THE ALTERED PROTEIN METABOLISM OF PEDIATRIC PATIENTS WITH HIV INFECTION

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 摘要 尽管高效抗逆转录病毒疗法(HAART)显著降低了艾滋病毒感染儿童的发病率和死亡率，但预期寿命的延长与部分患者的一系列复杂的代谢紊乱有关。这些疾病包括生长障碍和较低的瘦体重(LBM)。虽然这种代谢紊乱的临床特征已被描述，但其机制基础尚不清楚。为了为儿科患者建立新的治疗方法，描述这些机制是很重要的，因为生长障碍会导致发育迟缓。在这个项目中，我们计划检验一种假设，即感染艾滋病毒的儿童由于蛋白质分解代谢上调而导致净蛋白质合成不足，从而导致LBM较低。为了验证这一假设，我们建议进行稳定的同位素示踪实验，以实现以下特定目标：测量感染HIV的青春期前儿童与年龄和性别匹配的暴露于HIV的儿童的瘦体重(LBM)和蛋白质动力学，并确定饮食能量和蛋白质补充对HIV感染组LBM和蛋白质动力学的影响。 一、假说 尽管有足够的膳食蛋白质摄入量，但艾滋病毒感染的儿童由于缺乏内源性蛋白质来支持LBM的合成，其LBM较低。这种蛋白质利用率的下降是相对于摄入量的蛋白质分解代谢的慢性上调的次要原因。我们进一步提出，这种情况可以通过饮食补充更多的能量和蛋白质来改善。 二、具体目标 测量青春期前艾滋病毒感染儿童与年龄和性别匹配的艾滋病毒感染儿童的身体成分和蛋白质动力学，并确定补充膳食能量和蛋白质对艾滋病毒感染者组蛋白质动力学的影响。 三、背景和意义 虽然瘦体重(LBM)在患有获得性免疫缺陷综合征(AIDS)的成年人中是常见的，但在无症状的HIV感染成年人中并不常见，也就是那些没有继发性感染的成年人(1，2)。对这类患者的研究，就像那些有其他应激状态的患者一样，显示出比健康对照组更快的全身蛋白质周转速度。然而，饮食中的蛋白质摄入量和蛋白质分解代谢的净速率与健康对照组的观察结果相似。因此，在感染艾滋病毒的成年人中保持蛋白质平衡(1，2)。相比之下，低瘦组织沉积率继发的生长障碍在感染艾滋病毒的婴儿和幼儿中很常见，包括那些没有继发感染的婴儿和幼儿(3-5)。有证据表明，线性和有质量的生长都会受到影响(6-8)，在一项回顾研究中，Arpadi报告说，42%的围产期感染艾滋病毒的儿童的生长速度低于第五个百分位数，这表明生长障碍(8)。因此，病毒本身似乎会导致蛋白质代谢紊乱，导致婴儿和幼儿蛋白质沉积减少，但成年人不会。事实上，有证据表明，与生长速度正常的受感染儿童相比，发育不良儿童的艾滋病毒RNA水平更高，这表明抑制艾滋病毒复制应该对生长有积极影响。最近的报告证实了这一点，该报告显示，HAART对体重和线性生长速度都有积极影响，特别是在较小的儿童(9-11岁)中。目前尚不清楚的是，生长的改善是否与蛋白质净合成的改善有关，从而增加了LBM。然而，Miller等人报告说，在接受HAART治疗7-10个月的~9岁艾滋病毒感染儿童中，手臂肌围改善了11.5%(9)，Verweel等人报告说，并不是所有接受HAART治疗的儿童的身体质量指数(BMI)都有所增加(11)。它只在开始HAART前基线营养不良的儿童中得到改善。另一方面，一项对197名2至17岁随机分配到含有利托那韦方案的儿童的研究报告称，那些在48至96周后达到并保持HIV-1 RNA水平在400拷贝/毫升或以下的儿童的生长恶化(12周)。为了解决这些相互矛盾的发现，有必要测量HIV感染儿童体内的蛋白质动力学。 意义 在感染艾滋病毒的儿童中，生长发育障碍是预后不良的重要预测指标。众所周知，在感染艾滋病毒的婴儿和儿童(如3-5岁)中，生长障碍往往先于继发感染，这表明蛋白质沉积不足可能是病毒感染的早期表现。然而，对感染艾滋病毒的婴儿和幼儿的蛋白质代谢知之甚少。根据我们在无症状的HIV感染儿童中的初步发现(13)，我们认为感染病毒会引起急性期反应。因此，面对膳食能量减少和蛋白质利用效率低下的情况，必须将更多的蛋白质和能量用于维持急性期蛋白质周转率的增加。基于这些数据，我们建议，通过HAART减少病毒载量，加上补充额外能量和蛋白质的饮食，应该可以消除HIV感染儿童较低的净蛋白质合成，从而促进生长和LBM。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT Although highly active anti-retroviral therapy (HAART) has markedly reduced the morbidity and mortality of HIV-infected children, the improved life expectancy is associated with a complex set of metabolic disorders in a subset of patients. These disorders include growth failure with lower lean body mass (LBM). Although the clinical features of this metabolic derangement is described, its mechanistic underpinnings are unknown. It is important to delineate these mechanisms in order to establish new therapies for pediatric patients because growth failure will lead to stunting. In this project we plan to test the hypothesis that HIV-infected children have a lower LBM due to a deficit in net protein synthesis because of upregulated protein catabolism. To test this hypothesis we propose to conduct stable isotope tracer experiments to achieve the following specific aim: measure lean body mass (LBM) and protein kinetics in HIV-infected prepubertal children versus age-and gender-matched HIV-exposed children and determine the effect of dietary energy and protein supplementation on LBM and protein kinetics in the HIV-infected group. I. HYPOTHESIS Despite an adequate dietary protein intake, HIV-infected children have a lower LBM due to a deficit in the availability of endogenous protein to support LBM synthesis. This decreased protein availability is secondary to a chronic upregulation of protein catabolism relative to intake. We further propose that this condition can be ameliorated by dietary supplementation with more energy and protein. II. SPECIFIC AIM Measure body composition and protein kinetics in prepubertal HIV-infected children versus age and gender matched HIV-exposed children and determine the effect