IMMUNOLOGIC APPROACHES TO THE THERAPY OF HIV-1 INFECTION

一项密集的努力被用于研究这一潜力 人类免疫缺陷的免疫学治疗方法 病毒(HIV)感染。一种免疫和抗病毒作用的评价研究 反复应用白介素2和核苷的疗效观察 类比仍在继续。IL-2治疗导致血浆中 CD4细胞数量和CD8活化标志物表达降低； 表现出这些免疫反应的可能性显示为 与基线CD_4计数直接相关。使用一种新的血浆艾滋病毒 RNA检测分析，病毒载量的瞬时和持续增加 每一次输液的结束都显示出来。在这些发现的后续行动中， IL-2诱导外周血病毒复制的体外模型 血液单个核细胞被培养出来，并对 IL-2诱导人类免疫缺陷病毒的机制已经开始。慢性阻塞性肺疾病患者白介素2的研究 卡波西肉瘤患者被发起，以试图 相关的免疫学和临床反应。一种随机对照 将IL-2加核苷类似物与单独核苷进行比较的试验 继续，和一项随机对照的多中心试验，比较3，4， 单独向核苷输注IL-2加核苷5天 已启动。一项评价安全性和免疫学的剂量递增试验 皮下注射IL-2的活性被启动，MTD被 已定义。皮下注射IL-2的毒性相同 对于静脉注射IL-2的患者，但通常没有那么严重。领养 利用活化和扩增同基因转移进行免疫治疗 完成多克隆淋巴细胞培养。显著但短暂的增长 在转移期后可见CD_4细胞计数，通常与 随着血浆中病毒复制的增加。CD4的反应是直接的 与基线CD_4计数有关。对基因标记细胞的研究是 作为尝试基因治疗的前奏。一项研究正在产生 人类免疫球蛋白基因的随机重组文库 被感染的人继续。一种抗gp120的抗体 已确定可用于临床开发。评估安全性和安全性的研究 抗肿瘤坏死因子(TNF-α)抗体的活性和 启动可溶性肿瘤坏死因子-α受体。循环抑制 肿瘤坏死因子-α与短期毒性无关；没有明显的意义 免疫学或病毒学方面的好处已经显现。

An intensive effort was directed toward studying the potential therapeutic aspects of immunologic approaches to human immunodeficiency virus (HIV) infection. A study evaluating the immunologic and antiviral effects of repeated administration of interleukin-2 (IL-2) and nucleoside analogs was continued. IL-2 therapy resulted in sustained increases in numbers of CD4 cells and decreased expression of CD8 activation markers; the probability of manifesting these immunologic responses was shown to be directly associated with baseline CD4 count. Using a new plasma HIV RNA detection assay, transient and consistent increases in viral load at the end of each infusion were revealed. In follow-up of these findings, an in vitro model of IL-2-induction of viral replication in peripheral blood mononuclear cells was developed and investigations into the mechanisms of IL-2 induction of HIV were begun. A study of IL-2 in patients with Kaposi's sarcoma was initiated, in order to attempt to correlate immunologic and clinical responses. A randomized controlled trial comparing IL-2 plus nucleoside analogs to nucleosides alone was continued, and a randomized controlled multicenter trial comparing 3, 4, and 5 day infusions of IL-2 plus nucleosides to nucleosides alone was initiated. A dose escalation trial evaluating the safety and immunologic activity of subcutaneously administered IL-2 was initiated and an MTD was defined. Toxicities of IL-2 administered subcutaneously were identical to those seen with intravenous IL-2, but generally less severe. Adoptive immunotherapy using transfers of activated and expanded syngeneic polyclonal lymphocytes was completed. Marked but transient increases in CD4 counts were seen in the post-transfer period, often in association with increased viral replication in plasma. CD4 responses were directly related to baseline CD4 count. Studies with gene-marked cells were initiated as a prelude to attempts at gene therapy. A study generating random recombinatorial libraries of human immunoglobulin genes from HIV- infected individuals was continued. An anti-gp120 antibody was identified for clinical development. Studies evaluating the safety and activity of an anti-tumor necrosis factor (TNF-alpha) antibody and a soluble TNF-alpha receptor were initiated. Inhibition of circulating TNF-alpha was not associated with short-term toxicity; no appreciable immunologic or virologic benefit was seen.