T-cell responses targeting HIV Nef uniquely correlate with infected cell frequencies after long-term antiretroviral therapy.
T-cell responses targeting HIV Nef uniquely correlate with infected cell frequencies after long-term antiretroviral therapy.
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DOI：
10.1371/journal.ppat.1006629
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发表时间：
2017-09
期刊：
影响因子：
6.7
通讯作者：
Jones RB
中科院分区：
文献类型：
--
作者：
Thomas AS;Jones KL;Gandhi RT;McMahon DK;Cyktor JC;Chan D;Huang SH;Truong R;Bosque A;Macedo AB;Kovacs C;Benko E;Eron JJ;Bosch RJ;Lalama CM;Simmens S;Walker BD;Mellors JW;Jones RB
HIV 特异性 CD8+ T 细胞反应限制了未经治疗的感染中的病毒复制。开始抗逆转录病毒治疗 (ART) 后，这些反应会减弱，并且通常认为 T 细胞看不到残留的受感染细胞群。我们假设，由于低水平或间歇性的蛋白质表达，HIV 抗原识别可能在接受 ART 治疗的个体中持续存在。我们假设，如果持续识别发生，它将优先针对早期 HIV 基因产物 Nef、Tat 和 Rev，而不是晚期基因产物，例如具有更高表达障碍的 Gag、Pol 和 Env。使用原代细胞潜伏期模型，我们观察到 Nef 特异性 CD8+ T 细胞克隆在重新激活之前表现出对受感染细胞的低水平识别，并在随后不久表现出强大的识别能力。 Gag 特异性 CD8+ T 细胞克隆在这些条件下无法识别受感染的细胞，这与缺乏可检测到的 Gag 表达相对应。我们测量了 96 名接受 ART 抑制时间平均为 7 年的个体的 HIV 特异性 T 细胞反应，并观察到细胞相关 HIV DNA 水平与产生 IFN-γ 的 Nef/Tat/Rev 特异性 T 细胞反应强度之间存在显着的直接相关性。这种相关性在一个独立队列 (n = 18) 中得到证实。未检测到 HIV 持久性测量与 T 细胞对其他 HIV 抗原反应之间的相关性。与 Nef/Tat/Rev 特异性 T 细胞的相关性可归因于 Nef 特异性反应，其广度也与 HIV DNA 水平相关。这些结果表明，接受 ART 治疗的个体中持续的 Nef 表达会优先维持和/或扩增对该蛋白具有反应性的 T 细胞，这意味着免疫系统能够感知受感染的细胞。然而，直接相关性表明识别并不能有效消除受感染的细胞。这些结果提出了这样一种可能性：增强 Nef 特异性 T 细胞的溶细胞活性可能会导致感染细胞频率的减少，即使在没有治疗潜伏期逆转的情况下也是如此。抗逆转录病毒疗法（ART）可以有效抑制艾滋病毒，以至于在接受治疗的个体中很难检测到。然而，艾滋病毒确实持续保持在低水平，如果停止抗逆转录病毒治疗，艾滋病毒就会反弹。人们普遍认为，HIV 持续存在的状态对于免疫反应是不可见的，例如杀伤性 T 细胞，否则免疫反应会消灭受感染的细胞。因此，治愈艾滋病毒的努力重点是制定策略，通过“潜伏期逆转”将这些隐藏的细胞暴露给免疫系统。我们假设，这些个体的 T 细胞中的病毒隐藏可能不是绝对的，并且一种名为“Nef”的特殊蛋白质可能会使 HIV 部分暴露。我们推断，如果这是真的，我们将观察到 T 细胞对 Nef 的反应强度与 HIV 感染细胞的频率之间存在关联。我们在 96 名接受长期 ART 治疗的个体中对此进行了测试。我们观察到这两个参数之间存在直接相关性，表明 Nef 特异性 T 细胞继续检测受感染的细胞，但不能有效消除这些暴露的靶细胞。我们的结果表明，增强 Nef 特异性 T 细胞的杀伤能力可能会减少病毒储库，从而有助于实现病毒根除或缓解。
HIV-specific CD8+ T-cell responses limit viral replication in untreated infection. After the initiation of antiretroviral therapy (ART), these responses decay and the infected cell population that remains is commonly considered to be invisible to T-cells. We hypothesized that HIV antigen recognition may persist in ART-treated individuals due to low-level or episodic protein expression. We posited that if persistent recognition were occurring it would be preferentially directed against the early HIV gene products Nef, Tat, and Rev as compared to late gene products, such as Gag, Pol, and Env, which have higher barriers to expression. Using a primary cell model of latency, we observed that a Nef-specific CD8+ T-cell clone exhibited low-level recognition of infected cells prior to reactivation and robust recognition shortly thereafter. A Gag-specific CD8+ T-cell clone failed to recognized infected cells under these conditions, corresponding with a lack of detectable Gag expression. We measured HIV-specific T-cell responses in 96 individuals who