of dietary energy and protein supplementation on protein kinetics in the HIV-infected group. III. BACKGROUND AND SIGNIFICANCE Although loss of lean body mass (LBM) is a common finding in adults with acquired immunodeficiency syndrome (AIDS), it is not a common finding in asymptomatic HIV-infected adults, that is, those without secondary infections (1,2). Studies in such patients, like those in patients with other stressed states, show faster rates of whole body protein turnover than observed in healthy controls. Dietary protein intake and net rates of protein catabolism, however, are similar to those observed in healthy controls. Hence, protein balance is maintained in HIV-infected adults (1,2). In contrast, growth failure secondary to low rates of lean tissue deposition is common in infants and young children with HIV infection, including those without secondary infections (3-5). There is evidence that both linear and ponderal growth are affected (6-8) and in a retrospective study, Arpadi reported that 42% of perinatally HIV-infected children had a growth velocity below the fifth percentile, indicating growth failure (8). Thus, it appears that the virus, per se, induces a disturbance in protein metabolism that leads to reduced protein deposition in infants and young children but not in adults. Indeed there is evidence that levels of HIV RNA are greater in children with poor growth compared with infected children with normal rates of growth, suggesting that suppression of HIV replication should have positive effects on growth. This has been confirmed by recent reports showing that HAART has positive effects on both weight and linear growth velocity, especially among younger children (9-11). What is not clear is whether improved growth is associated with improved net protein synthesis, hence increased LBM. Whereas, Miller et al reported an 11.5% improvement in arm muscle circumference in a cohort of ~9 year old HIV-infected children who were on HAART for 7-10 months (9), Verweel et al reported that body mass index (BMI) did not increase in all children treated with HAART (11). It only improved in children who were undernourished at baseline prior to starting HAART. On the other hand, one study of 197 children aged 2 to 17 years randomly assigned to ritonavir containing regimens reported a worsening of growth in those children who achieved and maintained HIV-1 RNA levels at and below 400 copies/mL after 48 to 96 weeks (12). To resolve these conflicting findings it is necessary to measure in vivo protein kinetics in HIV-infected children. Significance In HIV-infected children growth failure is an important predictor of a poor prognosis. It is well established that growth failure often precedes secondary infections in HIV-infected infants and children (e.g. 3-5) indicating that inadequate protein deposition may be an early manifestation of infection by the virus. However, little is known about protein metabolism of HIV-infected infants and young children. Based on our preliminary findings in asymptomatic HIV-infected children (13), we propose that infection by the virus elicits an acute phase response. Hence, more protein and energy has to be channeled towards sustaining increased turnover of acute phase proteins in the face of reduced dietary energy and inefficient utilization of dietary protein. Based on these data we propose that a reduction of viral load by HAART plus a diet supplemented with extra energy and protein should abolish the lower net protein synthesis of HIV-infected children, thereby increasing growth and LBM.