Modulation of Antiviral Immunity and Therapeutic Efficacy by 25-Hydroxycholesterol in Chronically SIV-Infected, ART-Treated Rhesus Macaques.
Modulation of Antiviral Immunity and Therapeutic Efficacy by 25-Hydroxycholesterol in Chronically SIV-Infected, ART-Treated Rhesus Macaques.
复制标题
DOI：
10.1007/s12250-021-00407-6
复制
发表时间：
2021-10
影响因子：
5.5
通讯作者：
Sun C
中科院分区：
文献类型：
--
作者：
Wu C;Zhao J;Li R;Feng F;He Y;Li Y;Huang R;Li G;Yang H;Cheng G;Chen L;Ma F;Li P;Sun C
胆固醇-25-羟化酶（CH 25 H）及其酶促产物25-羟基胆固醇（25 HC）具有广泛的抗病毒活性，包括抑制HIV-1感染。然而，它们在非人灵长类动物模型中的抗病毒免疫和治疗功效是未知的。在这里，我们报告说，25 HC与抗逆转录病毒治疗（ART）相结合的方案，提供了深刻的免疫调节，以抑制病毒复制在慢性SIVmac 239感染的恒河猴（RM）。与单独ART相比，该方案更有效地控制了SIV复制，增强了SIV特异性细胞免疫应答，恢复了CD 4/CD 8细胞的比例，逆转了CD 4 + T细胞的过度活化状态，并抑制了慢性SIV感染RM中CD 4+和CD 8 + T淋巴细胞分泌促炎细胞因子。此外，在该RM模型中评估了25 HC化合物的体内安全性和初步药代动力学。总之，这些评估有助于解释胆固醇代谢，免疫调节和25 HC的抗病毒活性之间的深刻关系。这些结果为开发新的治疗HIV-1感染和其他相关疾病的候选药物提供了见解。在线版本包含补充材料，可通过10.1007/s12250-021-00407-6获得。
Cholesterol-25-hydroxylase (CH25H) and its enzymatic product 25-hydroxycholesterol (25HC) exert broadly antiviral activity including inhibiting HIV-1 infection. However, their antiviral immunity and therapeutic efficacy in a nonhuman primate model are unknown. Here, we report that the regimen of 25HC combined with antiretroviral therapy (ART), provides profound immunological modulation towards inhibiting viral replication in chronically SIVmac239-infected rhesus macaques (RMs). Compared to the ART alone, this regimen more effectively controlled SIV replication, enhanced SIV-specific cellular immune responses, restored the ratio of CD4/CD8 cells, reversed the hyperactivation state of CD4+ T cells, and inhibited the secretion of proinflammatory cytokines by CD4+ and CD8+ T lymphocytes in chronically SIV-infected RMs. Furthermore, the in vivo safety and the preliminary pharmacokinetics of the 25HC compound were assessed in this RM model. Taken together, these assessments help explain the profound relationship between cholesterol metabolism, immune modulation, and antiviral activities by 25HC. These results provide insight for developing novel therapeutic drug candidates against HIV-1 infection and other related diseases. The online version contains supplementary material available at 10.1007/s12250-021-00407-6.
登录
查看更多内容
影响因子：
39
作者：
Freiberg MS;Chang CC;Kuller LH;Skanderson M;Lowy E;Kraemer KL;Butt AA;Bidwell Goetz M;Leaf D;Oursler KA;Rimland D;Rodriguez Barradas M;Brown S;Gibert C;McGinnis K;Crothers K;Sico J;Crane H;Warner A;Gottlieb S;Gottdiener J;Tracy RP;Budoff M;Watson C;Armah KA;Doebler D;Bryant K;Justice AC
通讯作者：
Justice AC
影响因子：
37.8
作者：
Gidding SS;Rana JS;Prendergast C;McGill H;Carr JJ;Liu K;Colangelo LA;Loria CM;Lima J;Terry JG;Reis JP;McMahan CA
通讯作者：
McMahan CA
DOI：
10.1073/pnas.1404271111
发表时间：
2014-07-22
影响因子：
11.1
作者：
Gold, Elizabeth S.;Diercks, Alan H.;Aderem, Alan
通讯作者：
Aderem, Alan
影响因子：
168.9
作者：
Huang, Chaolin;Wang, Yeming;Cao, Bin
通讯作者：
Cao, Bin
影响因子：
7
作者：
Kimata, Jason T.;Rice, Andrew P.;Wang, Jin
通讯作者：
Wang, Jin