Avila-Ríos S, Reyes-Terán G, Espinosa E
Center for Infectious Diseases Research, National Institute of Respiratory Diseases, Calzada de Tlalpan 4502, CP 14080 Mexico City, Mexico.
Med Hypotheses. 2007;69(2):422-31. doi: 10.1016/j.mehy.2006.12.012. Epub 2007 Feb 5.
Adaptive immune responses, cellular restrictive factors and antiretroviral drugs, target multiple regions in the Human Immunodeficiency Virus (HIV) proteome, imposing diverse pressures to viral adaptation. However, the virus is remarkably able to escape from these pressures as mutations are selected. In many cases these mutants have diminished viral fitness. We propose that the concerted action of strategically placed agents and pressures in a host can limit HIV variation capacity while inhibiting its replication. These mechanisms would corner HIV by selecting conflicting adaptive mutations, each having a disadvantage in face of another selective pressure. This would keep the virus unable to efficiently escape the suppressive effects of selective pressures. Cornering between antiretroviral drugs and cytotoxic T lymphocytes may explain recent observations, and can be predicted and used in viral control strategies. This idea can be extended to numerous other identified sites in the viral genome that confer selective pressures. We describe these other sites and how they could be induced to interact in prophylactic or therapeutic cornering strategies, as well as their experimental verifications. Cornering would control HIV infection better than current strategies, focused on few, albeit important, sites in the HIV genome.
适应性免疫反应、细胞限制性因子和抗逆转录病毒药物靶向人类免疫缺陷病毒（HIV）蛋白质组中的多个区域，给病毒适应性带来多种压力。然而，随着突变的产生，病毒能够显著地逃避这些压力。在许多情况下，这些突变体的病毒适应性有所降低。我们提出，宿主中策略性放置的因子和压力的协同作用可以在抑制HIV复制的同时限制其变异能力。这些机制将通过选择相互冲突的适应性突变来使HIV陷入困境，每个突变在面对另一种选择压力时都处于劣势。这将使病毒无法有效逃避选择压力的抑制作用。抗逆转录病毒药物和细胞毒性T淋巴细胞之间的“围剿”可能解释了最近的观察结果，并且可以在病毒控制策略中进行预测和应用。这个想法可以扩展到病毒基因组中其他许多产生选择压力的位点。我们描述了这些其他位点，以及它们如何在预防性或治疗性“围剿”策略中相互作用，以及它们的实验验证。“围剿”将比目前聚焦于HIV基因组中少数（尽管很重要）位点的策略更好地控制HIV感染。
