VIRUS AND IMMUNE RESPONSE CHANGES IN AIDS PROGRESSION

在大多数人中，艾滋病毒感染激发了一种相对有效的免疫 应答，包括中和抗体和细胞免疫， 消除大部分(但不是全部)病毒复制。矛盾的是， 持续低水平的慢性感染导致免疫系统不可阻挡 退化、艾滋病和死亡率在很大程度上是 从个人到下一个。越来越清楚的是，这一点 感染的不同自然病史是由于 多种因素(例如免疫反应、病毒负担、非特异性免疫 激活等。)在感染之间和感染内独立变化 个人。疾病的进程也伴随着较快的速度 病毒变种或准种的出现，呈现出一种正在进行的 挑战免疫系统，并为 致病潜能增强的病毒的进化。整体而言 拟议研究的目的是对 纵向变化之间的相互作用；生物多样性 准种群，体液免疫反应，病毒表型，病毒 负担，以及艾滋病毒疾病的进展率具有良好的特征 个人，从感染开始，在很长一段时间内 临床随访。虽然主机病毒的每一个组件 变异已经并将继续被独立地研究，系统地 对同一个体的多种因素进行比较应提供新的 对艾滋病毒破坏的复杂多组分机制的洞察 免疫系统。 我们将对前18个月内发生血清转换的20名受试者进行特征分析 一项正在进行的前瞻性研究，包括一些在3-6岁时患上艾滋病的人 年和其他保持无症状的人，超过800名CD4+T- 细胞，超过78个月。我们将采用新开发的异质双工 凝胶漂移(HGSA)和同源双链跟踪分析(HTA)和选择性 用核苷酸测序来表征病毒的时间变化 成群结队。还将评估中和抗体和V3 PND结合抗体 在整个随访过程中使用异源和自体病毒。最后， 体外趋向性反映的病毒分离株的致病潜能 和细胞病理学，将在每次检查中进行评估。这个 这些因素的相互关系将被用来测试替代方案 关于生物意义的假说的出现 抗中和准种和/或增加的准种 潜在的细胞病变。如果由于克隆显性而发生逃逸突变 我们应该在中和中和时观察有限的特异性，尽管 病毒异质性的进化。如果问题是耗尽 免疫学曲目，在接触了过多的新的 抗原，我们应该观察中和特异性的扩大 在毒力更强的菌株逃脱之前。在这两种情况下， 更多致病准种的出现将与快速 前进或在加速前进之前。或者， 细胞病变变异可能是先前免疫系统的晚期后果 与病毒表型无关的崩溃或由 特定的准种，尽管它们作为次要变种存在。

In most individuals, HIV infection provokes a relatively effective immune response, including neutralizing antibody and cellular immunity which eliminates most but not all virus replication. Paradoxically, the remaining low-level chronic infection leads inexorable to immune system degeneration, AIDS and death at rates that vary substantially from one individual to the next. It is becoming increasingly clear that this variable natural history of infection is due to a complex interaction of multiple factors (e.g. immune response, viral burden, non-specific immune activation, etc.) which vary independently between and within infected individuals. The disease process is also accompanied by relatively rapid emergence of viral variants, or quasispecies, which present an ongoing challenge to the immune system and provide the opportunity for the evolution of viruses with increased pathogenic potential. The overall purpose of the proposed study is to perform an extensive analysis of the interactions between longitudinal changes in; the diversity of the quasispecies swarm, the humoral immune response, viral phenotype, viral burden, and the rate of HIV disease progression in well characterized individuals, beginning at infection and throughout an extended period of clinical follow-up. While each of these components of host-virus variation has, and continues to be, studied independently, the systematic comparison of multiple factors in the same individuals should provide new insights into the complex multi-component mechanism by which HIV destroys the immune system. We will characterize 20 subjects who seroconverted in the first 18 months of an ongoing prospective study, including some who developed AIDS in 3-6 years and others who have remained asymptomatic, with over 800 CD4+ T- cells, for over 78 months. We will employ newly developed heteroduplex gel shift (HGSA) and homoduplex tracking analyses (HTA) and selective nucleotide sequencing to characterize temporal changes in the virus swarms. Neutralizing and V3 PND binding antibody will also be evaluated throughout follow-up using heterologous and autologous viruses. Finally, the pathogenic potential of viral isolates, reflected by in vitro tropism and cytopathology, will be assessed at each examination. The intercorrelation of these factors will be used to test alternative hypothesis for the biological significance of the emergence of neutralization resistant quasispecies and/or those with increased cytopathic potential. If escape mutants occur because of clonal dominance we should observe restricted specificity in neutralization despite the evolution of virus heterogeneity. If the problem is exhaustion of the immunologic repertoire, after exposure to an excessive number of new antigens, we should observe broadening of neutralizing specificities prior to the escape of more virulent strains. In either case, the emergence of more pathogenic quasispecies would be associated with rapid progression or precede accelerated progression. Alternatively, cytopathic variants may be a late consequence of prior immune system collapse which is either independent of viral phenotype or caused by particular quasispecies despite their presence as minor variants.