一步凸显了接种减毒活逆转录病毒疫苗的潜在安全问题。
