TLR7 agonist administration to SIV-infected macaques receiving early initiated cART does not induce plasma viremia
TLR7 agonist administration to SIV-infected macaques receiving early initiated cART does not induce plasma viremia
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DOI：
10.1172/jci.insight.127717
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发表时间：
2019-06-06
期刊：
影响因子：
8
通讯作者：
Lifson, Jeffrey D.
中科院分区：
文献类型：
--
作者：
Del Prete, Gregory Q.;Alvord, W. Gregory;Lifson, Jeffrey D.
减少/消除尽管联合抗逆转录病毒治疗（cART）仍持续存在的HIV-1储库可能需要通过残余感染细胞诱导病毒表达并增强这些细胞的清除。TLR 7激动剂具有介导这些活性的潜力。我们评估了重复剂量的TLR 7激动剂GS-9620在接受cART的SIV感染恒河猴中的免疫学和病毒学作用，cART在感染后13天开始，并在GS-9620给药前持续75周。在cART期间，GS-9620诱导血液和组织中IFN刺激基因的瞬时上调、血浆细胞因子的增加以及免疫细胞群活化和表型的变化，但未导致血浆病毒血症或PBMC或组织中病毒RNA与病毒DNA比率的可测量增加，也未导致PBMC或组织中病毒DNA的减少。SIV特异性CD 8（+）T细胞应答。在GS 9620治疗前，可忽略不计的，没有通过治疗可测量地加强：GS-9620给药的第二个疗程与后来的cART停药重叠，与病毒复发期间CD 8（+）T细胞应答增加相关。这些结果证实并扩展了GS-9620介导的SIV感染猕猴抗病毒免疫应答增强的证据，但表明GS-9620介导的病毒诱导可能关键取决于cART的启动时间和持续时间以及由此产生的病毒储库特征。
Reduction/elimination of HIV-1 reservoirs that persist despite combination antiretroviral therapy (cART) will likely require induction of viral expression by residual infected cells and enhanced clearance of these cells. TLR7 agonists have potential to mediate these activities. We evaluated immunologic and virologic effects of repeated doses of the TLR7 agonist GS-9620 in SIV-infected rhesus macaques receiving cART, which was initiated at 13 days after infection and was continued for 75 weeks prior to GS-9620 administration. During cART, GS-9620 induced transient upregulation of IFN-stimulated genes in blood and tissues, increases in plasma cytokines, and changes in immune cell population activation and phenotypes but did not result in measurable increases in plasma viremia or viral RNA-to-viral DNA ratio in PBMCs or tissues nor decreases in viral DNA in PBMC or tissues. SIV-specific CD8(+ )T cell responses. negligible prior to GS 9620 treatment, were not measurably boosted by treatment: a second course of GS-9620 administration overlapping with later cART discontinuation was associated with increased CD8(+) T cell responses during viral recrudescence. These results confirm and extend evidence for GS-9620-mediated enhancement of antiviral immune responses in SIV-infected macaques but suggest that GS-9620-mediated viral induction may depend critically on the timing of initiation and duration of cART and resulting characteristics of viral reservoirs.