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，反映在CD 4 + T细胞数量的下降，发生在免疫抑制的环境中，反映在血液中的HIV水平。外周血CD 4 + T细胞计数反映了当前的免疫能力水平，而HIV RNA的血浆水平反映了CD 4 T细胞计数预期下降的速度。一般来说，患者不会生病，直到CD 4计数下降到临界阈值以下。该阈值的水平取决于血液中病毒的量。HIV的血浆水平越高，CD 4 + T细胞计数下降得越快，机会性疾病发展的CD 4 + T细胞计数越高。目前的联合抗逆转录病毒治疗方案能够降低病毒水平，并使免疫系统得到一定程度的恢复。不幸的是，这些药物也与随着时间的推移变得更加明显的显着程度的副作用。该项目的目的是开发针对免疫系统而不是病毒的新疗法。该项目的一个主要重点是研究细胞因子如IL-2和IL-7作为基于扩大CD 4 T细胞池大小的治疗的作用。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。 在过去的一年中，两项独立的研究表明，IL-2诱导的CD 4 + T细胞增加可以发生，并可以在没有抗逆转录病毒治疗的情况下持续。 在其他IL-2相关研究中，继续对两项III期临床终点研究（ESPRIT和SILCAAT）和一项II期研究（STALWART）中招募的约6000名患者的队列进行分析。

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 cytokines such as IL-2 and 7 as treatment 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, analysis 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).