Clin Infect Dis：免疫系统可重新激活HIV

marine0425030

简要：

近日，来自牛津大学等研究者通过对一位进行骨髓移植的精英控制者研究发现，人类机体的免疫系统可以处理大规模的HIV活性爆发，这或许对于开发治疗HIV感染的新型策略提供了一定的思路，相关研究刊登于国际杂志Clinical Infectious Diseases上。

详情：

这种新型策略可以通过利用疫苗来刺激机体免疫系统，随后利用化学的刺激作用重新唤醒白细胞中休眠隐藏的HIV，以便机体增强的免疫系统可以识别并且杀灭病毒。虽然这种方法在理论上是有前途的，以前研究者并不清楚是否人类的免疫系统会在病毒全面被激活后来控制HIV，但这项研究中研究者利用单一患者进行了验证。

Ravi Gupta博士指出，本文研究揭示，免疫系统可以和鸡尾酒药物组合一样强大，目前我们离成功治疗HIV病人还差距甚远，因此我们需要开发并且检测一些有效疫苗，而本文研究让我们距离目标更近了一步；研究者对一名59岁的英国男性进行了研究，该研究对象属于精英控制者(Elite controller)，即其在不需要疗法治疗的情况下机体免疫系统可以控制HIV很长一段时间；精英控制者在HIV病人中占到了0.3%的比例，最终其需要疗法来抑制疾病向AIDS发展，但其在不需要疗法的情况下可以生存很久，因为患者机体的免疫系统完全具有活性来抵御HIV。

研究中的病人都患有HIV和骨髓瘤，骨髓可以产生白细胞，包括哪些帮助控制HIV的白细胞；为了治疗骨髓瘤患者，其骨髓会被完全移除并且利用自身的干细胞进行替代.

当骨髓被移除后，机体的免疫系统就会被严重破坏，从而使得HIV重新激活复制，这就会导致病毒进入血液中，使得病毒的拷贝由低于50拷贝/毫升升高至将近28000拷贝/毫升。

当在骨髓移植后患者机体的免疫功能恢复大约两周后，其血液中的HIV水平会迅速下降，机体免疫系统就会以一定的速度来降低HIV的水平，从而再次将HIV的水平降低至50拷贝/毫升。

最后研究者指出，刺激机体休眠的HIV重新激活的药物目前仍然并不完美，而且研究者并不知道是否他们可以将患者机体所有的HIV清除出去；同样地，研究者也并不清楚是否疫苗可以使得正常HIV病人机体的免疫系统来杀灭病毒，而本文研究就提出了一种非常有潜力的策略，这或许对于后期开发彻底治疗HIV患者的新型靶向疗法提供了新的希望。

原文阅读

doi:10.1093/cid/civ219
PMC:
PMID:

Proof-of-Principle for Immune Control of Global HIV-1 Reactivation In Vivo.

Nicola M. G. Smith1,a, Petra Mlcochova2,a, Sarah A. Watters2,a, Marlene M. I. Aasa-Chapman2, Neil Rabin3, Sally Moore3, Simon G. Edwards4, Jeremy A. Garson2, Paul R. Grant3, R. Bridget Ferns2, Angela Kashuba5, Neema P. Mayor6,7, Jennifer Schellekens6,7, Steven G. E. Marsh6,7, Andrew J. McMichael1, Alan S. Perelson8, Deenan Pillay2,9,b, Nilu Goonetilleke1,10,b, and Ravindra K. Gupta2,b

Background

Emerging data relating to human immunodeficiency virus type 1 (HIV-1) cure suggest that vaccination to stimulate the host immune response, particularly cytotoxic cells, may be critical to clearing of reactivated HIV-1–infected cells. However, evidence for this approach in humans is lacking, and parameters required for a vaccine are unknown because opportunities to study HIV-1 reactivation are rare.

Methods

We present observations from a HIV-1 elite controller, not treated with combination antiretroviral therapy, who experienced viral reactivation following treatment for myeloma with melphalan and autologous stem cell transplantation. Mathematical modeling was performed using a standard viral dynamic model. Enzyme-linked immunospot, intracellular cytokine staining, and tetramer staining were performed on peripheral blood mononuclear cells; in vitro CD8 T-cell–mediated control of virion production by autologous CD4 T cells was quantified; and neutralizing antibody titers were measured.

Results

Viral rebound was measured at 28 000 copies/mL on day 13 post-transplant before rapid decay to <50 copies/mL in 2 distinct phases with t1/2 of 0.71 days and 4.1 days. These kinetics were consistent with an expansion of cytotoxic effector cells and killing of productively infected CD4 T cells. Following transplantation, innate immune cells, including natural killer cells, recovered with virus rebound. However, most striking was the expansion of highly functional HIV-1–specific cytotoxic CD8 T cells, at numbers consistent with those applied in modeling, as virus control was regained.

Conclusions

These observations provide evidence that the human immune response is capable of controlling coordinated global HIV-1 reactivation, remarkably with potency equivalent to combination antiretroviral therapy. These data will inform design of vaccines for use in HIV-1 curative interventions.

marine0425030

需要补充一下。

这个病人的自体干细胞移植手术除了干细胞外还有 NK (0.18%), NKT (2.3%), CD4+ T cells (32.7%), CD8+ T cells (23.4%)and monocytes (1.5%). CD19+ B cells were not detected (Table 1).


这些CD8 细胞里有HIV特异性的T细胞，而且都是棒棒的细胞啊。

Calculationof transfer of HIV-1 specific CD8 T cells: Approximately, 19billion total cells were transplanted of which 14.1% were memory CD8 T cells.2.05% of cells were HIV-1 specific for TL9 and LY9 epitopes (the two strongestmapped epitopes). Assuming comparablecell viability at transplantation as for ICS experiments (47·4%), then thesubject received ~26 million HIV-1 reactive CD8+ T cells.

当时候我一直觉得是 干细胞分化出来的免疫细胞控制了病毒，仔细想来这些病毒应该是2.05%特异性T免疫细胞激活，扩增以后控制住病毒的可能性更大。

这不是相当于一种自体的免疫疗法吗？

其结果应该是首次在人体上验证了CD8 T 细胞的重要性，因为之前在猴子实验有类似的结果。