Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
J Virol. 2018 Sep 12;92(19). doi: 10.1128/JVI.00157-18. Print 2018 Oct 1.
Human immunodeficiency virus type 1 (HIV-1) infection often arises from a single transmitted/founder (TF) viral variant among a large pool of viruses in the quasispecies in the transmitting partner. TF variants are typically nondominant in blood and genital secretions, indicating that they have unique traits. The plasmacytoid dendritic cell (pDC) is the primary alpha interferon (IFN-α)-producing cell in response to viral infections and is rapidly recruited to the female genital tract upon exposure to HIV-1. The impact of pDCs on transmission is unknown. We investigated whether evasion of pDC responses is a trait of TF viruses. pDCs from healthy donors were stimulated with a panel of 20 HIV-1 variants, consisting of one TF variant and three nontransmitted (NT) variants each from five transmission-linked donor pairs, and secretion of IFN-α and tumor necrosis factor alpha (TNF-α) was measured by enzyme-linked immunosorbent assay (ELISA). No significant differences in cytokine secretion in response to TF and NT viruses were observed, despite a trend toward enhanced IFN-α and TNF-α production in response to TF viruses. NT viruses demonstrated polarization toward production of either IFN-α or TNF-α, indicating possible dysregulation. Also, for NT viruses, IFN-α secretion was associated with increased resistance of the virus to inactivation by IFN-α , suggesting evolution. Thus, TF viruses do not appear to preferentially subvert pDC activation compared to that with nontransmitted HIV-1 variants. pDCs may, however, contribute to the evolution of HIV-1. The plasmacytoid dendritic cell (pDC) is the first cell type recruited to the site of HIV-1 exposure; however, its contribution to the viral bottleneck in HIV-1 transmission has not been explored previously. We hypothesized that transmitted/founder viruses are able to avoid the pDC response. In this study, we used previously established donor pair-linked transmitted/founder and nontransmitted (or chronic) variants of HIV-1 to stimulate pDCs. Transmitted/founder HIV-1, instead of suppressing pDC responses, induced IFN-α and TNF-α secretion to levels comparable to those induced by viruses from the transmitting partner. We noted several unique traits of chronic viruses, including polarization between IFN-α and TNF-α production as well as a strong relationship between IFN-α secretion and the resistance of the virus to neutralization. These data rule out the possibility that TF viruses preferentially suppress pDCs in comparison to the pDC response to nontransmitted HIV variants. pDCs may, however, be important drivers of viral evolution .
人类免疫缺陷病毒 1 型（HIV-1）感染通常源于传播伴侣准种中大量病毒中的单一传播/创始（TF）病毒变异体。TF 变体在血液和生殖分泌物中通常不是优势，表明它们具有独特的特征。浆细胞样树突状细胞（pDC）是对病毒感染产生α干扰素（IFN-α）的主要细胞，在接触 HIV-1 后会迅速招募到女性生殖道。pDC 对传播的影响尚不清楚。我们研究了逃避 pDC 反应是否是 TF 病毒的特征。用一组由 20 种 HIV-1 变体组成的面板刺激来自健康供体的 pDC，这些变体包括来自五个传播相关供体对的一个 TF 变体和三个非传播（NT）变体，通过酶联免疫吸附试验（ELISA）测量 IFN-α和肿瘤坏死因子-α（TNF-α）的分泌。尽管 TF 病毒的 IFN-α和 TNF-α产生呈增强趋势，但对 TF 和 NT 病毒的细胞因子分泌没有观察到显著差异。NT 病毒表现出产生 IFN-α或 TNF-α的极化，表明可能存在失调。此外，对于 NT 病毒，IFN-α的分泌与病毒对 IFN-α失活的抵抗力增加有关，这表明病毒发生了进化。因此，与非传播的 HIV-1 变体相比，TF 病毒似乎并没有优先抑制 pDC 的激活。然而，pDC 可能会促进 HIV-1 的进化。浆细胞样树突状细胞（pDC）是招募到 HIV-1 暴露部位的第一类细胞；然而，其在 HIV-1 传播中的病毒瓶颈中的贡献尚未被探索。我们假设传播/创始病毒能够逃避 pDC 反应。在这项研究中，我们使用先前建立的供体对相关的传播/创始和非传播（或慢性）HIV-1 变体来刺激 pDC。与来自传播伴侣的病毒相比，传播/创始 HIV-1 诱导 IFN-α和 TNF-α 的分泌达到了相同的水平，而不是抑制 pDC 反应。我们注意到慢性病毒的几个独特特征，包括 IFN-α和 TNF-α产生之间的极化以及 IFN-α分泌与病毒对中和的抵抗力之间的强关系。这些数据排除了 TF 病毒与非传播的 HIV 变体相比更优先抑制 pDC 的可能性。然而，pDC 可能是病毒进化的重要驱动因素。
