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CD4+ T细胞计数反映当前免疫能力水平，而血浆HIV RNA水平反映CD4 T细胞计数可预期下降的速度。一般来说，患者在CD4计数降到临界阈值以下时才发病。这个阈值的水平取决于血液中病毒的数量。血浆HIV水平越高，CD4+ T细胞计数下降越快，CD4+ T细胞计数越高，机会性疾病就会发生。目前的抗逆转录病毒联合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，这些药物也伴随着严重的副作用，随着时间的推移，这些副作用会变得更加明显。这个项目的目的是开发针对免疫系统而不是病毒的新治疗方法。该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）作为基于扩大CD4 T细胞池大小的治疗策略的作用。额外的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，IL-2诱导的CD4+ T细胞增加可以发生并持续。在其他IL-2相关研究中，继续对约6000名患者进行随访，这些患者参加了两项III期临床终点研究（ESPRIT和SILCAAT）。

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).