VIRUS AND IMMUNE RESPONSE CHANGES IN AIDS PROGRESSION

在大多数人中，艾滋病毒感染引起相对有效的免疫 反应，包括中和抗体和细胞免疫， 消除了大部分但不是全部的病毒复制。 奇怪的是， 残留的低水平慢性感染导致免疫系统的不可逆转 退化，艾滋病和死亡的速度从一个大大不同， 个人到下一个。 越来越明显的是， 感染的自然史可变是由于以下因素的复杂相互作用 多种因素（例如免疫反应、病毒负荷、非特异性免疫 激活等）在感染者之间和感染者体内 个体 发病过程也伴随着比较迅速的 病毒变种或准种的出现， 对免疫系统的挑战，并提供机会， 病毒的进化具有增加的致病潜力。 整体 拟议研究的目的是对 纵向变化之间的相互作用; 准种群，体液免疫应答，病毒表型，病毒 艾滋病毒疾病的进展速度， 个体，从感染开始，并在整个延长期内， 临床随访。 虽然宿主病毒的每一个组成部分 变异已经，并将继续，独立研究，系统的 对同一个体的多个因素进行比较， 深入了解艾滋病毒破坏的复杂多组分机制， 免疫系统. 我们将描述20名在前18个月内发生血清转化的受试者的特征 一项正在进行的前瞻性研究，包括一些在3-6年内患上艾滋病的人， 年和其他人一直保持无症状，有超过800个CD 4 + T- 细胞，超过78个月。 我们将采用新开发的异源双链 凝胶位移（HGSA）和同源双链追踪分析（HTA）和选择性 核苷酸测序来表征病毒的时间变化 成群结队 还将评价中和和V3 PND结合抗体 在整个随访期间使用异源和自体病毒。 最后， 通过体外嗜性反映的病毒分离株的致病潜力 和细胞病理学，将在每次检查时进行评估。 的 这些因素的相互关系将用于测试替代方案， 的生物学意义的假说 中和抗性准种和/或那些具有增加的 细胞病变潜能如果逃逸突变体的出现是因为克隆优势 我们应该在中和中观察到有限的特异性， 病毒异质性的进化。 如果问题在于 在接触过多的新的免疫系统后， 抗原，我们应该观察到中和特异性的扩大 在更致命的菌株逃逸之前。 在任何一种情况下， 更多致病性准种的出现将与快速 进展或提前加速进展。 可选择地， 细胞病变变异可能是先前免疫系统的晚期结果， 不依赖于病毒表型或 特别准种，尽管他们的存在作为微小的变种。

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.