Pandrea Ivona, Xu Cuiling, Stock Jennifer L, Frank Daniel N, Ma Dongzhu, Policicchio Benjamin B, He Tianyu, Kristoff Jan, Cornell Elaine, Haret-Richter George S, Trichel Anita, Ribeiro Ruy M, Tracy Russell, Wilson Cara, Landay Alan L, Apetrei Cristian
Center for Vaccine Research, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, Penssylvania, United States of America.
PLoS Pathog. 2016 Jan 14;12(1):e1005384. doi: 10.1371/journal.ppat.1005384. eCollection 2016 Jan.
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.
慢性免疫激活和炎症增加是HIV/SIV感染的标志，与进展为艾滋病以及非艾滋病合并症（如高凝状态和心血管疾病）的发生高度相关。肠道功能障碍导致微生物易位，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。我们的目标是评估一种治疗策略的生物学和临床影响，该策略旨在通过减少肠道微生物含量（利福昔明-RFX）和肠道炎症（柳氮磺胺吡啶-SFZ）来减少微生物易位。RFX是一种腔内抗生素，已成功用于肝性脑病患者。SFZ是一种抗炎药物，已成功用于轻度至中度炎症性肠病患者。这两种临床情况都与微生物易位增加有关，类似于HIV感染患者。从感染时开始，对五只急性感染SIV的猪尾猕猴（PTM）进行为期90天的治疗；七只未治疗的感染SIVsab的PTM用作对照。RFX+SFZ也对三只慢性感染SIVsab的PTM进行了90天的给药。在PTM急性感染SIVsab期间给予RFX+SFZ导致：微生物易位显著降低、全身免疫激活降低、病毒复制降低、黏膜CD4+T细胞得到更好的保存以及高凝生物标志物水平显著降低。这种效果在治疗的前40天很明显，在治疗的最后阶段消失。对慢性感染SIVsab的PTM给予RFX+SFZ对感染没有明显影响。因此，我们的数据表明，早期给予RFX+SFZ可短暂改善急性和急性后SIV感染的自然病程，但在慢性感染期间没有效果。
