Estimating Initial Viral Levels during Simian Immunodeficiency Virus/Human Immunodeficiency Virus Reactivation from Latency
Estimating Initial Viral Levels during Simian Immunodeficiency Virus/Human Immunodeficiency Virus Reactivation from Latency
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DOI：
10.1128/jvi.01667-17
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发表时间：
2018-01-01
影响因子：
5.4
通讯作者：
Davenport, Miles P.
中科院分区：
文献类型：
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作者：
Pinkevych, Mykola;Fennessey, Christine M.;Davenport, Miles P.
人类免疫缺陷病毒（HIV）病毒血症在治疗中断后迅速反弹，目前正在探索各种策略来减少或控制治疗后的病毒再激活。这种病毒反弹是由单个潜伏感染细胞的重新激活引起的，这些细胞在持续的生产性感染过程中传播。最初的单个再活化细胞产生的病毒水平尚不清楚，尽管它可能对不同免疫干预控制病毒反弹的能力有重大影响。在这里，我们使用来自HIV和猴免疫缺陷病毒（SIV）治疗中断研究的数据来估计中断后的初始病毒载量，从而估计初始个体再激活事件。使用条形码病毒（SIVmac 239 M）来跟踪来自单个潜伏细胞的再活化，我们使用观察到的病毒生长速率和再活化频率来模拟再活化的动力学，以估计单个再活化的潜伏细胞可以产生相当于0.1至0.5病毒RNA（vRNA）拷贝/ml的平均病毒载量。HIV治疗中断的建模表明初始病毒载量相当于0.6至1 vRNA拷贝/ml。潜伏细胞再活化后立即出现的这些低病毒载量为宿主免疫控制病毒提供了一个机会窗口，然后进一步复制使病毒扩散。这项工作显示了病毒产生的初始水平，必须加以控制，以成功地抑制艾滋病毒重新激活后，治疗中断。重要性目前的治疗艾滋病毒是能够抑制病毒复制，防止疾病的进展。然而，治疗不能根除感染，因为病毒在潜伏感染的细胞内沉默。如果停止治疗，病毒通常会在几周内反弹到检测水平以上。有许多方法正在测试，旨在消除潜伏感染的细胞或控制病毒，如果它返回。研究潜伏感染细胞的小池和病毒再活化期间的早期事件是困难的，因为这些涉及很难直接测量的非常小的病毒水平。在这里，我们结合联合收割机的实验数据和数学建模，以了解从潜伏期的HIV感染的人类和猴SIV感染的病毒重新激活过程中的非常早期的事件。我们发现病毒的初始水平很低，这可能有助于设计控制早期病毒再激活的疗法。
Human immunodeficiency virus (HIV) viremia rebounds rapidly after treatment interruption, and a variety of strategies are being explored to reduce or control viral reactivation posttreatment. This viral rebound arises from reactivation of individual latently infected cells, which spread during ongoing rounds of productive infection. The level of virus produced by the initial individual reactivating cells is not known, although it may have major implications for the ability of different immune interventions to control viral rebound. Here we use data from both HIV and simian immunodeficiency virus (SIV) treatment interruption studies to estimate the initial viral load postinterruption and thereby the initial individual reactivation event. Using a barcoded virus (SIVmac239M) to track reactivation from individual latent cells, we use the observed viral growth rates and frequency of reactivation to model the dynamics of reactivation to estimate that a single reactivated latent cell can produce an average viral load equivalent to similar to 0.1 to 0.5 viral RNA (vRNA) copies/ml. Modeling of treatment interruption in HIV suggests an initial viral load equivalent of similar to 0.6 to 1 vRNA copies/ml. These low viral loads immediately following latent cell reactivation provide a window of opportunity for viral control by host immunity, before further replication allows viral spread. This work shows the initial levels of viral production that must be controlled in order to successfully suppress HIV reactivation following treatment interruption.IMPORTANCE Current treatment for HIV is able to suppress viral replication and prevent disease progression. However, treatment cannot eradicate infection, because the virus lies silent within latently infected cells. If treatment is stopped, the virus usually rebounds above the level of detection within a few weeks. There are a number of approaches being tested aimed at either eradicating latently infected cells or controlling the virus if it returns. Studying both the small pool of latently infected cells and the early events during viral reactivation is difficult, because these involve very small levels of virus that are difficult to measure directly. Here, we combine experimental data and mathematical modeling to understand the very early events during viral reactivation from latency in both HIV infection of humans and SIV infection of monkeys. We find that the initial levels of virus are low, which may help in designing therapies to control early viral reactivation.