Persistence of virus reservoirs in ART-treated SHIV-infected rhesus macaques after autologous hematopoietic stem cell transplant.
Persistence of virus reservoirs in ART-treated SHIV-infected rhesus macaques after autologous hematopoietic stem cell transplant.
复制标题
DOI：
10.1371/journal.ppat.1004406
复制
发表时间：
2014-09
期刊：
影响因子：
6.7
通讯作者：
Silvestri G
中科院分区：
文献类型：
--
作者：
Mavigner M;Watkins B;Lawson B;Lee ST;Chahroudi A;Kean L;Silvestri G
尽管艾滋病研究取得了许多进展，但治愈艾滋病毒感染的方法仍然难以捉摸。在这里，我们使用感染前收集的抗逆转录病毒治疗（ART）的恒河猴（RMs）进行了自体造血干细胞移植（HSCT），并将它们与三只感染了SHIV、ART治疗的未移植对照动物进行了比较，以评估条件调节和自体造血干细胞移植对病毒持久性的影响。正如预期的那样，抗逆转录病毒疗法大大减少了病毒的复制，在所有动物中，每毫升血浆中的SHIV-RNA拷贝数低于100个。在接受ART治疗数周后，实验小鼠接受清髓性全身照射（1080 cGy），导致循环CD4+ t细胞减少94-99%，外周血单个核细胞中的SHIV-DNA水平降低至无法检测。在HSC输注和移植成功后，ART中断（移植后40-75天）。尽管观察到外周血病毒库的急剧减少，但在三分之二的移植RMs中观察到血浆病毒血症的快速反弹。在第三只移植动物中，在art中断后的第2周，大量pbmc的血浆SHIV- rna和SHIV DNA仍未检测到。由于该动物因临床原因被安乐死，因此无法进一步评估时间点；然而，在该动物的尸检中，可在分选的循环CD4+ t细胞、脾脏和淋巴结中检测到SHIV-DNA，但在胃肠道和扁桃体中未检测到。此外，art中断后SIV DNA水平在移植动物和对照动物的几个组织中是相同的。虽然在短期抗逆转录病毒治疗中，尽管骨髓消融和HSCT仍观察到病毒库的持久性，但本实验表明，自体HSCT可以成功地在siv感染的抗逆转录病毒治疗的rm中进行，为测试旨在治愈人类HIV感染的创新干预措施提供了一个新的实验体内平台。虽然抗逆转录病毒疗法（ART）可以减少艾滋病毒的复制，但它不能从感染者身上根除病毒。具有复制能力的病毒在抗逆转录病毒治疗中持续存在，我们对这些病毒储存库的不完全了解极大地复杂化了艾滋病毒治疗方法的产生。在这项研究中，我们首次在建立的恒河猴SIV感染模型中进行了造血干细胞移植（HSCT）。在SIV感染前采集来自骨髓的HSC。在SIV感染后，RM接受抗逆转录病毒治疗数周，以减少病毒复制，然后进行全身照射和用自身感染前的干细胞移植。辐照消除了94-99%的循环CD4+ t细胞，这是HIV/SIV感染的主要靶细胞。观察到HSC的成功植入，血液病毒库急剧减少。然而，当中断抗逆转录病毒治疗时，3例移植的RM中有2例血浆病毒血症迅速反弹，这表明在短期抗逆转录病毒治疗的情况下，造血室的大量重置不足以消除全身病毒库。这种siv感染RM的HSCT模型为研究HIV根除策略提供了一个新的平台。
Despite many advances in AIDS research, a cure for HIV infection remains elusive. Here, we performed autologous hematopoietic stem cell transplantation (HSCT) in three Simian/Human Immunodeficiency Virus (SHIV)-infected, antiretroviral therapy (ART)-treated rhesus macaques (RMs) using HSCs collected prior to infection and compared them to three SHIV-infected, ART-treated, untransplanted control animals to assess the effect of conditioning and autologous HSCT on viral persistence. As expected, ART drastically reduced virus replication, below 100 SHIV-RNA copies per ml of plasma in all animals. After several weeks on ART, experimental RMs received myeloablative total body irradiation (1080 cGy), which resulted in the depletion of 94–99% of circulating CD4+ T-cells, and low to undetectable SHIV-DNA levels in peripheral blood mononuclear cells. Following HSC infusion and successful engraftment, ART was interrupted (40–75 days post-transplant). Despite the observed dramatic reduction of the peripheral blood viral reservoir, rapid rebound of plasma viremia was observed in two out of three transplanted RMs. In the third transplanted animal, plasma SHIV-RNA and SHIV DNA in bulk PBMCs remained undetectable at week two post-ART interruption. No further time-points could be assessed as this animal was euthanized for clinical reasons; however, SHIV-DNA could be detected in this animal at necropsy in sorted circulating CD4+ T-cells, spleen and lymph nodes but not in the gastro-intestinal tract or tonsils. Furthermore, SIV DNA levels post-ART interruption were equivalent in several tissues in transplanted and control animals. While persistence of virus reservoir was observed despite myeloablation and HSCT in the setting of short term ART, this experiment demonstrates that autologous HSCT can be successfully performed in SIV-infected ART-treated RMs offering a new experimental in vivo platform to test innovative interventions aimed at curing HIV infection in humans. While antiretroviral therapy (ART) can reduce HIV replication, it does not eradicate the virus from an infected individual. Replication-competent viruses persist on ART and our incomplete understanding of these viral reservoirs greatly complicates the generation of a cure for HIV. In this study we performed, for the first time, hematopoietic stem cell transplant (HSCT) in the established model of SIV infection of rhesus macaques (RM). The HSC originating from the bone marrow were collected before SIV infection. After SIV infection, RM were treated with ART for several weeks to reduce viral replication before performing a total body irradiation and a transplant with their own, pre-infection, stem cells. The irradiation eliminated 94–99% of the circulating CD4+ T-cells, the main cell target of HIV/SIV infection. A successful engraftment of the HSC was observed and blood viral reservoirs were drastically reduced. However, when ART was interrupted, a rapid rebound of plasma viremia was observed in two out of three transplanted RM indicating that the massive reset of the hematopoietic compartment was not sufficient to eliminate the total-body virus reservoir in the setting of short term ART. This model of HSCT in SIV-infected RM provides a new platform to investigate HIV eradication strategies.
登录
查看更多内容
影响因子：
6.7
作者：
Shytaj IL;Norelli S;Chirullo B;Della Corte A;Collins M;Yalley-Ogunro J;Greenhouse J;Iraci N;Acosta EP;Barreca ML;Lewis MG;Savarino A
通讯作者：
Savarino A
影响因子：
4.1
作者：
Evans DT;Silvestri G
通讯作者：
Silvestri G
影响因子：
5.4
作者：
North, Thomas W.;Higgins, Joanne;Luciw, Paul A.
通讯作者：
Luciw, Paul A.
影响因子：
6.4
作者：
Henrich, Timothy J.;Hu, Zixin;Kuritzkes, Daniel R.
通讯作者：
Kuritzkes, Daniel R.
DOI：
10.1073/pnas.94.24.13193
发表时间：
1997-11-25
影响因子：
11.1
作者：
Chun, TW;Stuyver, L;Fauci, AS
通讯作者：
Fauci, AS