Adrienne E Swanstrom, Kelli Oswald, Randy Fast, Rebecca Shoemaker, James A Thomas, Cathi Pyle, Michael Hull, William J Bosche, Yuan Li, Matthew W Breed, Joshua A Kramer, Duncan Donohue, Charles M Trubey, Claire Deleage, Romas Geleziunas, Jeffrey D Lifson, Gregory Q Del Prete
{"title":"在接受慢性感染期间开始的联合抗逆转录病毒治疗的猕猴中,TLR7激动剂vesatolimod不能显著诱导SIV表达。","authors":"Adrienne E Swanstrom, Kelli Oswald, Randy Fast, Rebecca Shoemaker, James A Thomas, Cathi Pyle, Michael Hull, William J Bosche, Yuan Li, Matthew W Breed, Joshua A Kramer, Duncan Donohue, Charles M Trubey, Claire Deleage, Romas Geleziunas, Jeffrey D Lifson, Gregory Q Del Prete","doi":"10.1128/aac.01073-25","DOIUrl":null,"url":null,"abstract":"<p><p>Lim et al. previously reported that TLR7 agonist (Vesatolimod [VES] or the related compound GS-986) administration to SIVmac251-infected macaques receiving combination antiretroviral therapy (cART) led to transient plasma viral load (PVL) increases, viral DNA (vDNA) reductions in blood and tissues, and, in some animals, extended viral remission after treatment cessation (S. Y. Lim, C. E. Osuna, P. T. Hraber, J. Hesselgesser, et al., Sci Transl Med 10:eaao4521, 2018, https://doi.org/10.1126/scitranslmed.aao4521). However, in multiple subsequent studies, TLR7 agonist administration in SIV or SHIV-infected macaques on cART did not induce measurable virus expression. Notably, these studies utilized earlier cART initiation, lengthier cART treatment before TLR7 agonist administration, different sampling time points, and/or less sensitive virologic assays compared to the Lim study. We hypothesized that study design and assay differences may have led to these apparently discrepant results due to quantitative or qualitative differences in the established viral reservoirs and/or a reduced capacity to detect virus induction. To more closely capture the Lim study conditions, we initiated cART at 65 days post-infection in 10 SIVmac239M-infected rhesus macaques. Six received VES (0.15 mg/kg orally, every 2 weeks for six doses), while four received vehicle control. Although VES treatment induced expected transient increases in interferon-stimulated gene expression and immune cell phenotypic changes, it did not lead to measurable PVL increases in peripheral or hepatic portal vein blood using a highly sensitive PVL assay or increases in cell-associated vRNA:vDNA ratios, nor to measurable reductions in vDNA in blood or tissues. These results align with recent clinical data and confirm that TLR7 agonist treatment does not reliably induce significant virus expression <i>in vivo</i>.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0107325"},"PeriodicalIF":4.5000,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"The TLR7 agonist vesatolimod does not measurably induce SIV expression in macaques receiving combination antiretroviral therapy initiated during chronic infection.\",\"authors\":\"Adrienne E Swanstrom, Kelli Oswald, Randy Fast, Rebecca Shoemaker, James A Thomas, Cathi Pyle, Michael Hull, William J Bosche, Yuan Li, Matthew W Breed, Joshua A Kramer, Duncan Donohue, Charles M Trubey, Claire Deleage, Romas Geleziunas, Jeffrey D Lifson, Gregory Q Del Prete\",\"doi\":\"10.1128/aac.01073-25\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Lim et al. previously reported that TLR7 agonist (Vesatolimod [VES] or the related compound GS-986) administration to SIVmac251-infected macaques receiving combination antiretroviral therapy (cART) led to transient plasma viral load (PVL) increases, viral DNA (vDNA) reductions in blood and tissues, and, in some animals, extended viral remission after treatment cessation (S. Y. Lim, C. E. Osuna, P. T. Hraber, J. Hesselgesser, et al., Sci Transl Med 10:eaao4521, 2018, https://doi.org/10.1126/scitranslmed.aao4521). However, in multiple subsequent studies, TLR7 agonist administration in SIV or SHIV-infected macaques on cART did not induce measurable virus expression. Notably, these studies utilized earlier cART initiation, lengthier cART treatment before TLR7 agonist administration, different sampling time points, and/or less sensitive virologic assays compared to the Lim study. We hypothesized that study design and assay differences may have led to these apparently discrepant results due to quantitative or qualitative differences in the established viral reservoirs and/or a reduced capacity to detect virus induction. To more