The differential short- and long-term effects of HIV-1 latency-reversing agents on T cell function.
The differential short- and long-term effects of HIV-1 latency-reversing agents on T cell function.
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DOI：
10.1038/srep30749
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发表时间：
2016-08-02
影响因子：
4.6
通讯作者：
Goonetilleke N
中科院分区：
文献类型：
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作者：
Clutton G;Xu Y;Baldoni PL;Mollan KR;Kirchherr J;Newhard W;Cox K;Kuruc JD;Kashuba A;Barnard R;Archin N;Gay CL;Hudgens MG;Margolis DM;Goonetilleke N
尽管HIV-1抗逆转录病毒治疗在延长生命方面取得了非凡的成功，但由于潜伏感染细胞的储存库含有可复制病毒，感染者面临终身治疗。最近，已经鉴定出可以逆转体内HIV-1潜伏期的化合物。这些潜伏期逆转剂（LRA）可以使潜伏感染的细胞易于被免疫细胞（包括溶细胞性CD 8 + T细胞）清除。我们研究了两类主要的LRA对CD 8 + T细胞表型和功能的影响：组蛋白脱乙酰酶抑制剂（HDACis）和蛋白激酶C调节剂（PKCms）。我们观察到，相对于HDACis，PKCms诱导更强的T细胞活化，伴随非特异性细胞因子产生和T细胞增殖。当检查抗原特异性CD 8 + T细胞功能时，除HDACi伏立诺他外的所有LRA降低但不消除CD 8 + T细胞功能的一个或多个测量值。重要的是，这些影响的程度和时间在不同的LRA之间不同。帕比司他在药物治疗的10小时内具有有害作用，而其他LRA的作用在48小时至5天之间观察到。这些观察结果表明，LRA和CD 8 + T细胞免疫治疗方案的安排可能是HIV-1储库的最佳清除的关键。
Despite the extraordinary success of HIV-1 antiretroviral therapy in prolonging life, infected individuals face lifelong therapy because of a reservoir of latently-infected cells that harbor replication competent virus. Recently, compounds have been identified that can reverse HIV-1 latency in vivo. These latency- reversing agents (LRAs) could make latently-infected cells vulnerable to clearance by immune cells, including cytolytic CD8+ T cells. We investigated the effects of two leading LRA classes on CD8+ T cell phenotype and function: the histone deacetylase inhibitors (HDACis) and protein kinase C modulators (PKCms). We observed that relative to HDACis, the PKCms induced much stronger T cell activation coupled with non-specific cytokine production and T cell proliferation. When examining antigen-specific CD8+ T cell function, all the LRAs except the HDACi Vorinostat reduced, but did not abolish, one or more measurements of CD8+ T cell function. Importantly, the extent and timing of these effects differed between LRAs. Panobinostat had detrimental effects within 10 hours of drug treatment, whereas the effects of the other LRAs were observed between 48 hours and 5 days. These observations suggest that scheduling of LRA and CD8+ T cell immunotherapy regimens may be critical for optimal clearance of the HIV-1 reservoir.