Herasimtschuk Anna, Downey Jocelyn, Nelson Mark, Moyle Graeme, Mandalia Sundhiya, Sikut Rein, Adojaan Maarja, Stanescu Ioana, Gotch Frances, Imami Nesrina
Imperial College London, London, UK.
Chelsea and Westminster Hospital, London, UK.
Vaccine. 2014 Dec 5;32(51):7005-7013. doi: 10.1016/j.vaccine.2014.09.072. Epub 2014 Oct 22.
This randomised, open label, phase I, immunotherapeutic study investigated the effects of interleukin (IL)-2, granulocyte-macrophage colony-stimulating factor (GM-CSF), recombinant human growth hormone (rhGH), and therapeutic immunisation (a Clade B DNA vaccine) on combination antiretroviral therapy (cART)-treated HIV-1-infected individuals, with the objective to reverse residual T-cell dysfunction.
Twelve HIV-1(+) patients on suppressive cART with baseline CD4 T-cell counts >400 cells/mm(3) blood were randomised into one of three groups: (1) vaccine, IL-2, GM-CSF and rhGH (n=3); (2) vaccine alone (n=4); or (3) IL-2, GM-CSF and rhGH (n=5). Samples were collected at weeks 0, 1, 2, 4, 6, 8, 12, 16, 24 and 48. Interferon (IFN)-γ, IL-2, IL-4 and perforin ELISpot assays performed at each time point quantified functional responses to Gag p17/p24, Nef, Rev, and Tat peptides; and detailed T-cell immunophenotyping was undertaken by flow cytometry. Proviral DNA was also measured.
Median baseline CD4 T-cell count was 757 cells/mm(3) (interquartile range [IQR] 567-886 cells/mm(3)), median age 48 years (IQR 42-51 years), and plasma HIV-1-RNA <50 copies/ml for all subjects. Patients who received vaccine plus IL-2, GM-CSF and rhGH (group 1) showed the most marked changes. Assessing mean changes from baseline to week 48 revealed significantly elevated numbers of CD4 T cells (p=0.0083) and improved CD4/CD8 T-cell ratios (p=0.0033). This was accompanied by a significant reduction in expression of CD38 on CD4 T cells (p=0.0194), significantly increased IFN-γ and IL-2 production in response to Gag (p=0.0122) and elevated IFN-γ production in response to Tat (p=0.041) at week 48 compared to baseline. Subjects in all treatment groups showed significantly reduced PD-1 expression at week 48 compared to baseline, with some reductions in proviral DNA.
Multifarious immunotherapeutic approaches in the context of fully suppressive cART further reduce immune activation, and improve both CD4 T-lymphocyte counts and HIV-1-specific T-cell responses (NCT01130376).
这项随机、开放标签的I期免疫治疗研究调查了白细胞介素(IL)-2、粒细胞-巨噬细胞集落刺激因子(GM-CSF)、重组人生长激素(rhGH)和治疗性免疫接种(一种B亚型DNA疫苗)对接受联合抗逆转录病毒治疗(cART)的HIV-1感染者的影响,目的是逆转残留的T细胞功能障碍。
12名接受抑制性cART且基线CD4 T细胞计数>400个细胞/mm³血液的HIV-1阳性患者被随机分为三组之一:(1)疫苗、IL-2、GM-CSF和rhGH(n = 3);(2)仅疫苗(n = 4);或(3)IL-2、GM-CSF和rhGH(n = 5)।在第0、1、2、4、6、8、12、16、24和48周采集样本。在每个时间点进行的干扰素(IFN)-γ、IL-2、IL-4和穿孔素ELISpot分析定量了对Gag p17/p24、Nef、Rev和Tat肽的功能性反应;并通过流式细胞术进行详细的T细胞免疫表型分析。还测量了前病毒DNA。
所有受试者的基线CD4 T细胞计数中位数为757个细胞/mm³(四分位间距[IQR]567 - 886个细胞/mm³),年龄中位数为48岁(IQR 42 - 51岁),血浆HIV-1-RNA<50拷贝/ml。接受疫苗加IL-2、GM-CSF和rhGH的患者(第1组)显示出最明显的变化。评估从基线到第48周的平均变化,发现CD4 T细胞数量显著增加(p = 0.0083),CD4/CD8 T细胞比率改善(p = 0.00३३)।这伴随着CD4 T细胞上CD38表达的显著降低(p = 0.0194),与基线相比,第48周时对Gag反应的IFN-γ和IL-2产生显著增加(p = 0.0122),对Tat反应的IFN-γ产生增加(p = 0.041)।与基线相比,所有治疗组的受试者在第48周时PD-1表达均显著降低,前病毒DNA也有一些减少。
在完全抑制性cART的背景下,多种免疫治疗方法进一步降低免疫激活,并改善CD4 T淋巴细胞计数和HIV-1特异性T细胞反应(NCT01130376)。