T cells in HCV/HIV co-infection

丙型肝炎病毒（HCV）仍然是一个紧迫的全球威胁，许多国家的新感染率不断增加， 由于注射毒品使用的死灰复燃，司法管辖区。注射毒品的人（PWID）和MSM也在 艾滋病毒感染的风险，当同时感染这两种病毒时，他们会患上加速性肝病 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- 使用直接作用抗病毒药物（DAA）的保守治疗导致治愈率超过95%，即使是HCV/HIV 共同感染者。然而，仍然迫切需要保护高危人群免受慢性HCV感染。 感染和再感染仅仅作为治疗可能不足以满足这些常常难以获得治疗的人群的需要 to health健康care保健.预防性干预需要更好地了解免疫反应 保护免受慢性感染以及如何防止治愈受试者再次感染所必需的， 特别考虑到艾滋病毒合并感染和药物使用方面的额外挑战。在这 我们的建议侧重于艾滋病毒合并感染和药物滥用对HCV的产生和恢复的影响- 特异性T细胞在原发感染和治疗后。 我们将利用来自明确定义的急性和慢性HCV/HIV合并感染人群的PBMC， 包括来自接受DAA治疗的患者的纵向样品，连同直接离体分析， 通过流式细胞术和RNAseq在单个细胞上分选细胞的HCV特异性CD 4和CD 8 T细胞， 人口水平。具体来说，我们将确定HIV合并感染对关键CD 4 T细胞质量的影响。 在HIV阳性宿主中原发性HCV感染期间产生的细胞应答，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HCV特异性CD 4应答， 将确定HIV合并感染和药物滥用是否会损害HCV特异性T细胞的恢复， DAA治疗慢性HCV感染研究结果将为丙型肝炎病毒的发病机制提供重要见解 感染，并将告知免疫学方法预防慢性HCV感染和再感染 艾滋病毒合并感染和/或使用药物的高危患者。

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.