Killing the Reservoir with Antibodies

描述(申请人提供)：抑制艾滋病毒复制需要终生抗逆转录病毒疗法，虽然以前的希望包括这种疗法最终可能导致宿主腐烂并逐渐消失，但现在的证据表明，目前的治疗方法不会消除宿主。相反，在过去十年中，包括柏林患者、密西西比州婴儿、巴黎治疗后控制员和波特兰猴子在内的4个独特案例都表明，更积极的治疗干预加上HAART可能会导致治愈。此外，目前正在进行紧张的研究，以开发能够复活并将病毒赶出潜伏期的新疗法，然而，一旦重新激活，几乎没有策略可以将这些细胞从体内消除。一些研究小组推测，疫苗诱导或自然产生的细胞毒性T细胞反应可以识别和消除重新激活的细胞，但这些细胞可能会受到损害，缺乏运输潜伏感染细胞的能力，或者由于表位变异或低水平的表位可获得性而共同错过潜伏感染细胞。相反，在肿瘤细胞疗法的背景下，在过去的20年里，已经投入了大量的努力来开发溶细胞的单抗疗法，如利妥昔单抗，它可以通过招募先天的 免疫细胞活动。这些类型的溶细胞抗体是在自然感染期间自然诱导的，在HAART的背景下积累，富含长期非进展性抗体，并且很容易通过接种疫苗诱导。然而，这些类型的抗体是否能杀死重新激活的潜伏感染细胞尚不清楚。在这里，我们建议开始确定单克隆性治疗策略，再加上病毒库的复活，是否可能有助于根除病毒库。此外，我们将定义在重新激活后最有效地识别潜伏感染细胞的特定单抗，确定这些抗体是否可以招募不同的固有效应细胞来消除重新激活的细胞，并最终优化单抗疗法以最具侵略性地杀死病毒库。与目前的根除方法相结合，这种单抗治疗性根除策略可能提供二线或替代方法，通过被动免疫、抗体基因转移或疫苗诱导抗体诱导消除病毒库。

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.