Immunologic Approaches To The Therapy Of HIV 1 Infection

HIV的发病机制可以概括为一种免疫缺陷状态，反映为CD4+T细胞数量的下降，发生在免疫抑制的环境中，反映为血液中的HIV水平。外周血中的CD4+T细胞计数反映了当前的免疫能力水平，而血浆中的HIV RNA水平反映了预计的CD4T细胞计数下降的速度。一般说来，直到CD4计数降到临界阈值以下，患者才会生病。这一阈值的水平取决于血液中的病毒数量。艾滋病毒的血浆水平越高，CD4+T细胞计数下降的速度就越快，发生机会性疾病的CD4细胞计数就越高。目前的联合抗逆转录病毒治疗方案能够降低病毒水平，并允许免疫系统在一定程度上恢复。不幸的是，它们也与严重程度的副作用有关，随着时间的推移，副作用会变得更加明显。该项目的目的是开发针对免疫系统而不是病毒的新的治疗方法。 这个项目的一个主要焦点是研究T细胞衍生的生长和生存因子白介素2(IL-2)作为一种基于扩大CD4T细胞池大小的治疗策略的作用。在过去的一年里，已经完成了两项第二阶段的试验，并启动了一项审查这一方法的第三阶段研究。在第一个多中心的随机研究中，我们证明了间歇性给予IL-2与大约两倍的CD4+T细胞计数有关，并且接受IL-2的人血液中的HIV水平略低。在第二项研究中，在随机对照试验的背景下，研究了IL-2的最佳持续时间和周期之间的最佳间隔。根据后面这项研究的数据，我们得出结论，5天的IL-2是一个周期的最佳持续时间，周期之间的最佳间隔不多于每8周一次。这些数据完成了进入第三阶段试验所需的第二阶段数据库，并启动了题为“在随机国际试验(ESPRIT)中评估皮下促红细胞生成素(ESPRIT)”的第三阶段随机研究。

HIV pathogenesis can be summarized as a state of immunodeficiency, reflected by a decline in CD4+ T cell numbers, occurring in a setting of immunosuppression, reflected by levels of HIV in the blood. The peripheral blood CD4+ T cell count reflects the current level of immune competence while the plasma level of HIV RNA reflects the rate at which the CD4 T cell count can be expected to decline. In general, patients do not become ill until the CD4 count drops below a critical threshold. The level of this threshold is dependent upon the amounts of virus in the blood. The higher the plasma levels of HIV, the faster the CD4+ T cel count will decline and the higher the CD4 count at which opportunistic illnesses will develop. Current combination antiretroviral treatment regimens are able to reduce levels of virus and allow for a degree of recovery of the immune system. Unfortunately they are also associated with a significant degree of side effects that become more pronounced over time. The purpose of this project is to develop novel approaches to therapy that target the immune system rather than the virus. A major focus of this project is to examine the role of the T cell derived growth and survival factor interleukin-2 (IL-2) as a treatment strategy based upon expanding the size of the CD4 T cell pool. Over the past year, two phase II trials have been completed and a phase III study has been initiated that examine this approach. In the first multicenter, randomized study, we demonstrated that the intermittent administration of IL-2 was associated with approximately a doubling of the CD4+ T cell count and that recipients of IL-2 had slightly lower levels of HIV in the blood. In the second study, the optimal duration of IL-2 and the optimal interval between cycles were examined in the setting of a randomized, controlled trial. Based upon the data from this later study we concluded that 5 days of IL-2 was the optimal duration for a cycle and that the optimal interval between cycles was no more often than every 8 weeks. These data completed the phase II database required to move to phase III trials and amultinational, phase III study entitled, "Evaluation of Subcutaneous Proleukin in a Randomized, International Trial (ESPRIT)" was initiated.