Antibiotic and Antiinflammatory Therapy Transiently Reduces Inflammation and Hypercoagulation in Acutely SIV-Infected Pigtailed Macaques.
Antibiotic and Antiinflammatory Therapy Transiently Reduces Inflammation and Hypercoagulation in Acutely SIV-Infected Pigtailed Macaques.
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DOI：
10.1371/journal.ppat.1005384
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发表时间：
2016-01
期刊：
影响因子：
6.7
通讯作者：
Apetrei C
中科院分区：
文献类型：
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作者：
Pandrea I;Xu C;Stock JL;Frank DN;Ma D;Policicchio BB;He T;Kristoff J;Cornell E;Haret-Richter GS;Trichel A;Ribeiro RM;Tracy R;Wilson C;Landay AL;Apetrei C
慢性免疫激活和炎症的增加是HIV/SIV感染的标志，并且与向AIDS的进展和非AIDS合并症（例如高凝状态和心血管疾病）的发展高度相关。肠道功能障碍导致的微生物易位已被认为是HIV/SIV感染中全身免疫激活和高凝状态的主要原因。我们的目标是评估通过减少肠道微生物含量（利福昔明-RFX）和肠道炎症（柳氮磺吡啶-SFZ）来减少微生物易位的治疗策略的生物学和临床影响。RFX是一种成功用于肝性脑病患者的管腔内抗生素。SFZ是一种成功用于轻度至中度炎症性肠病患者的治疗药物。这两种临床状况都与增加的微生物易位有关，类似于HIV感染患者。从感染时开始，对5只急性SIV感染的猪尾猕猴（PTM）进行90天的治疗; 7只未经治疗的SIV sab感染的PTM用作对照。RFX+SFZ也给药90天，以三个慢性SIVsab感染的PTM。在PTM的急性SIVsab感染期间给予RFX+SFZ导致：显著降低的微生物易位、较低的全身免疫活化、较低的病毒复制、更好地保存粘膜CD 4 + T细胞和显著降低的高凝生物标志物水平。这种效应在治疗的前40天很明显，在治疗的最后阶段消失。对慢性SIVsab感染的PTM给予RFX+SFZ对感染没有明显的影响。因此，我们的数据表明，早期RFX+SFZ管理短暂改善急性和急性后SIV感染的自然史，但在慢性感染没有效果。我们报告了对急性SIV感染的猪尾猕猴给予腔内抗生素利福昔明和肠道聚焦抗炎药柳氮磺胺吡啶与炎症-微生物易位-免疫激活的恶性循环的短暂中断有关，这是致病性HIV/SIV感染的特异性，并驱动HIV感染患者的HIV疾病进展和非AIDS共病。这种治疗方法导致在整个急性SIV感染过程中短暂的较低的微生物易位、较低的全身免疫激活、较低的病毒复制、粘膜CD 4 + T细胞的更好保存和较低水平的高凝生物标志物。因此，我们的研究结果支持使用治疗方法来减少微生物易位，改善接受抗逆转录病毒治疗的HIV感染患者的临床结果，并预防非艾滋病合并症。我们的研究结果也加强了艾滋病毒感染的早期治疗管理的重要性。
Increased chronic immune activation and inflammation are hallmarks of HIV/SIV infection and are highly correlated with progression to AIDS and development of non-AIDS comorbidities, such as hypercoagulability and cardiovascular disease. Intestinal dysfunction resulting in microbial translocation has been proposed as a lead cause of systemic immune activation and hypercoagulability in HIV/SIV infection. Our goal was to assess the biological and clinical impact of a therapeutic strategy designed to reduce microbial translocation through reduction of the microbial content of the intestine (Rifaximin-RFX) and of gut inflammation (Sulfasalazine-SFZ). RFX is an intraluminal antibiotic that was successfully used in patients with hepatic encephalopathy. SFZ is an antiinflammatory drug successfully used in patients with mild to moderate inflammatory bowel disease. Both these clinical conditions are associated with increased microbial translocation, similar to HIV-infected patients. Treatment was administered for 90 days to five acutely SIV-infected pigtailed macaques (PTMs) starting at the time of infection; seven untreated SIVsab-infected PTMs were used as controls. RFX+SFZ were also administered for 90 days to three chronically SIVsab-infected PTMs. RFX+SFZ administration during acute SIVsab infection of PTMs resulted in: significantly lower microbial translocation, lower systemic immune activation, lower viral replication, better preservation of mucosal CD4+ T cells and significantly lower levels of hypercoagulation biomarkers. This effect was clear during the first 40 days of treatment and was lost during the last stages of treatment. Administration of RFX+SFZ to chronically SIVsab–infected PTMs had no discernible effect on infection. Our data thus indicate that early RFX+SFZ administration transiently improves the natural history of acute and postacute SIV infection, but has no effect during chronic infection. We report that administration of the intraluminal antibiotic Rifaximin and the gut-focused anti-inflammatory drug Sulfasalazine to acutely SIV-infected pigtailed macaques is associated with a transient disruption of the vicious circle of inflammation-microbial translocation-immune activation which is pathognomonic to pathogenic HIV/SIV infection and drives HIV disease progression and non-AIDS comorbidities in HIV-infected patients. This therapeutic approach resulted in transient lower microbial translocation, lower systemic immune activation, lower viral replication, better preservation of mucosal CD4+ T cells and lower levels of hypercoagulation biomarkers throughout acute SIV infection. Our results thus support the use of therapeutic approaches to reduce microbial translocation, improve the clinical outcome of HIV-infected patients receiving antiretroviral therapy and prevent non-AIDS comorbidities. Our results also reinforce the importance of early therapeutic management of HIV infection.