ROLE OF AN ANTIAPOPTOTIC AGENT IN AIDS PROGRESSION

艾滋病研究的核心挑战是，尽管宿主免疫反应通常很强，但病毒感染持续存在，疾病进展。尽管处于感染的急性期，但病毒复制受到MHC限制性CTL和病毒特异性抗体应答的抑制。最近的几篇出版物（关于疱疹病毒、黄病毒和逆转录病毒）表明，Fas配体阳性（FasL+）、CD 4 + T细胞在感染过程中被诱导并抑制病毒特异性免疫应答。我们在SIV/恒河猴艾滋病模型中的研究暗示FasL介导的细胞死亡可能是艾滋病疾病进展的加速剂。我们发现：i）未感染的动物含有FasL+。能够裂解以MHC不受限制的方式表达SIVenv的靶标的CD 4+细胞，裂解活性在个体猕猴中是稳定的，和iv）高水平的基线MHC不受限制的裂解活性与SIV感染后的快速疾病进展相关（Yin等人，J Virol. 1999年）。在这里，我们建议测试的假设，FasL+，CD 4+效应抵消病毒特异性宿主免疫和促进疾病进展。在SIV/猕猴模型中，疾病进展在病毒载量、抗体水平和CD 4+细胞损失率方面得到了很好的定义。我们将通过用结合FasL的抗体治疗猕猴来直接测试FasL在疾病进展中的作用，该抗体已被证明在体外阻断MHC不受限制的裂解。根据初步数据，抗FasL治疗可降低急性SIV感染期间的病毒负荷，提高SIV抗原的血清抗体，并提供与接种疫苗后观察到的病毒负荷降低相当或更好的保护程度。我们正在探索抗FasL的疗效和作用机制，作为病毒诱导的FasL介导的细胞凋亡对宿主免疫反应的破坏和疾病进展的贡献。

The central challenge in AIDS research is that virus infection persists and disease progresses, despite often vigorous host immune responses. Despite the acute phase of the infection, virus replication is countered by the onset of MHC-restricted CTL and virus-specific antibody responses. Several recent publications (on herpes-, flavi-, and retroviruses) suggest that Fas ligand positive (FasL+), CD4+ T cells are elicited during infection and suppress virus-specific immune responses. Our studies in the SIV/rhesus macaque model for AIDS implicate FasL-mediated cell death as a possible accelerator of disease progression in AIDS. We showed: i) uninfected animals contain FasL+. CD4+ cells capable of lysing targets expressing SIVenv in an MHC-unrestricted manner, lytic activity are stable in individual macaques, and iv) high levels of baseline MHC-unrestricted lytic activity are correlated with rapid disease progression after SIV infection (Yin et al, J Virol. 1999). Here we propose to test the hypothesis that FasL+, CD4+ effectors counteract virus-specific host immunity and promote disease progression. Disease progression is well-defined in the SIV/macaque model in terms of virus loads, antibody levels and the rate of CD4+ cell loss. We will perform a direct test of the role of FasL in disease progression by treating macaques with an antibody that binds FasL and has been shown to block MHC-unrestricted lysis in vitro. Based on preliminary data, treatment with anti-FasL reduces viral burden during acute SIV infection, raises serum antibody to SIV antigens, and gives a degree of protection that is comparable or better than reductions in virus burden observed after vaccination. We are exploring the efficacy and mechanism of action for anti-FasL as a contribution of virus-induced FasL-mediated apoptosis to the destruction of host immune responses and to the progression of disease.