The apparent interferon resistance of transmitted HIV-1 is possibly a consequence of enhanced replicative fitness.
The apparent interferon resistance of transmitted HIV-1 is possibly a consequence of enhanced replicative fitness.
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DOI：
10.1371/journal.ppat.1010973
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发表时间：
2022-11
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影响因子：
6.7
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中科院分区：
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通过性接触传播HIV-1是一个效率低下的过程。当传播确实发生时，新感染的个体被单个病毒体或极少数已建立的病毒体的后代定殖。这些传播的创始者（TF）病毒比传播后6个月存在的慢性对照（CC）病毒更具干扰素（IFN）抗性。为了确定特定的分子防御，使CC病毒更容易受到干扰素诱导的“抗病毒状态”，我们建立了一个单一的荧光TF和CC病毒对，并使用阵列干扰素刺激基因（ISG）表达筛选，以确定候选的抗病毒效应。然而，我们观察到一个相对统一的ISG耐药性的传播HIV-1，这指导我们调查可能的潜在机制。简单的模拟，我们改变了一个参数，说明降低生长速度可能是明显的干扰素敏感性的基础。为了研究这种可能性，我们密切监测模型TF/CC对（复制适应性密切匹配）在IFN浓度的目标范围内的体外繁殖。拟合标准的四参数逻辑生长模型，其中实验变量对生长速率和承载能力进行回归，我们在体外生长曲线，进一步强调了复制生长速率的小差异可以概括我们在体外观察。我们推断，如果生长速率是干扰素明显耐药性的基础，那么传播的HIV-1对任何生长速率抑制剂都具有类似的耐药性。因此，我们发现两种传播的创始人HIV-1病毒对抗逆转录病毒药物具有相对耐药性，而它们匹配的慢性对照病毒则更敏感。我们建议，当存在时，传播的HIV-1的明显的IFN抗性可能被解释为增强的复制适应性，而不是对单个IFN诱导的防御的特异性抗性。然而，需要进一步的工作，以确定如何推广这种机制的相对干扰素耐药性可能。HIV-1性传播的效率低得惊人。在相对罕见的成功传播事件中，通常存在严重的遗传瓶颈，例如仅通过单个（或少量）遗传变异建立感染，称为传播的创始人（TF）病毒。这种有限的传播被认为是由限制病毒的物理和免疫屏障引起的，例如干扰素系统。TF病毒已被描述为比存在于慢性感染个体中的病毒更具干扰素抗性。在这里，我们发现一种抗干扰素的HIV-1病毒对多种干扰素刺激的基因具有一致的抗性，这使我们研究了潜在的机制。我们对单个TF和慢性病毒对（复制适应性密切匹配）的表征表明，复制生长速率的微小差异可能解释了广泛的干扰素耐药性，尽管需要进一步的研究来证实这一点。我们的研究提供了关于生长速率相对较小的差异如何仍然具有表型显著性的见解，并且一种非特异性机制可能解释了HIV-1传播的干扰素抗性。
HIV-1 transmission via sexual exposure is an inefficient process. When transmission does occur, newly infected individuals are colonized by the descendants of either a single virion or a very small number of establishing virions. These transmitted founder (TF) viruses are more interferon (IFN)-resistant than chronic control (CC) viruses present 6 months after transmission. To identify the specific molecular defences that make CC viruses more susceptible to the IFN-induced ‘antiviral state’, we established a single pair of fluorescent TF and CC viruses and used arrayed interferon-stimulated gene (ISG) expression screening to identify candidate antiviral effectors. However, we observed a relatively uniform ISG resistance of transmitted HIV-1, and this directed us to investigate possible underlying mechanisms. Simple simulations, where we varied a single parameter, illustrated that reduced growth rate could possibly underly apparent interferon sensitivity. To examine this possibility, we closely monitored in vitro propagation of a model TF/CC pair (closely matched in replicative fitness) over a targeted range of IFN concentrations. Fitting standard four-parameter logistic growth models, in which experimental variables were regressed against growth rate and carrying capacity, to our in vitro growth curves, further highlighted that small differences in replicative growth rates could recapitulate our in vitro observations. We reasoned that if growth rate underlies apparent interferon resistance, transmitted HIV-1 would be similarly resistant to any growth rate inhibitor. Accordingly, we show that two transmitted founder HIV-1 viruses are relatively resistant to antiretroviral drugs, while their matched chronic control viruses were more sensitive. We propose that, when present, the apparent IFN resistance of transmitted HIV-1 could possibly be explained by enhanced replicative fitness, as opposed to specific resistance to individual IFN-induced defences. However, further work is required to establish how generalisable this mechanism of relative IFN resistance might be. HIV-1 sexual transmission is surprisingly inefficient. In the relatively unusual event of successful transmission, there is typically a severe genetic bottleneck, such that infection is established by just a single (or small number) of genetic variants, described as transmitted founder (TF) viruses. Such limited transmission is considered to arise from both physical and immunological barriers that restrict viruses, such as the interferon system. TF viruses have been described as more interferon resistant than viruses present in chronically infected individuals. Here we found that an IFN-resistant transmitted HIV-1 virus is uniformly resistant to multiple interferon-stimulated genes, which led us to investigate the underlying mechanism. Our characterisation of a single TF and chronic virus pair (closely matched in replicative fitness) revealed that small differences in replicative growth rates could possibly explain the broad interferon resistance frequently associated with transmitted HIV-1, although further studies are required to confirm this. Our study provides insight into how relatively small differences in growth rate could still be phenotypically significant, and that a nonspecific mechanism could possibly explain the interferon resistance of transmitted HIV-1.
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DOI：
10.1126/science.1254031
发表时间：
2014-07-11
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Carlson JM;Schaefer M;Monaco DC;Batorsky R;Claiborne DT;Prince J;Deymier MJ;Ende ZS;Klatt NR;DeZiel CE;Lin TH;Peng J;Seese AM;Shapiro R;Frater J;Ndung'u T;Tang J;Goepfert P;Gilmour J;Price MA;Kilembe W;Heckerman D;Goulder PJ;Allen TM;Allen S;Hunter E
通讯作者：
Hunter E
干扰素-α对无细胞和细胞对HIV-1感染的反对作用。
影响因子：
4.3
作者：
通讯作者：
--
影响因子：
4.8
作者：
Cohen, GB;Rangan, VS;Baltimore, D
通讯作者：
Baltimore, D
影响因子：
32.4
作者：
Ferguson AL;Mann JK;Omarjee S;Ndung'u T;Walker BD;Chakraborty AK
通讯作者：
Chakraborty AK
影响因子：
5.4
作者：
Brockman, Mark A.;Schneidewind, Arne;Allen, Todd M.
通讯作者：
Allen, Todd M.