ROLE OF AN ANTIAPOPTOTIC AGENT IN AIDS PROGRESSION

艾滋病研究的主要挑战是，尽管宿主的免疫反应往往很强烈，但病毒感染持续存在，疾病不断发展。尽管感染处于急性期，但病毒复制会被mhc限制性CTL和病毒特异性抗体反应的发作所抵消。最近的一些出版物（关于疱疹病毒、黄病毒和逆转录病毒）表明，Fas配体阳性（FasL+）、CD4+ T细胞在感染期间被激发并抑制病毒特异性免疫反应。我们在SIV/恒河猴艾滋病模型中的研究表明fasl介导的细胞死亡可能是艾滋病疾病进展的加速因素。我们发现：i)未感染动物含有FasL+。CD4+细胞能够以不受mhc限制的方式裂解表达SIVenv的靶标，在单个猕猴中裂解活性是稳定的，iv)高水平的基线mhc不受限制的裂解活性与SIV感染后疾病的快速进展相关（Yin等，J Virol. 1999）。在这里，我们提出验证FasL+、CD4+效应物抵消病毒特异性宿主免疫并促进疾病进展的假设。在SIV/猕猴模型中，根据病毒载量、抗体水平和CD4+细胞损失率，疾病进展是明确的。我们将对FasL在疾病进展中的作用进行直接测试，方法是用一种结合FasL的抗体治疗猕猴，该抗体已被证明可以在体外阻断mhc无限制的裂解。根据初步数据，抗fasl治疗减少了急性SIV感染期间的病毒负担，提高了对SIV抗原的血清抗体，并提供了与疫苗接种后观察到的病毒负担减少相当或更好的保护程度。我们正在探索抗fasl的功效和作用机制，作为病毒诱导的fasl介导的细胞凋亡对宿主免疫应答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.