Determinants of Immune Control in HIV perinatally infected children in sub-Sahara

描述（由申请人提供）：有250万儿童感染艾滋病毒。这些儿童中的绝大多数在围产期获得感染，并感染了HIV-1进化枝C。 虽然抗逆转录病毒疗法（ART）是有效的，但仍存在与儿童终身治疗相关的重大依从性和成本挑战。对于受感染的儿童，需要采取治疗性疫苗等药物节约方法。这些策略将试图在儿童中实现功能性治愈状态，从而导致与HIV精英控制者（EC）的免疫表型非常相似的免疫表型，这些控制者在没有ART的情况下维持不可检测的病毒载量。CD 4+和CD 8 + T细胞应答可能在任何治疗性疫苗接种策略中发挥重要作用。虽然有相当多的 扩展我们对成人EC和长期非进展者（LTNP）中CD 4 + T细胞应答的理解，但对儿童中这些应答的理解较少。特别是，对撒哈拉以南非洲儿童的CD 4 + T细胞反应知之甚少，这些儿童在免疫系统不成熟时获得感染，并在儿童时期获得CMV等合并感染。CD 4 + T细胞是适应性免疫应答的核心，并且对于病毒特异性CD 8 + T细胞的发育是重要的，所述病毒特异性CD 8 + T细胞在宿主病毒控制中起重要作用。我们将研究南部非洲围产期感染LTNP（pLTNP）、快速进展者和缓慢进展者队列中的HIV特异性CD 4 + T细胞应答。我们将确定CD 4 + T细胞的特异性、宽度、大小、功能和表型是否决定病毒控制和疾病进展。我们将评估病毒特异性CD 8 + T细胞的数量、功能和表型，并确定它们如何与CD 4 + T细胞应答相关。我们将确定这些儿童的胸腺如何维持T细胞稳态，以及CD 4+和CD 8 + T细胞亚型如何对调节细胞因子（如IL-7）做出反应，这些细胞因子对胸腺生成、存活和幼稚细胞和记忆细胞的外周扩增至关重要。我们还将确定ART的免疫重建如何影响病毒特异性T细胞应答和T细胞稳态。 围产期感染的儿童。这项综合研究的数据将导致识别在免疫控制中重要的病毒表位，其中一些可能是治疗性疫苗的候选者。将确定的CD 4+和CD 8 + T细胞功能和表型的缺陷将指导可能恢复这些儿童T细胞功能的策略的制定。这项研究将拓宽我们对胸腺和IL-7/IL-7 R通路在CMV阳性人群中疾病进展的理解，并帮助我们确定IL-7是否是该人群中合适的免疫治疗。通过纵向评估围产期感染儿童对ART的反应，我们将了解尽管ART仍会发生免疫恢复的缺陷，并将这些反应与ART初治pLTNP中确定的反应进行比较。这将有助于为接受ART的儿童开发治疗性疫苗，使他们能够形成类似于pLTNP或EC的免疫特征。

DESCRIPTION (provided by applicant): There are 2.5 million children living with HIV. The vast majority of these children acquired infection perinatally and are infected with HIV-1 clade C. Although antiretroviral therapy (ART) is effective, there are significant adherence and cost challenges associated with lifelong therapy in children. Drug sparing approaches such as therapeutic vaccines are needed for infected children. These strategies would try to achieve functional cure status in children resulting in an immunologic phenotype that closely resembles that of HIV elite controllers (ECs) who maintain undetectable viral loads in the absence of ART. CD4+ and CD8+ T cell responses are likely to play an important role in any therapeutic vaccination strategy. Although there has been a considerable expansion of our understanding of CD4+ T cell responses in adult EC and long-term non progressors (LTNPs) less is understood about these responses in children. In particular, very little is known about CD4+ T cell responses in children in sub-Saharan Africa who acquire infection while their immune system is immature and acquire co-infections such as CMV in childhood. CD4+ T cells are central to the adaptive immune response and are important for the development of virus specific CD8+ T cells that play an important role in host viral control. We will study HIV specific CD4+ T cell responses in a cohort of perinatally infected LTNP (pLTNPs), rapid progressors and slow progressors in southern Africa. We will determine if the specificity, breadth, magnitude, function and phenotype of CD4+ T cells determines viral control and disease progression. We will evaluate the magnitude, function and phenotype of virus specific CD8+ T cells and determine how they correlate with the CD4+ T cell responses. We will define how the thymus in these children maintains T cell homeostasis and how CD4+ and CD8+ T cell subtypes respond to regulatory cytokines such as IL-7 which are important for thymopoiesis, survival and peripheral expansion of na¿ve and memory cells. We will also determine how immune reconstitution on ART affects virus specific T cell responses and T cell homeostasis in perinatally infected children. The data from this comprehensive study will lead to the identification of viral epitopes that are important in immune control some of which may be candidates for inclusion in therapeutic vaccines. The deficits in CD4+ and CD8+ T cell function and phenotype that will be identified will guide the development of strategies that may work to restore T cell function in these children. The study will broaden our understanding of the thymus and IL-7/IL-7R¿ pathway in disease progression in a largely CMV positive population, and help us determine if IL-7 would be an appropriate adjunctive immunotherapy in this population. By longitudinally evaluating responses in perinatally infected children on ART, we will understand the deficits in immune restoration that occur despite ART and compare those responses to those identified in ART na¿ve pLTNPs. This will help facilitate the development of therapeutic vaccines for children on ART that may enable them to develop an immune profile that resembles that in pLTNPs or ECs.