closely capture the Lim study conditions, we initiated cART at 65 days post-infection in 10 SIVmac239M-infected rhesus macaques. Six received VES (0.15 mg/kg orally, every 2 weeks for six doses), while four received vehicle control. Although VES treatment induced expected transient increases in interferon-stimulated gene expression and immune cell phenotypic changes, it did not lead to measurable PVL increases in peripheral or hepatic portal vein blood using a highly sensitive PVL assay or increases in cell-associated vRNA:vDNA ratios, nor to measurable reductions in vDNA in blood or tissues. These results align with recent clinical data and confirm that TLR7 agonist treatment does not reliably induce significant virus expression <i>in vivo</i>.</p>\",\"PeriodicalId\":8152,\"journal\":{\"name\":\"Antimicrobial Agents and Chemotherapy\",\"volume\":\" \",\"pages\":\"e0107325\"},\"PeriodicalIF\":4.5000,\"publicationDate\":\"2025-10-07\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Antimicrobial Agents and Chemotherapy\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1128/aac.01073-25\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"MICROBIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Antimicrobial Agents and Chemotherapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1128/aac.01073-25","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"MICROBIOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
Lim等人先前报道,接受联合抗逆转录病毒治疗(cART)的sivmac251感染猕猴给予TLR7激动剂(Vesatolimod [VES]或相关化合物hs -986)可导致短暂性血浆病毒载量(PVL)升高,血液和组织中病毒DNA (vDNA)降低,并且在一些动物中,停药后病毒缓解期延长(S. Y. Lim, C. E. Osuna, P. T. Hraber, J. Hesselgesser,等)。https://doi.org/10.1126/scitranslmed.aao4521)。然而,在随后的多项研究中,TLR7激动剂在cART上给药SIV或shiv感染的猕猴并没有诱导可测量的病毒表达。值得注意的是,与Lim研究相比,这些研究使用了更早的cART起始,TLR7激动剂施用前更长时间的cART治疗,不同的采样时间点和/或更不敏感的病毒学分析。我们假设,由于已建立的病毒库的数量或质量差异和/或检测病毒诱导的能力降低,研究设计和试验的差异可能导致这些明显差异的结果。为了更密切地捕捉Lim研究条件,我们在10只感染sivmac239m的恒河猴感染后65天启动cART。6例接受VES治疗(0.15 mg/kg口服,每2周一次,共6次),4例接受对照。尽管VES治疗诱导干扰素刺激基因表达的预期短暂增加和免疫细胞表型改变,但使用高度敏感的PVL测定法,VES治疗并没有导致外周或肝门静脉血液中可测量的PVL增加或细胞相关vRNA:vDNA比值的增加,也没有导致血液或组织中可测量的vDNA减少。这些结果与最近的临床数据一致,并证实TLR7激动剂治疗并不可靠地诱导体内显著的病毒表达。
The TLR7 agonist vesatolimod does not measurably induce SIV expression in macaques receiving combination antiretroviral therapy initiated during chronic infection.
Lim et al. previously reported that TLR7 agonist (Vesatolimod [VES] or the related compound GS-986) administration to SIVmac251-infected macaques receiving combination antiretroviral therapy (cART) led to transient plasma viral load (PVL) increases, viral DNA (vDNA) reductions in blood and tissues, and, in some animals, extended viral remission after treatment cessation (S. Y. Lim, C. E. Osuna, P. T. Hraber, J. Hesselgesser, et al., Sci Transl Med 10:eaao4521, 2018, https://doi.org/10.1126/scitranslmed.aao4521). However, in multiple subsequent studies, TLR7 agonist administration in SIV or SHIV-infected macaques on cART did not induce measurable virus expression. Notably, these studies utilized earlier cART initiation, lengthier cART treatment before TLR7 agonist administration, different sampling time points, and/or less sensitive virologic assays compared to the Lim study. We hypothesized that study design and assay differences may have led to these apparently discrepant results due to quantitative or qualitative differences in the established viral reservoirs and/or a reduced capacity to detect virus induction. To more closely capture the Lim study conditions, we initiated cART at 65 days post-infection in 10 SIVmac239M-infected rhesus macaques. Six received VES (0.15 mg/kg orally, every 2 weeks for six doses), while four received vehicle control. Although VES treatment induced expected transient increases in interferon-stimulated gene expression and immune cell phenotypic changes, it did not lead to measurable PVL increases in peripheral or hepatic portal vein blood using a highly sensitive PVL assay or increases in cell-associated vRNA:vDNA ratios, nor to measurable reductions in vDNA in blood or tissues. These results align with recent clinical data and confirm that TLR7 agonist treatment does not reliably induce significant virus expression in vivo.
期刊介绍:
Antimicrobial Agents and Chemotherapy (AAC) features interdisciplinary studies that build our understanding of the underlying mechanisms and therapeutic applications of antimicrobial and antiparasitic agents and chemotherapy.