Humoral immune responses to HIV clade C isolates

广泛有效的HIV-12免疫疗法的开发受到限制，因为HIV包膜在天然病毒体上表达的固有结构特性。HIV感染涉及env抗原结构和表位呈递的一系列逐步变化，在此期间，病毒展开并暴露与靶细胞表面结构非常接近的中和表位。我们提出，免疫系统很难以更高阶的整合反应，其中抗体反应可以修饰包膜以暴露并随后识别暴露的中和表位。这种更高的整合必须通过主动或被动免疫施加于免疫系统，其中诱导或包括多种类型的抗体，这些抗体一起介导病毒中和，我们使用了掺入初级分离病毒体的测定。当对来自进化枝B感染个体的血清进行IgG抗体检测时，36%的感染个体捕获了病毒，但其中只有7%的个体捕获了大量病毒。病毒粒子特异性抗体与CD 4计数相关，与原代分离株中和作用相关性更显著。与原代分离株病毒粒子反应的抗体的低流行率可能与血清一般不能中和原代分离株有关。迄今为止，大多数研究利用进化枝B分离株，关于中和抗体对其他进化枝分离株的应答的信息相对较少。由于感染与进化枝C占一半以上的感染woldwide，我们建议分离和表征人类单克隆抗体与进化枝C主要分离病毒粒子反应，研究这些感染中的中和抗体反应。这些抗体将被进一步研究用于新生猕猴中针对粘膜攻击的被动免疫。确定这些抗体用于被动免疫的功效将有助于设计广泛有效的主动疫苗疗法。

Development of a broadly effective HIV-12 immunotherapy has been limited because of the inherent structural properties the HIV envelope expressed on the native virion. HIV infection involves a series of stepwise changes in env antigenic structures and epitope presentation during which the virus unfolds and exposes neutralizing epitopes in close proximity to the target cell surface structure. We propose, that it is difficult for the immune system to respond in a higher order integration in which an antibody response an modify the envelope to expose and then recognize exposed neutralizing epitopes. This higher integration must be imposed on the immune system through active or passive immunization in which multiple classes of antibodies are induced or included which together mediate viral neutralization, we have used an assay incorporating primary isolate virions. When serum from clade B infected individuals was tested for IgG antibodies, 36% of infected individuals captured virus but only 7% of these individuals captured significant quantities of virus. Virion specific antibody correlated with CD4 counts, and of more significance, primary isolate neutralization. The low prevalence of antibodies reactive with primary isolate virions may be related to the general inability of sera to neutralize primary isolates. Most studies to date have utilized clade B isolates with relatively little information as to neutralizing antibody responses to isolates of other clades. Since infection with clade C accounts for over half of the infections wold-wide, we propose to isolate and characterize human monoclonal antibodies reactive with clade C primary isolate virions to study the neutralizing antibody response in these infections. These antibodies will be further studied for passive immunization against mucosal challenge in neonatal macaques. Determinations of the efficacy of the these antibodies for passive immunization will facilitate the design of broadly effective active vaccine therapies.