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。其他工作检查了免疫抑制疗法的作用，细胞因子IL-7的作用，以及使CD4+T细胞对艾滋病毒感染更具抵抗力的遗传修饰的作用。在过去的一年里，利用体内标记技术已经表明，间歇性IL-2导致的CD4+T细胞数量的增加是由于幼稚和中央记忆的CD4+T细胞存活率的显著增加。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)的约6000名患者进行随访。在另一项工作中，10名受试者接受了来自他们同卵双胞胎兄弟姐妹的转基因CD4+T细胞的注射。这些细胞被改造成表达反义核酸和一种旨在干扰rev基因功能的蛋白质。通过分子分析，发现表达外源基因的CD4+T细胞比对照细胞具有生存优势。

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, the role of the cytokine IL-7 and the role of genetic modification of CD4+ T cells to make them more resistant to HIV infection. Over the past year, utilizing in vivo labeling techniques it has been shown that the increases in CD4+ T cell counts seen with intermittent IL-2 are due to profound increases in the survival of naive and central memory CD4+ T cells. 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). In other work, ten subjects received infusions of genetically modified CD4+ T cells from their identical twin siblings. These cells were modified to express anti-sense nucleic acids and a protein designed to interfere with the function of the rev gene. Through molecular analyses, the CD4+ T cells expressing the foreign genes were found to have a survival advantage over the control cells.