HIV Replication and Thymopoiesis in Adolescents

描述（由申请人提供）：大量患有围产期获得性艾滋病毒感染的儿童现在存活到青春期和成年期。对于其中许多人来说，艾滋病毒感染没有得到诊断和治疗，直到已经存在显著的免疫异常。此外，几乎所有人在青春期前的几年里都对艾滋病毒复制的抑制作用很差，治疗方案效力较低。我们假设，这些人在整个童年时期长期和控制不良的HIV感染将导致早期至中期的免疫性过早衰老，这可能是通过加速发生在儿童和青春期的生理性胸腺退化。拟议研究的总体目标是更好地了解围产期艾滋病毒感染长期幸存者的免疫状况和预后，并确定可能的治疗策略，以促进这一日益增长的受感染青年人口的正常健康寿命。利用当地大量围产期感染青少年的科学优势，我们建议进行研究，以检查HIV的致病特性，抗逆转录病毒治疗的抑制和选择性能力以及这些个体中存在的免疫系统的再生能力之间的平衡。具体目标是：1）使用体内标记方法和其他方法比较来自围产期HIV感染的青少年/年轻成人与来自两个年龄匹配的对照组的胸腺生成的定量参数：血清阴性受试者和通过近期成人行为获得的HIV感染的年轻人;（2）评价胸腺生成指标之间的关系，pol和nef基因型以及患者HIV分离株的复制特性; 3）检测围产期感染青少年对HIV和常见感染因子的细胞免疫应答的幅度和广度（包括巨细胞病毒、流感病毒和EB病毒）。

DESCRIPTION (provided by applicant): A large number of children with perinatally-acquired HIV infection are now surviving into adolescence and adulthood. For many of these, HIV infection was not diagnosed and treated until significant immunological abnormalities were already present. In addition, nearly all had poor suppression of HIV replication with the less potent treatment regimens available during their pre-adolescent years. We hypothesize that prolonged and poorly controlled HIV infection throughout childhood in these individuals will lead to premature immunological senescence in early to mid-adulthood, perhaps by accelerating the physiological thymic involution that occurs in childhood and adolescence. The general goal of the studies proposed is to better understand the immunological status and prognosis of long-term survivors of perinatal HIV infection, and to identify possible therapeutic strategies to promote a normal, healthy lifespan for this growing population of infected youths. Taking scientific advantage of the availability of a large local cohort of perinatally infected adolescents, we are proposing studies to examine the balance between the pathogenic properties of HIV, the suppressive and selective power of antiretroviral therapy, and the regenerative capacity of the immune system that exists in these individuals. The specific aims are: 1) To use in vivo labeling methods and other approaches to compare quantitative parameters of thymopoiesis from adolescents/young adults with perinatal HIV infection with those from two age-matched control groups: seronegative subjects, and youths with HIV infection acquired via recent adult behaviors; 2) To evaluate the relationship between these parameters of thymopoiesis, and the pol and nef genotypes and the replication properties of patient HIV isolates, and 3) To examine the magnitude and breadth of cellular immune responses of perinatally infected adolescents to HIV and common infectious agents (including cytomegalovirus, influenza, and Epstein-Barr Virus) compared to the age matched controls.