Administration of fludarabine-loaded autologous red blood cells in simian immunodeficiency virus-infected sooty mangabeys depletes pSTAT-1-expressing macrophages and delays the rebound of viremia after suspension of antiretroviral therapy
Administration of fludarabine-loaded autologous red blood cells in simian immunodeficiency virus-infected sooty mangabeys depletes pSTAT-1-expressing macrophages and delays the rebound of viremia after suspension of antiretroviral therapy
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DOI：
10.1128/jvi.00472-06
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发表时间：
2006-11-01
影响因子：
5.4
通讯作者：
Magnani, M.
中科院分区：
文献类型：
--
作者：
Cervasi, B.;Paiardini, A.;Magnani, M.
高度活跃的一个主要限制。抗逆转录病毒疗法的另一个缺点是，由于其对携带复制能力HIV的病毒储库（包括单核细胞/巨噬细胞（M/M））的作用有限，它不能根除人类免疫缺陷病毒（HIV）感染。因此，针对HIV感染M/M的治疗方法可能在HIV感染患者的临床管理中证明是有用的。在以前的研究中，我们已经表明，氟达拉滨负载的红细胞（RBC）在体外通过pSTAT 1依赖性途径选择性诱导HIV感染的M/M细胞死亡。为了确定这种新的治疗策略的体内疗效，我们用9-[2-（R）-（膦酰甲氧基）丙基]腺嘌呤（PMPA）单独治疗了6只天然猴免疫缺陷病毒（SIV）感染的白眉猴（SM），仅用氟达拉滨加载的RBC治疗，或PMPA与氟达拉滨加载的RBC联合治疗。这种治疗的基本原理是在PMPA抑制活化的CD 4（+）T细胞中发生的病毒复制时，用氟达拉滨负载的RBC靶向感染的M/M。体内给药氟达拉滨加载的红细胞耐受性良好，没有引起任何明显的副作用。重要的是，在PNIPA中加入氟达拉滨负载的RBC延迟了治疗暂停后病毒复制的反弹，从而表明SIV储库的大小减小。虽然氟达拉滨负载的RBC给药不会引起CD 4（+）或CD 8（+）T细胞区室的任何变化，但我们观察到，在慢性SIV感染的SM中，表达pSTAT 1的M/M选择性耗竭。这项研究表明，基于氟达拉滨加载的红细胞管理的治疗策略，可进一步探讨为干预措施，旨在减少慢性HIV感染期间的M/M水库的大小。
A major limitation of highly active. antiretroviral therapy is that it fails to eradicate human immunodeficiency virus (HIV) infection due to its limited effects on viral reservoirs carrying replication-competent HIV, including monocytes/macrophages (M/M). Therefore, therapeutic approaches aimed at targeting HIV-infected M/M may prove useful in the clinical management of HIV-infected patients. In previous studies, we have shown that administration of fludarabine-loaded red blood cells (RBC) in vitro selectively induces cell death in HIV-infected M/M via a pSTAT1-dependent pathway. To determine the in vivo efficacy of this novel therapeutic strategy, we treated six naturally simian immunodeficiency virus (SIV)-infected sooty mangabeys (SMs) with either 9-[2-(R)-(phosphonomethoxy)propyl] adenine (PMPA) only, fludarabine-loaded RBC only, or PMPA in association with fludarabine-loaded RBC. The rationale of this treatment was to target infected M/M with fludarabine-loaded RBC at a time when PMPA is suppressing viral replication taking place in activated CD4(+) T cells. In vivo administration of fludarabine-loaded RBC was well tolerated and did not induce any discernible side effect. Importantly, addition of fludarabine-loaded RBC to PNIPA delayed the rebound of viral replication after suspension of therapy, thus suggesting a reduction in the size of SIV reservoirs. While administrations of fludarabine-loaded RBC did not induce any change in the CD4(+) or CD8(+) T-cell compartments, we observed, in chronically SIV-infected SMs, a selective depletion of M/M expressing pSTAT1. This study suggests that therapeutic strategies based on the administration of fludarabine-loaded RBC may be further explored as interventions aimed at reducing the size of the M/M reservoirs during chronic HIV infection.