HIV Replication and Thymopoiesis in Adolescents

描述（由申请人提供）：大量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。对其中许多人来说，直到出现明显的免疫异常才诊断和治疗艾滋病毒感染。此外，几乎所有人在青春期前对艾滋病毒复制的抑制都很差，治疗方案的效力也较弱。我们假设，在这些个体中，儿童期长期且控制不良的HIV感染将导致成年早期到中期的过早免疫衰老，可能是通过加速儿童期和青春期发生的生理胸腺退化。这些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态和预后，并确定可能的治疗策略，以促进这一不断增长的感染青年群体的正常、健康寿命。利用大量当地围产期感染青少年的科学优势，我们建议进行研究，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个体中存在的免疫系统的再生能力之间的平衡。具体目的是：1)利用体内标记法等方法比较围生期HIV感染青少年/青年与两组年龄匹配的对照组（血清阴性受试者和近期成人行为感染HIV的青少年）胸腺功能的定量参数；2)评估这些胸腺功能参数与HIV患者分离株的pol和nef基因型及复制特性之间的关系；3)与年龄匹配的对照组相比，检测围产期感染青少年对HIV和常见感染因子（包括巨细胞病毒、流感和eb病毒）的细胞免疫应答的程度和广度。

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.