T cells in HCV/HIV co-infection

丙型肝炎病毒(丙型肝炎病毒)仍然是一个紧迫的全球威胁，许多国家的新感染率不断上升。 由于注射毒品使用的死灰复燃，许多司法管辖区也出现了这种情况。注射毒品(PWID)和男男性接触者也在 感染艾滋病毒的风险，当与这两种病毒混合感染时，他们会患上加速的肝病 当使用基于干扰素的治疗时，进展和较低的治疗应答率。新型干扰素- 节省使用直接作用抗病毒药物(DAA)的治疗可导致超过95%的治愈率，即使是在丙型肝炎病毒/艾滋病毒中也是如此 共同感染的人。然而，仍然迫切需要保护高危人群免受慢性丙型肝炎病毒的侵袭。 在这些机会往往有限的人群中，感染和再感染作为单独治疗可能是不够的。 为医疗保健服务。预防性干预需要更好地了解免疫反应。 预防慢性感染所必需的，以及如何防止治愈的受试者再次感染 特别考虑艾滋病毒合并感染和药物使用方面的其他挑战。在这 建议我们重点关注艾滋病毒合并感染和药物滥用对丙型肝炎病毒的产生和恢复的影响- 初次感染期间和治疗后的特异性T细胞。 我们将利用来自明确界定的急性和慢性丙型肝炎病毒/艾滋病毒混合感染者队列的PBMC， 包括来自接受DAA治疗的患者的纵向样本，以及直接的体外分析 流式细胞术检测丙型肝炎病毒特异性的CD4和CD8T细胞及分离的单个细胞和 人口水平。具体地说，我们将定义HIV混合感染对关键CD4T细胞质量的影响 HIV阳性宿主在初次感染丙型肝炎期间产生的细胞反应将确定其机制 在接受早期DAA治疗的患者中实现持续和功能性的丙型肝炎病毒特异性CD4应答，以及 将确定HIV合并感染和药物滥用是否会损害丙型肝炎病毒特异性T细胞的恢复 DAA治疗慢性丙型肝炎病毒感染。这一结果将为丙型肝炎病毒的发病机制提供重要的见解。 并将为预防慢性丙型肝炎病毒感染和再感染的免疫学方法提供信息 艾滋病毒合并感染和/或药物使用的高危患者。

Hepatitis C virus (HCV) remains an urgent global threat, with increasing rates of new infections in many jurisdictions due to a resurgence of injection drug use. People who inject drugs (PWID) and MSM are also at risk for HIV infection and when co-infected with these two viruses they suffer from accelerated liver disease progression and lower treatment response rates when interferon-based therapies were used. New interferon- sparing therapies with direct-acting antivirals (DAAs) lead to cure rates of over 95%, even in HCV/HIV coinfected persons. However, there remains an urgent need to protect high-risk populations from chronic HCV infection and re-infection as treatment alone might be insufficient in these populations with often limited access to health care. Prophylactic interventions will require a better understanding of the immune response necessary for protection from chronic infection and how cured subjects can be prevented from re-infection, with special considerations of additional challenges in the context of HIV co-infection and substance use. In this proposal we focus on the impact of HIV co-infection and of drug abuse on the generation and recovery of HCV- specific T cells during primary infection and after therapy. We will utilize PBMC from well-defined cohorts of persons with acute and chronic HCV/HIV co-infection, including longitudinal samples from patients undergoing DAA therapy, together with direct ex-vivo analysis of HCV-specific CD4 and CD8 T cells by flow cytometry and RNAseq of sorted cells on the single cell and population level. Specifically we will define the impact of HIV co-infection on the quality of the critical CD4 T cell response generated during primary HCV infection in HIV positive hosts, will identify the mechanism enabling sustained and functional HCV-specific CD4 responses in patients receiving early DAA treatment, and will determine whether HIV co-infection and substance abuse impair the recovery of HCV-specific T cells after DAA therapy for chronic HCV infection. The results will deliver important insights into the pathogenesis of HCV infection and will inform immunological approaches for the prevention of chronic HCV infection and re-infection in high risk patients with HIV co-infection and/or substance use.