Randomized, placebo-controlled trial of nonpegylated and pegylated forms of recombinant human alpha interferon 2a for suppression of dengue virus viremia in rhesus monkeys
Randomized, placebo-controlled trial of nonpegylated and pegylated forms of recombinant human alpha interferon 2a for suppression of dengue virus viremia in rhesus monkeys
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DOI：
10.1128/aac.49.11.4508-4514.2005
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发表时间：
2005-11-01
影响因子：
4.9
通讯作者：
Libraty, DH
中科院分区：
文献类型：
--
作者：
Ajariyakhajorn, C;Mammen, MP;Libraty, DH
登革热和登革出血热是由感染四种登革病毒中的任何一种引起的，在整个热带地区都是严重的公共卫生负担。更高的病毒血症水平与更严重的登革热疾病相关。在DV感染早期抑制病毒血症的治疗干预可能会潜在地改善严重的疾病。重组α干扰素2a(rIFN-α-2a，Roferon-A)体外抑制人外周血单核细胞中DV的复制。因此，我们研究了重组干扰素-α-2a和聚乙二醇化重组干扰素-α-2a(聚乙二醇化重组干扰素-α-2a，PEGASYS)对恒河猴DV-2型病毒血症的影响。将未感染黄病毒的猴子接种DV-2病毒，并在病毒血症发作1天后随机接受单剂量r干扰素-α-2a(1000万国际单位/米(2))与安慰剂或聚乙二醇化重组干扰素-α-2a(6ug/kg)与安慰剂对照。每日连续测定病毒血症水平，并测定恢复期DV-2中和抗体效价。与安慰剂相比，单次注射重组干扰素-α-2a暂时抑制了DV-2的复制，并将病毒血症达到峰值的时间推迟了中位数3天。然而，两组患者的总病毒载量指标并无不同。从给药后48小时开始，单次注射聚乙二醇-重组干扰素-α-2a可显著降低每日病毒血症水平并改善病毒清除。在感染后30天和90天，治疗组和安慰剂组之间的DV-2中和抗体滴度没有显著差异。基于它们的单独作用，未来的研究应该调查r干扰素-α-2a和聚乙二醇-r干扰素-α-2a的组合抑制登革病毒病毒血症，并作为一种潜在的治疗干预措施。
Dengue fever and dengue hemorrhagic fever are caused by infection with any one of the four dengue viruses (DVs) and are significant public health burdens throughout the tropics. Higher viremia levels are associated with greater dengue disease severity. A therapeutic intervention to suppress viremia early in DV infection could potentially ameliorate severe disease. Recombinant alpha interferon 2a(rIFN-alpha-2a, Roferon-A) suppressed DV replication in human peripheral blood mononuclear cells in vitro. We therefore examined the effects of rIFN-alpha-2a and pegylated recombinant IFN-alpha-2a (PEG-rIFN-alpha-2a, PEGASYS) on DV serotype 2 (DV-2) viremia in rhesus monkeys. Flavivirus-naive monkeys were inoculated with DV-2 and randomized to receive a single dose of rIFN-alpha-2a (10 million international units/m(2)) versus placebo or PEG-rIFN-alpha-2a (6 mu g/kg) versus placebo 1 day after the onset of viremia. Serial daily viremia levels were measured, and convalescent-phase DV-2 neutralizing antibody titers were determined. Compared to placebo, a single injection of rIFN-alpha-2a temporarily suppressed DV-2 replication and delayed the time to peak viremia by a median of 3 days. However, measures of total viral burden were not different between the two groups. A single injection of PEG-rIFN-a-2a significantly lowered daily viremia levels and improved virus clearance, starting 48 h after administration. There were no significant differences in DV-2 neutralizing antibody titers between the treatment and placebo groups at 30 and 90 days postinfection. Based on their individual effects, future studies should investigate a combination of rIFN-alpha-2a and PEG-rIFN-alpha-2a for suppression of dengue virus viremia and as a potential therapeutic intervention.