کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
5675214 1594207 2017 13 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
The histone deacetylase inhibitor SAHA simultaneously reactivates HIV-1 from latency and up-regulates NKG2D ligands sensitizing for natural killer cell cytotoxicity
موضوعات مرتبط
علوم زیستی و بیوفناوری ایمنی شناسی و میکروب شناسی ویروس شناسی
پیش نمایش صفحه اول مقاله
The histone deacetylase inhibitor SAHA simultaneously reactivates HIV-1 from latency and up-regulates NKG2D ligands sensitizing for natural killer cell cytotoxicity
چکیده انگلیسی


- PMA/Ionomycin and SAHA induce NKG2DLs on primary T cells harboring reactivated HIV-1.
- SAHA reactivates HIV-1 and up-regulates NKG2DLs in J-Lat and J1.1 cell lines.
- SAHA up-regulates MICA/B and ULBP2 acting at the transcriptional level and via ATR.
- SAHA sensitizes J1.1 cells to NK-cell mediated killing via NKG2D/NKG2DL interactions.
- IL-2 and IL-15 boost NKG2D and cytotoxicity of NK cells against SAHA-reactivated J1.1.

In pilot HIV-1 eradication studies, patients' immune responses were ineffective at killing viral reservoirs reactivated through latency reversing agents (LRAs) like suberoylanilide hydroxamic acid (SAHA). We hypothesized that T cells harboring reactivated HIV-1 express MIC and ULBP ligands for the activating NKG2D receptor of natural killer (NK) cells. Here, we demonstrated that MICA/B and ULBP2 are induced by SAHA on primary T cells harboring reactivated virus. Using latently HIV-1-infected J-Lat 6.3/8.4/9.2 and J1.1 cell lines, we showed that SAHA reverts latency and, simultaneously, up-regulates MICA/B and ULBP2 acting at the transcriptional level and through ATR activation, thus sensitizing T cells with reactivated virus to NKG2D-mediated killing by NK cells. Moreover, IL-2 and IL-15 potently boosted NKG2D expression and cytotoxicity of NK cells against SAHA-reactivated p24+ target cells. Therefore, immunotherapy with cytokines enhancing NKG2D-mediated NK-cell cytotoxicity combined with administration of LRAs up-modulating NKG2D ligands, represents a promising approach towards HIV-1 eradication.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Virology - Volume 510, October 2017, Pages 9-21
نویسندگان
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