Chissumba Raquel Matavele, Luciano Abílio, Namalango Eduardo, Bauer Asli, Bhatt Nilesh, Wahren Britta, Nilsson Charlotta, Geldmacher Christof, Scarlatti Gabriella, Jani Ilesh, Kestens Luc
Instituto Nacional de Saúde, Ministry of Health, Maputo, Mozambique; Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium; Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
Instituto de Ciências de Saúde, Ministry of Health, Maputo, Mozambique.
Immunobiology. 2018 Dec;223(12):792-801. doi: 10.1016/j.imbio.2018.08.006. Epub 2018 Aug 12.
Little is known about regulatory CD4 T cells (Tregs) in the context of HIV vaccines. Tregs can be differentiated into resting (FoxP3CD45RA - rTregs), activated (FoxP3CD45RA - aTregs) and memory (FoxP3CD45RA - mTregs). Tregs, as CD4 T cells, are also frequent targets for HIV infection. We studied how the abundance and phenotypes of Tregs in terms of activation status and expression of HIV-1 binding molecules would have changed during vaccination in healthy volunteers participating in a phase IIa HIV vaccine clinical trial. Subjects were primed three times with HIVIS-DNA and boosted twice with MVA-CMDR-HIV alone (n = 12) or MVA-CMDR combined with protein CN54rgp140 (n = 13). The proportions of β7 integrin in all CD4 T cells and in the Tregs subset decreased moderately after the final vaccination (p = 0.001 and p = 0.033, respectively) and the rTregs proportion within the total Tregs were also decreased after the final vaccination (p = 0.038). All these proportions returned to normal values within the three months after the final vaccination. The magnitude of HIV-Envelope-specific IFNγ + T cells after vaccination (r = 0.66; p = 0.021) correlated directly with the proportion of Tregs, and correlated inversely correlated with ratios of Th17/Tregs (r = -0.75; p = 0.0057) and Th17/mTregs (r = -0.78; p = 0.0065). Higher titers of IgG gp140 antibodies were observed in subjects with higher mTregs proportions (r = 0.52; p = 0.022). Interestingly, pre-vaccination levels of mTregs correlated with vaccine-induced Env-binding antibodies (r = 0.57; p = 0.01) and presence of neutralizing antibodies (r = 0.61; p = 0.01), while the pre-vaccination Th17/mTregs ratio correlated inversely with the magnitude of cellular IFN-γ ELISpot responses (r = -0.9; p = 0.002). Taken together, these results suggest that pre- and post-vaccination Tregs, their activation status, the Th17/Tregs ratio and other host factors affecting Treg abundance, have an impact on the magnitude of HIV vaccine-induced immune responses. Moreover, the DNA-HIVIS/MVA-HIV regimen, alone or in combination with CN54rgp140 induced moderate and temporary alterations of the Tregs activation status. We also show a decrease in expression of the HIV-1 ligand β7 integrin on Tregs and all CD4 T cells.
在HIV疫苗的背景下，人们对调节性CD4 T细胞（Tregs）了解甚少。Tregs可分化为静息型（FoxP3CD45RA - rTregs）、活化型（FoxP3CD45RA - aTregs）和记忆型（FoxP3CD45RA - mTregs）。作为CD4 T细胞，Tregs也是HIV感染的常见靶标。我们研究了在参与一项IIa期HIV疫苗临床试验的健康志愿者接种疫苗期间，Tregs在激活状态和HIV-1结合分子表达方面的丰度和表型是如何变化的。受试者用HIVIS-DNA进行三次初免，单独用MVA-CMDR-HIV（n = 12）或MVA-CMDR与蛋白CN54rgp140联合（n = 13）进行两次加强免疫。最终接种疫苗后，所有CD4 T细胞和Tregs亚群中β7整合素的比例适度下降（分别为p = 0.001和p = 0.033），最终接种疫苗后总Tregs中的rTregs比例也下降（p = 0.038）。所有这些比例在最终接种疫苗后的三个月内恢复到正常水平。接种疫苗后HIV包膜特异性IFNγ + T细胞的幅度（r = 0.66；p = 0.021）与Tregs比例直接相关，与Th17/Tregs比例（r = -0.75；p = 0.0057）和Th17/mTregs比例（r = -0.78；p = 0.0065）呈负相关。在mTregs比例较高的受试者中观察到更高滴度的IgG gp140抗体（r = 0.52；p = 0.022）。有趣的是，接种疫苗前mTregs的水平与疫苗诱导的Env结合抗体（r = 0.57；p = 0.01）和中和抗体的存在（r = 0.61；p = 0.01）相关，而接种疫苗前Th17/mTregs比例与细胞IFN-γ ELISpot反应的幅度呈负相关（r = -0.9；p = 0.002）。综上所述，这些结果表明，接种疫苗前后的Tregs、它们的激活状态、Th17/Tregs比例以及影响Treg丰度的其他宿主因素，对HIV疫苗诱导的免疫反应幅度有影响。此外，DNA-HIVIS/MVA-HIV方案单独或与CN54rgp14'联合诱导了Tregs激活状态的适度和暂时改变。我们还显示Tregs和所有CD4 T细胞上HIV-1配体β7整合素的表达下降。
