Risk assessment of HIV infected to HIV infected transplantation in SA

 描述(申请人提供)：抗逆转录病毒疗法(ART)的成功导致越来越多的艾滋病毒感染者经历复杂的慢性非传染性疾病，包括艾滋病毒相关性肾病(HIVAN)和随后的终末期肾病(ESRD)。虽然肾移植是最有利的，通常也是唯一的治疗选择，但在等待健康器官的等待名单上死亡的概率高于接受一个器官的概率。使用艾滋病毒感染的已故捐赠者(HIVDD)作为一种新的肾脏来源可以缓解器官短缺的问题。南非是全球唯一对艾滋病毒感染者进行HIVDD肾移植的国家，美国正在考虑这一选择。因此，有必要对HIV感染的器官移植的有效性和安全性进行评估。在这项应用中，我们将研究世界上唯一的HIV阳性到阳性的移植患者群体，以确定 这是移植后HIVAN重新出现的基础。为此，我们将首先使用耐药性检测、数字滴状聚合酶链式反应和两种不同的下一代测序技术来确定供体与受者之间艾滋病毒重叠感染的发生率、程度和性质。其次，我们将利用激光引导的显微切割技术，对移植肾中病毒的渗入情况进行量化，并研究肾上皮中病毒的区划。最后，我们将调查这些因素和其他因素是否与HIV感染到HIV感染的接受者重新出现HIVAN有关。这项研究的结果将对南非的移植临床实践以及美国的临床决策和政策产生直接和立竿见影的影响，正如2013年11月美国里程碑式的艾滋病毒器官政策公平法案(HOPE)所呼吁的那样。此外，我们的研究提供了一个机会来回答围绕HIV-SI的多个基本生物学问题、病毒对组织的渗透、微小ART耐药性在未来治疗中的作用以及影响组织特异性病毒库建立的因素，这将为HIV治疗研究提供信息。

 DESCRIPTION (provided by applicant): The success of anti-retroviral therapy (ART) has led to an increased number of HIV-infected individuals experiencing complicated chronic non-infectious diseases including HIV-Associated Nephropathy (HIVAN) and subsequent End Stage Renal Disease (ESRD). Although renal transplantation is the most favorable and often only treatment option, the probability of dying on the waiting list for a healthy organ is higher than te probability of receiving one. The use of HIV-infected Deceased Donors (HIVDD) as a novel source of kidneys could alleviate the organ shortage. South Africa is the only country globally doing HIVDD kidney transplantation to HIV infected recipients, and the US is considering this option. Hence there is a need to evaluate the efficacy and safety of HIV- infected-to-HIV-infected organ transplantation. In this application we will study the only population of HIV-positive to positive transplant patients in the world in order to identify virological factors that underlie the re-emergence of HIVAN after transplantation. To this end we will first determine the incidence, extent, and nature of donor-to- recipient HIV-superinfection using drug resistance testing, digital droplet PCR, and two distinct next- generation sequencing techniques. Secondly we will quantify recipient's virus infiltration into the graft kidney and investigate virus compartmentalization in the kidney epithelium using laser directed microdissection. And finally we will investigate whether these and other factors are associated with re- emergence of HIVAN in HIV-infected-to-HIV-infected recipients. The results of this study will have a direct and immediate influence on transplant clinical practice in South Africa and on clinical decisions and policy in the US as was called for in the US landmark HIV Organ Policy Equity (HOPE) Act in November 2013. Additionally, our study provides an opportunity to answer multiple fundamental biological questions surrounding HIV-SI, viral infiltration into tissues, the role of minor ART resistance for future care, and factors that influence establishment of tissue specific viral reservoirs, which would be informative for HIV cure research.