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。HIV的血浆水平越高，CD4+T细胞数量下降的速度就越快，发生机会性疾病的CD4+T细胞数量就越高。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，这些药物还与显著程度的副作用有关，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。其他工作检查免疫抑制治疗的作用和细胞因子IL-15的作用。在过去的一年里，两项独立的研究表明，在没有抗逆转录病毒治疗的情况下，可以发生并持续由IL-2诱导的CD4+T细胞增加。在其他与IL-2相关的研究中，继续对参加两项III期临床终点研究(ESPRIT和SILCAAT)和一项II期研究(STORART)的约6000名患者进行随访。

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 cell count will decline and the higher the CD4+ T cell 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, these drugs 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. Additional work examines the role of immunosuppressive therapy and the role of the cytokine IL-15. Over the past year two independent studies have demonstrated that the CD4+ T cell increases induced by IL-2 can occur and can be sustained in the absence of antiretroviral therapy. In other IL-2 related studies, follow-up continues on a cohort of approximately 6000 patients enrolled in two phase III clinical endpoint studies (ESPRIT and SILCAAT) and one phase II study (STALWART).