Emory Vaccine Center and Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA.
Case Western Reserve University, Cleveland, Ohio, USA.
J Virol. 2018 Apr 13;92(9). doi: 10.1128/JVI.01760-17. Print 2018 May 1.
Pathogenic human immunodeficiency virus (HIV)/simian immunodeficiency virus (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 interferon alpha (IFN-α) in SIV pathogenesis, 12 RMs were treated prior to intravenous (i.v.) SIV infection with a high or a low dose of an antibody (AGS-009) that neutralizes most IFN-α subtypes and were compared with six mock-infused, SIV-infected controls. Plasma viremia was measured postinfection to assess the effect of IFN-α blockade on virus replication, and peripheral blood and lymphoid tissue samples were analyzed by immunophenotypic staining. Consistent with the known antiviral effect of IFN-I, high-dose AGS-009 treatment induced a modest increase in acute-phase viral loads versus controls. Four out of 6 RMs receiving a high dose of AGS-009 also experienced an early decline in CD4 T cell counts that was associated with progression to AIDS. Interestingly, 50% of the animals treated with AGS-009 (6/12) developed AIDS within 1 year of infection compared with 17% (1/6) of untreated controls. Finally, blockade of IFN-α 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-α-blockaded animals supports the hypothesis that IFN-α 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-α blockade should be explored as a strategy to reduce immune activation in HIV-infected individuals. Interferon alpha (IFN-α) is a member of a family of molecules (type I interferons) that prevent or limit virus infections in mammals. However, IFN-α production may contribute to the chronic immune activation that is thought to be the primary cause of immune decline and AIDS in HIV-infected patients. The study presented here attempts to understand the contribution of IFN-α to the natural history and progression of SIV infection of rhesus macaques, the primary nonhuman primate model system for testing hypotheses about HIV infection in humans. Here, we show that blockade of IFN-α action promotes lower chronic immune activation but higher early viral loads, with a trend toward faster disease progression. This study has significant implications for new treatments designed to impact the type I interferon system.
致病性人类免疫缺陷病毒（HIV）/猴免疫缺陷病毒（SIV）感染人类和恒河猴（RMs）会导致 I 型干扰素（IFN-I）的持续高水平产生，这被认为有助于疾病的进展。为了阐明干扰素-α（IFN-α）在 SIV 发病机制中的具体作用，在静脉（i.v.）SIV 感染前，用中和大多数 IFN-α亚型的高或低剂量抗体（AGS-009）治疗 12 只 RM，并与 6 只模拟感染、SIV 感染的对照进行比较。感染后测量血浆病毒载量，以评估 IFN-α阻断对病毒复制的影响，并通过免疫表型染色分析外周血和淋巴组织样本。与 IFN-I 的已知抗病毒作用一致，高剂量 AGS-009 治疗与对照组相比，诱导急性期病毒载量适度增加。6 只接受高剂量 AGS-009 治疗的 RM 中有 4 只也经历了 CD4 T 细胞计数的早期下降，这与进展为艾滋病有关。有趣的是，与未接受治疗的对照组（17%，1/6）相比，接受 AGS-009 治疗的动物（6/12）中有 50%在感染后 1 年内发展为艾滋病。最后，阻断 IFN-α降低了激活的 CD4 和 CD8 T 细胞以及 B 细胞的水平，如通过 PD-1 和/或 Ki67 表达测量。IFN-α 阻断动物中激活淋巴细胞的水平较低支持这样的假设，即 IFN-α 信号在 SIV 感染期间有助于淋巴细胞的激活，并表明该信号通路参与控制急性感染期间的病毒复制。作为减少 HIV 感染者免疫激活的策略，应探索 IFN-α 阻断的潜在抗炎作用。干扰素-α（IFN-α）是一类分子（I 型干扰素）的成员，可防止或限制哺乳动物中的病毒感染。然而，IFN-α 的产生可能有助于慢性免疫激活，这被认为是 HIV 感染患者免疫下降和艾滋病的主要原因。本研究试图了解 IFN-α 对恒河猴 SIV 感染的自然史和进展的贡献，恒河猴是测试 HIV 感染相关假说的主要非人类灵长类动物模型系统。在这里，我们表明，阻断 IFN-α 作用会促进更低的慢性免疫激活，但更高的早期病毒载量，并呈现出更快的疾病进展趋势。这项研究对旨在影响 I 型干扰素系统的新治疗方法具有重要意义。
