Paul-Ehrlich-Institut, Paul-Ehrlich-Strasse 51-59, 63225 Langen, Germany.
BMC Evol Biol. 2009 Nov 30;9:274. doi: 10.1186/1471-2148-9-274.
The entry of HIV into its target cells is facilitated by the prior binding to the cell surface molecule CD4 and a secondary coreceptor, mostly the chemokine receptors CCR5 or CXCR4. In early infection CCR5-using viruses (R5 viruses) are mostly dominant while a receptor switch towards CXCR4 occurs in about 50% of the infected individuals (X4 viruses) which is associated with a progression of the disease. There are many hypotheses regarding the underlying dynamics without yet a conclusive understanding.
While it is difficult to isolate key factors in vivo we have developed a minimal in silico model based on the approaches of Nowak and May to investigate the conditions under which the receptor switch occurs. The model allows to investigate the evolution of viral strains within a probabilistic framework along the three stages of disease from primary and latent infection to the onset of AIDS with a a sudden increase in viral load which goes along with the impairment of the immune response. The model is specifically applied to investigate the evolution of the viral quasispecies in terms of R5 and X4 viruses which directly translates into the composition of viral load and consequently the question of the coreceptor switch.
The model can explain the coreceptor switch as a result of a dynamical change in the underlying environmental conditions in the host. The emergence of X4 strains does not necessarily result in the dominance of X4 viruses in viral load which is more likely to occur in the model after some time of chronic infection. A better understanding of the conditions leading to the coreceptor switch is especially of interest as CCR5 blockers have recently been licensed as drugs which suppress R5 viruses but do not seem to necessarily induce a coreceptor switch.
HIV 进入其靶细胞是通过先前与细胞表面分子 CD4 和辅助受体的结合来促进的，这些辅助受体主要是趋化因子受体 CCR5 或 CXCR4。在早期感染中，使用 CCR5 的病毒（R5 病毒）占主导地位，而大约 50%的感染者会发生向 CXCR4 的受体转换（X4 病毒），这与疾病的进展有关。对于潜在的动态，有许多假说，但尚未有明确的理解。
虽然在体内分离关键因素很困难，但我们已经开发了一种基于 Nowak 和 May 方法的最小化计算模型，以研究受体转换发生的条件。该模型允许在概率框架内沿着疾病的三个阶段（原发性和潜伏期感染以及艾滋病的发作）从病毒株的演变来进行研究，其中病毒载量突然增加，同时伴随着免疫反应的受损。该模型特别适用于研究 R5 和 X4 病毒的病毒准种的演变，这直接转化为病毒载量的组成，从而引发了辅助受体转换的问题。
该模型可以将辅助受体转换解释为宿主中潜在环境条件的动态变化的结果。X4 株的出现并不一定会导致 X4 病毒在病毒载量中占主导地位，在慢性感染一段时间后，模型中更有可能发生这种情况。更好地理解导致辅助受体转换的条件尤为重要，因为 CCR5 阻滞剂最近已被批准为药物，可抑制 R5 病毒，但似乎不一定会诱导辅助受体转换。
