Reduced chronic lymphocyte activation following Interferon-α blockade in the acute phase of SIV infection in rhesus macaques

Pathogenic HIV/SIV infection of humans and rhesus macaques (RMs) induces persistently high production of type-I interferon (IFN-I) which is thought to contribute to disease progression. To elucidate the specific role of IFN in SIV pathogenesis, 12 RMs were treated prior to i.v. SIVmac239 infection with a high or a low dose of an antibody (AGS-009) that neutralizes most IFN subtypes, and compared with six mock-infused, SIV-infected controls. Plasma viremia was measured post infection to assess the effect of IFNα blockade on virus replication, and peripheral blood and lymphoid tissue samples were analyzed by immunophenotypical staining. Consistent with the known antiviral effect of IFN-I, high-dose AGS-009 treatment induced a modest increase in acute phase viral loads vs. controls. 4 out of 6 RMs receiving a high dose of AGS-009 also experienced an early decline in CD4+ T cell counts which was associated with progression to AIDS. Interestingly, 50% of animals treated with AGS-009 (6/12) developed AIDS within one year of infection, compared with 17% (1/6) of untreated controls. Finally, blockade of IFN decreased the levels of activated CD4+ and CD8+ T cells, as well as B-cells, as measured by PD-1 and/or Ki67 expression. The lower levels of activated lymphocytes in IFN-blockade animals supports the hypothesis that IFN signaling contributes to lymphocyte activation during SIV infection, and suggests that this signaling pathway is involved in controlling virus replication during acute infection. The potential anti-inflammatory effect of IFN blockade should be explored as a strategy to reduce immune activation in HIV-infected individuals. 107 Rhesus macaque whole blood samples were hybridized to Illumina Human RefSeq-12 V4 BeadChips.

致病性人类免疫缺陷病毒/猴免疫缺陷病毒（HIV/SIV）感染人类与恒河猴（rhesus macaques, RMs）后，会持续诱导大量I型干扰素（type-I interferon, IFN-I）产生，而该干扰素被认为可促进疾病进展。为阐明干扰素α（IFNα）在SIV致病过程中的具体作用，研究人员在12只恒河猴经静脉接种SIVmac239前，分别给予高、低剂量的可中和绝大多数IFNα亚型的抗体AGS-009，并设置6只接受模拟输注的SIV感染恒河猴作为对照。于感染后检测血浆病毒血症水平，以评估IFNα阻断对病毒复制的影响；同时通过免疫表型染色分析外周血与淋巴组织样本。与已知的IFN-I抗病毒效应一致，与对照组相比，高剂量AGS-009处理组的急性期病毒载量出现小幅升高。6只接受高剂量AGS-009的恒河猴中有4只出现CD4+T细胞计数早期下降，该表现与艾滋病（AIDS）进展相关。值得注意的是，接受AGS-009处理的恒河猴中有50%（6/12）在感染后1年内进展为艾滋病，而未处理对照组的这一比例仅为17%（1/6）。最终，IFNα阻断可降低经PD-1和/或Ki67表达检测的活化CD4+T细胞、CD8+T细胞与B细胞水平。IFNα阻断组动物的活化淋巴细胞水平更低，这支持了“IFNα信号通路在SIV感染过程中促进淋巴细胞活化”这一假说，并提示该信号通路在急性感染期参与调控病毒复制。未来可探索IFNα阻断的潜在抗炎效应，将其作为降低HIV感染者免疫活化的治疗策略。本研究共将107份恒河猴全血样本与Illumina人类RefSeq-12 V4微珠芯片（Illumina Human RefSeq-12 V4 BeadChips）进行杂交。