Petravic Janka, Martyushev Alexey, Reece Jeanette C, Kent Stephen J, Davenport Miles P
Centre for Vascular Research, UNSW Australia, Kensington, New South Wales, Australia.
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia.
J Virol. 2014 Dec;88(24):14050-6. doi: 10.1128/JVI.01701-14. Epub 2014 Sep 24.
Latently infected cells are considered a major barrier to the cure of HIV infection, since they are long-lived under antiretroviral therapy (ART) and cause viral replication to restart soon after stopping ART. In the last decade, different types of antilatency drugs have been explored with the aim of reactivating and purging this latent reservoir and the hope of achieving a cure. Because of toxicity and safety considerations, antilatency drugs can only be given for a short time to patients on long-term ART, with little effect. We recently investigated the turnover of latently infected cells during active infection and have found that it was strongly correlated with viral load. This implies that although latently infected cells had long life spans in a setting of a low viral load (such as during ART), they turned over quickly under a high viral load. Possible reasons for this could be that an increased viral load causes increased activation or death of CD4(+) T cells, including those that are latently infected. Taking these results into account, we developed a mathematical model to study the most appropriate timing of antilatency drugs in relationship to the initiation of ART. We found that the best timing of a short-term antilatency drug would be the start of ART, when viral load, CD4(+) T cell activation, and latent cell turnover are all high. These results have important implications for the design of HIV cure-related clinical trials.
The antiretroviral therapy (ART) of HIV-infected patients currently needs to be lifelong, because the cells latently infected with HIV start new rounds of infection as soon as the treatment is stopped. In the last decade, a number of different types of antilatency drugs have been explored with the aim of "reactivating" and "purging" this latent reservoir and thus achieving a cure. These drugs have thus far been tested on patients only after long-term ART and have demonstrated little or no effect. We use mathematical modeling to show that the most efficacious timing of a short-term antilatency treatment may be the start of ART because of possible interactions of antilatency drugs with natural activation pathways.
潜伏感染细胞被认为是治愈HIV感染的主要障碍，因为它们在抗逆转录病毒疗法（ART）下寿命很长，并且在停止ART后不久会导致病毒复制重新开始。在过去十年中，人们探索了不同类型的抗潜伏药物，目的是重新激活并清除这个潜伏库，以期实现治愈。出于毒性和安全性考虑，抗潜伏药物只能在长期接受ART治疗的患者中短期使用，效果甚微。我们最近研究了活跃感染期间潜伏感染细胞的更新情况，发现其与病毒载量密切相关。这意味着，虽然潜伏感染细胞在低病毒载量环境下（如在ART期间）寿命很长，但在高病毒载量下它们更新很快。可能的原因是病毒载量增加会导致CD4(+)T细胞（包括潜伏感染的细胞）的激活或死亡增加。考虑到这些结果，我们建立了一个数学模型来研究抗潜伏药物与ART开始时间的最合适时机。我们发现，短期抗潜伏药物的最佳时机是在ART开始时，此时病毒载量、CD4(+)T细胞激活和潜伏细胞更新都很高。这些结果对HIV治愈相关临床试验的设计具有重要意义。
目前，HIV感染患者的抗逆转录病毒疗法（ART）需要终身进行，因为一旦治疗停止，潜伏感染HIV的细胞就会开始新一轮感染。在过去十年中，人们探索了多种不同类型的抗潜伏药物，旨在“重新激活”和“清除”这个潜伏库，从而实现治愈。到目前为止，这些药物仅在长期接受ART治疗的患者身上进行了测试，效果甚微或没有效果。我们通过数学建模表明，由于抗潜伏药物与自然激活途径可能存在相互作用，短期抗潜伏治疗的最有效时机可能是ART开始时。
