Ciupe Stanca M, Ribeiro Ruy M, Nelson Patrick W, Dusheiko Geoffrey, Perelson Alan S
Santa Fe Institute, 1399 Hyde Park Road, Santa Fe, NM 87507, USA.
Proc Natl Acad Sci U S A. 2007 Mar 20;104(12):5050-5. doi: 10.1073/pnas.0603626104. Epub 2007 Mar 14.
During acute hepatitis B virus (HBV) infection viral loads reach high levels ( approximately 10(10) HBV DNA per ml), and nearly every hepatocyte becomes infected. Nonetheless, approximately 85-95% of infected adults clear the infection. Although the immune response has been implicated in mediating clearance, the precise mechanisms remain to be elucidated. As infection clears, infected cells are replaced by uninfected ones. During much of this process the virus remains plentiful but nonetheless does not rekindle infection. Here, we analyze data from a set of individuals identified during acute HBV infection and develop mathematical models to test the role of immune responses in various stages of early HBV infection. Fitting the models to data we are able to separate the kinetics of the noncytolytic and the cytolytic immune responses, thus explaining the relative contribution of these two processes. We further show that we need to hypothesize that newly generated uninfected cells are refractory to productive infection. Without this assumption, viral resurgence is observed as uninfected cells are regenerated. Such protection, possibly mediated by cytokines, may also be important in resolving other acute viral infections.
在急性乙型肝炎病毒（HBV）感染期间，病毒载量会达到高水平（每毫升约10¹⁰个HBV DNA），几乎每个肝细胞都会被感染。然而，约85 - 95%的受感染成年人能够清除感染。虽然免疫反应被认为在介导清除过程中发挥作用，但其确切机制仍有待阐明。随着感染的清除，被感染的细胞被未感染的细胞所取代。在这个过程的大部分时间里，病毒数量仍然很多，但却不会再次引发感染。在此，我们分析了一组在急性HBV感染期间被识别出的个体的数据，并建立数学模型来测试免疫反应在早期HBV感染各个阶段的作用。将模型与数据拟合后，我们能够区分非细胞溶解免疫反应和细胞溶解免疫反应的动力学，从而解释这两个过程的相对贡献。我们进一步表明，需要假设新产生的未感染细胞对有生产性的感染具有抗性。没有这个假设，随着未感染细胞的再生，会观察到病毒的再次出现。这种可能由细胞因子介导的保护作用，在解决其他急性病毒感染中可能也很重要。
