HIV Replication and Thymopoiesis in Adolescents

描述(申请人提供)：大量通过围产期感染艾滋病毒的儿童现在可以存活到青春期和成年期。对于这些患者中的许多人，直到出现显著的免疫异常时才诊断和治疗艾滋病毒感染。此外，几乎所有人在青春期前使用的有效治疗方案对艾滋病毒复制的抑制作用都很差。我们假设，这些人在整个童年期间长期且控制不佳的艾滋病毒感染将导致成年早期到中期的过早免疫衰老，可能是通过加速发生在童年和青春期的生理胸腺退化。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，我们提议进行研究，以检查艾滋病毒的致病特性、抗逆转录病毒治疗的抑制和选择性能力以及这些人存在的免疫系统的再生能力之间的平衡。其具体目的是：1)使用体内标记方法和其他方法来比较围产期HIV感染的青少年/青壮年与两个年龄匹配的对照组：血清阴性的受试者和通过最近的成人行为获得的艾滋病毒感染的青少年胸腺生成的定量参数；2)评估这些胸腺生成参数与患者HIV分离株的pol型和nef基因型以及复制特性之间的关系；以及3)检测围产期感染的青少年对HIV和常见感染物(包括巨细胞病毒、流感和Epstein-Barr病毒)与年龄匹配的对照组的细胞免疫反应的幅度和广度。

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.