Relative resistance of HIV-1 founder viruses to control by interferon-alpha.
Relative resistance of HIV-1 founder viruses to control by interferon-alpha.
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DOI：
10.1186/1742-4690-10-146
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发表时间：
2013-12-03
期刊：
影响因子：
3.3
通讯作者：
Borrow P
中科院分区：
文献类型：
--
作者：
Fenton-May AE;Dibben O;Emmerich T;Ding H;Pfafferott K;Aasa-Chapman MM;Pellegrino P;Williams I;Cohen MS;Gao F;Shaw GM;Hahn BH;Ochsenbauer C;Kappes JC;Borrow P
在粘膜人类免疫缺陷病毒1型（HIV-1）传播后，1型干扰素（ifn）在粘膜和引流淋巴结的初始病毒复制位点被迅速诱导。然而，在感染的初始阶段，ifn刺激的抗病毒活性在限制HIV-1复制中发挥的作用尚不清楚。我们假设，如果1型ifn在感染的早期阶段对HIV-1复制施加选择性压力，那么成功建立全身性感染的创始病毒将比慢性感染期间复制的病毒更具ifn抗性，而慢性感染期间产生的1型ifn的水平要低得多。为了验证这一假设，研究人员分析了急性和慢性感染期间hiv -1感染者分离的病毒对1型干扰素控制的相对抗性。从急性HIV-1感染受试者和分子克隆的HIV-1始祖株中产生的血浆病毒分离株的复制可以被1型ifn减少，但不能被完全抑制。IFNα2的平均IC50值（22 U/ml）低于IFNβ (346 U/ml)，尽管在最大抑制浓度下，两种IFN亚型对病毒复制的抑制程度相似。单个病毒分离株对IFNα2和IFNβ的抑制表现出不同的敏感性，可能反映了对不同上调的ifn刺激基因的抗性差异。从急性感染HIV-1的受试者中分离出的病毒比从慢性无症状感染的同一个体中分离出的病毒对IFNα体外控制的抵抗力更强。病毒对IFN的耐药性在感染急性期后迅速下降：在5名受试者中，来自6个月共识分子克隆的病毒对IFN的抗病毒作用明显比相应的创始病毒更敏感。相对耐IFNα的始发病毒建立了HIV-1的全身性感染，这有力地支持了IFNα在感染早期、在病毒全身性传播之前控制HIV-1复制方面发挥重要作用的假设。这些发现表明，有可能利用1型ifn的抗病毒活性来预防和潜在地治疗HIV-1感染。
Following mucosal human immunodeficiency virus type 1 (HIV-1) transmission, type 1 interferons (IFNs) are rapidly induced at sites of initial virus replication in the mucosa and draining lymph nodes. However, the role played by IFN-stimulated antiviral activity in restricting HIV-1 replication during the initial stages of infection is not clear. We hypothesized that if type 1 IFNs exert selective pressure on HIV-1 replication in the earliest stages of infection, the founder viruses that succeed in establishing systemic infection would be more IFN-resistant than viruses replicating during chronic infection, when type 1 IFNs are produced at much lower levels. To address this hypothesis, the relative resistance of virus isolates derived from HIV-1-infected individuals during acute and chronic infection to control by type 1 IFNs was analysed. The replication of plasma virus isolates generated from subjects acutely infected with HIV-1 and molecularly cloned founder HIV-1 strains could be reduced but not fully suppressed by type 1 IFNs in vitro. The mean IC50 value for IFNα2 (22 U/ml) was lower than that for IFNβ (346 U/ml), although at maximally-inhibitory concentrations both IFN subtypes inhibited virus replication to similar extents. Individual virus isolates exhibited differential susceptibility to inhibition by IFNα2 and IFNβ, likely reflecting variation in resistance to differentially up-regulated IFN-stimulated genes. Virus isolates from subjects acutely infected with HIV-1 were significantly more resistant to in vitro control by IFNα than virus isolates generated from the same individuals during chronic, asymptomatic infection. Viral IFN resistance declined rapidly after the acute phase of infection: in five subjects, viruses derived from six-month consensus molecular clones were significantly more sensitive to the antiviral effects of IFNs than the corresponding founder viruses. The establishment of systemic HIV-1 infection by relatively IFNα-resistant founder viruses lends strong support to the hypothesis that IFNα plays an important role in the control of HIV-1 replication during the earliest stages of infection, prior to systemic viral spread. These findings suggest that it may be possible to harness the antiviral activity of type 1 IFNs in prophylactic and potentially also therapeutic strategies to combat HIV-1 infection.
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