艾滋病"功能性治愈"猕猴模型创建及其病毒潜伏机制研究

Highly active antiretroviral therapy (HAART) is the best way to treat HIV/AIDS, it can decline plasma HIV viral load to an undetectable level. Unfortunately, it does not cure AIDS, because viruses always recover replication at any time if the antiviral therapy is interrupted. Now it is widely accepted that the existence of long-lived latent HIV reservoirs is the primary obstacle to clear the virus infection.Recently,a small proportion of HIV patients were identified as post-treatment controllers whose viremia remained controlled for several years after the interruption of prolonged HAART initiated during the primary infection,these patients reach to a "function cure" state and bring great hope to the expectation of AIDS cure. However, The underlying reason to control virus replication and maintain its latency is not revealed by now. Rhesus macaques infected with SIV can closely resemble human AIDS and have facilitated many important advances in understanding the biology of HIV latency in human. In this study, Chinese rhesus macaque model will used to study the "function cure":1) A number of Chinese macaques will be infected SIVmac239 and iniated a early and stretched combined HAART, then the treatment will be ceased for a extended time and some portion of macaques which can control virus repliction were distinguished as "functional cure" macaques, and the therapeutics applied will be determined. 2) Compared with "non funtional cure" macaques, the latent state of the viruses of "functional cure" macaques, such as the viral reservoirs, viral diversity and infectious ability will be detected in peripheral blood during the full procedure and in the mainly possible tissues and organs after animals were sacrificed. 3) Some viroloy and immunology parameters of "functional cure" macaques, such as virus variation, microRNA, host restriction factors, immune activation, CD8+ cytotoxic lymphocyte and neutralizing antibody will be tested and evaluated their role in virus latency.4)The underlying mechanism to control persistent low levels of virus replication and maintain virus latency in "functional cure" macaques will be analysed and somewhat explained. This work will contributed some solid data and set a better possible direction to the clinical therapy of HIV/AIDS.

高效抗逆转录病毒疗法(HAART)是目前临床上最行之有效的抗HIV/AIDS治疗方案，但不能根治艾滋病，其根本原因是无法清除潜伏于机体中的病毒库。近年发现在少数(5-15％)早期治疗的HIV/AIDS患者中，停药后数年内病毒都没有出现反弹，实现了"功能性治愈"，为艾滋病治愈带来一线曙光。在这些患者体内，病毒的潜伏状态及其维持机制尚不清楚。本项目拟在前期艾滋病灵长类动物模型研究和技术平台基础上：用SIVmac239病毒感染中国猕猴，在感染早期进行HAART治疗，建立艾滋病"功能性治愈"猕猴模型；确定其治疗时机和方案；研究模型猕猴体内潜伏病毒在血液、各主要组织和器官的数量、活性和变异特征；研究病毒变异、宿主限制因子、免疫活化、microRNA和中和抗体对病毒潜伏的影响；了解"功能性治愈"的病毒潜伏机制。本项目将有助于阐明"功能性治愈"的机制，为艾滋病治疗策略提供科学依据。

HIV感染后由于病毒整合入宿主基因组中导致AIDS/HIV 不能彻底根治，目前的治疗主要以实现停止治疗后病毒能长期控制，各项免疫指标维持正常，即功能性治愈为目标。目前实现功能性治愈的方法主要有：早期治疗，免疫治疗，干细胞治疗，抗体治疗，基因治疗等。早期治疗在临床上已报道能够实现3.6~11.89%治疗个体的功能性治愈，但是其实现功能性治愈机制还不完全清除。本研究我们采用感染后早期治疗建立了停药后病毒得到长期控制，免疫系统维持稳定的AIDS功能性治愈模型。通过对病毒特征（病毒库，产毒能力，病毒的感染性），病毒特异的体液免疫和细胞免疫的检测，发现早期治疗能减少病毒库的大小，但是病毒库的大小、稳定性以及抗体的作用并不能完全解释停药后对病毒复制的控制作用；感染猴体内存在SIV病毒特异的T细胞反应，同时病毒控制者毒性CD8细胞的功能较强，其与停药后病毒的水平成负相关，提示其可能在病毒控制中起关键作用；治疗期治疗效果与停药后细胞的产毒率相关，同时其也与病毒的反弹相关。该研究为HIV 感染“早发现早治疗”治疗策略的提供支持，并为早治疗实现功能性治愈提供理论基础。