had been suppressed on ART for a median of 7 years, and observed a significant, direct correlation between cell-associated HIV DNA levels and magnitudes of IFN-γ-producing Nef/Tat/Rev-specific T-cell responses. This correlation was confirmed in an independent cohort (n = 18). Correlations were not detected between measures of HIV persistence and T-cell responses to other HIV antigens. The correlation with Nef/Tat/Rev-specific T-cells was attributable to Nef-specific responses, the breadth of which also correlated with HIV DNA levels. These results suggest that ongoing Nef expression in ART-treated individuals drives preferential maintenance and/or expansion of T-cells reactive to this protein, implying sensing of infected cells by the immune system. The direct correlation, however, suggests that recognition does not result in efficient elimination of infected cells. These results raise the possibility that enhancing the cytolytic activity of Nef-specific T-cells may lead to reductions in infected cell frequencies, even in the absence of therapeutic latency reversal. Antiretroviral therapy (ART) potently suppresses HIV, to the point where it is difficult to detect in treated individuals. HIV does persist at low levels, however, and rebounds if ART is stopped. The state in which HIV persists is commonly thought to be invisible to immune responses, such as killer T-cells, which would otherwise eliminate infected cells. Efforts to cure HIV have therefore focused on developing strategies to expose these hidden cells to the immune system through ‘latency reversal’. We hypothesized that the concealment of the virus from T-cells in these individuals may not be absolute, and that a particular protein called ‘Nef’ may leave HIV partially exposed. We reasoned that, if this were true, we would observe an association between the strength of the T-cell response to Nef and the frequencies of HIV-infected cells. We tested this in population of 96 individuals on long-term ART. We observed a direct correlation between these two parameters, suggesting that Nef-specific T-cells continue to detect infected cells, but do not efficiently eliminate these exposed target cells. Our results suggest that boosting the killing ability of Nef-specific T-cells may reduce viral reservoirs, and thus contribute to achieving viral eradication or remission.
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影响因子：
9.4
作者：
Cillo, Anthony R.;Vagratian, David;Mellors, John W.
通讯作者：
Mellors, John W.
DOI：
10.1073/pnas.94.24.13193
发表时间：
1997-11-25
影响因子：
11.1
作者：
Chun, TW;Stuyver, L;Fauci, AS
通讯作者：
Fauci, AS
DOI：
10.1073/pnas.1609057113
发表时间：
2016-08-02
影响因子：
11.1
作者：
Imamichi, Hiromi;Dewar, Robin L.;Lane, H. Clifford
通讯作者：
Lane, H. Clifford
影响因子：
20.3
作者：
Bosque, Alberto;Planelles, Vicente
通讯作者：
Planelles, Vicente
影响因子：
5.4
作者：
Hermankova, M;Siliciano, JD;Siliciano, RF
通讯作者：
Siliciano, RF