Pankrac Joshua, Klein Katja, McKay Paul F, King Deborah F L, Bain Katie, Knapp Jason, Biru Tsigereda, Wijewardhana Chanuka N, Pawa Rahul, Canaday David H, Gao Yong, Fidler Sarah, Shattock Robin J, Arts Eric J, Mann Jamie F S
1Department of Microbiology and Immunology, University of Western Ontario, London, ON N6A 5C1 Canada.
2Division of Infectious Diseases, Department of Medicine, Case Western Reserve University, Cleveland, OH 44106 USA.
NPJ Vaccines. 2018 Jan 19;3:2. doi: 10.1038/s41541-017-0040-6. eCollection 2018.
First identified as the etiological agent behind Acquired Immunodeficiency Syndrome (AIDS) in the early 1980s, HIV-1 has continued to spread into a global pandemic and major public health concern. Despite the success of antiretroviral therapy at reducing HIV-1 viremia and preventing the dramatic CD4 T-cell collapse, infected individuals remain HIV positive for life. Unfortunately, it is increasingly clear that natural immunity is not, and may never be, protective against this pathogen. Therefore, efficacious vaccine interventions, which can either prevent infection or eradicate the latent viral reservoir and effect cure, are a major medical priority. Here we describe the development of a safe vaccine platform, currently being utilized in on-going prophylactic and therapeutic preclinical studies and consisting of highly heterogeneous virus-like particle formulations that represent the virus diversity within infected individuals. These VLPs contain no 5'LTR, no functional integrase, and have a severely mutated stem loop 1-thereby preventing any potential reverse transcription, integration, and RNA packaging. Furthermore, we demonstrate that these VLPs are morphologically identical to wild-type virus with polyvalent Env in a functional form. Finally, we show that the VLPs are antigenic and capable of generating strong immune recall responses.
20世纪80年代初,HIV-1首次被确认为获得性免疫缺陷综合征(艾滋病)背后的病原体,此后它持续蔓延,成为全球大流行病和主要的公共卫生问题。尽管抗逆转录病毒疗法在降低HIV-1病毒血症和防止CD4 T细胞急剧减少方面取得了成功,但感染者终生仍呈HIV阳性。不幸的是,越来越明显的是,天然免疫目前没有,而且可能永远无法对这种病原体起到保护作用。因此,能够预防感染或根除潜伏病毒库并实现治愈的有效疫苗干预措施是医学上的一项重大优先事项。在此,我们描述了一个安全疫苗平台的开发情况,该平台目前正在进行预防性和治疗性临床前研究,由高度异质性的病毒样颗粒制剂组成,这些制剂代表了受感染个体体内的病毒多样性。这些病毒样颗粒不含5'LTR,没有功能性整合酶,并且茎环1发生了严重突变,从而阻止了任何潜在的逆转录、整合和RNA包装。此外,我们证明这些病毒样颗粒在形态上与具有功能性多价Env的野生型病毒相同。最后,我们表明这些病毒样颗粒具有抗原性,能够产生强烈的免疫回忆反应。
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