Killing the Reservoir with Antibodies

描述（由申请人提供）：抑制HIV复制需要终身抗逆转录病毒治疗，虽然以前的希望包括治疗最终导致水库衰减和逐渐删除的可能性，但现在的证据表明，目前的治疗方法不会消除水库。相反，在过去的十年中，包括柏林患者、密西西比婴儿、巴黎治疗后控制者和波特兰猴在内的4个独特实例都指出，更积极的治疗干预与HAART结合可能导致治愈。此外，目前正在进行紧张的研究，以开发能够复活并将病毒从潜伏期中驱逐出来的新疗法，然而，一旦重新激活，几乎没有策略可以将这些细胞从体内清除。几个研究小组推测，疫苗诱导的或天然存在的细胞毒性T细胞应答可以识别并消除再活化的细胞，然而这些细胞可能受损，缺乏运输到潜伏感染细胞所在部位的能力，或者由于表位变异或低水平表位可用性而一起错过潜伏感染细胞。相反，在肿瘤细胞治疗的背景下，在过去的20年中，已经投入了大量的努力来开发溶细胞单克隆抗体治疗剂，如利妥昔单抗，其可以通过募集先天性免疫球蛋白来快速消除血液和组织中的靶细胞。 免疫细胞活性。这些类型的溶细胞抗体在自然感染期间自然诱导，在HAART背景下积累，在长期非进展者中富集，并且容易通过疫苗接种诱导。然而，这些类型的抗体是否可以杀死重新激活的潜伏感染细胞尚不清楚。在这里，我们建议开始，以确定是否单克隆治疗策略，再加上复活的病毒水库，可能有助于根除病毒水库。此外，我们将定义在再活化后最有效地识别潜伏感染细胞的特异性单克隆抗体，确定这些抗体是否可以招募不同的先天效应细胞以消除再活化的细胞，并最终优化单克隆治疗以最积极地杀死病毒库。结合目前的根除方法，这种单克隆治疗根除策略可以提供第二线或替代方法，通过被动免疫、抗体的基因转移或疫苗诱导的抗体诱导来消除病毒储库。

DESCRIPTION (provided by applicant): Suppression of HIV replication requires life-long antiretroviral therapy, and while previous hopes included the possibility that the therapy would eventually lead to a decay and gradual deletion of the reservoir, evidence now suggests that current therapeutic approaches will not eliminate the reservoir. Conversely, over the past decade 4 unique instances including the Berlin patient, the Mississippi baby, the Parisian post-treatment controllers, and the Portland monkeys all point to the possibility of that more aggressive therapeutic interventions coupled to HAART may lead to a cure. Moreover, intense investigation is now underway to develop new classes of therapeutics able to resurrect and drive the virus out of latency, however, once reactivated, few strategies exist to eliminate these cells from the body. Several groups have speculated that vaccine induced or naturally occurring cytotoxic T cell responses may recognize and eliminate reactivated cells, however these cells may be impaired, lack the capacity to traffic to sites harboring latently infected cells, or all together miss latently infected cells due to epitope variation or low level epitope availability. Conversely, in the context of tumor cell therapeutics, significant efforts has been invested over the past 2 decades in developing cytolytic monoclonal antibody therapeutics, like rituximab, that can rapidly eliminate target cells, both in the blood and tissues through the recruitment of innate immune cellular activity. These types of cytolytic antibodies are naturally induced during natural infection, accumulate in the context of HAART, are enriched in long-term non-progressors, and are easily induced via vaccination. However, whether these types of antibodies can kill reactivated latently infected cells is unknown. Here we propose to begin to define whether a monoclonal therapeutic strategy, coupled to resurrection of the viral reservoir, may aide in the eradication of the viral reservoir. Moreover, we will define the specific monoclonal antibodies that recognize latently infected cells most effectively following reactivation, determine whether these antibodies can recruit distinct innate effector cells to eliminate reactivated cells, and finlly to optimize monoclonal therapeutics to most aggressively kill the viral reservoir. Coupled to current eradication approaches, such a monoclonal therapeutic eradication strategy may offer a second line or alternate approach eliminate the viral reservoir either through passive immunization, gene transfer of the antibody, or vaccine-induced antibody induction.