IMPACT OF AGING ON IMMUNE CONTROL OF A PERSISTENT VIRUS

随着人类寿命的延长，我们迫切需要确定衰老对免疫力的影响，并制定预防或治疗策略来对抗与年龄相关的免疫力下降。持续性病毒感染的免疫控制是一个与衰老相关的问题，如有充分证据证明的α-疱疹病毒水痘带状疱疹在老年人中重新激活的例子所示，引起带状疱疹后神经痛（带状疱疹）。人类疱疹病毒（humangarnma-herpesviruses，EBV）和卡波西肉瘤相关疱疹病毒（Kaposi 'ssarcoma-associatedherpesviruses，Kaposi' ssarcoma-associatedherpesviruses）是人类重要的病原体，与淋巴组织增生性疾病有关 以及各种恶性肿瘤，包括伯基特淋巴瘤、霍奇金病、鼻咽癌和卡波西肉瘤。需要持续的免疫监测以维持潜伏期并防止病毒再活化。因此，我们必须了解老年人控制这些感染的能力。在目前的建议中，我们将利用一个充分表征的小鼠模型，小鼠γ-疱疹病毒-68，MHV-68，研究衰老对这类重要的致癌病毒的免疫控制的影响。累积的数据表明，CD 4 + T细胞，CD 8 + T细胞和抗体都有助于病毒潜伏期的免疫控制。我们的初步数据显示，老年人的中和抗体呈进行性下降， 老年小鼠控制病毒潜伏期的能力受到损害。这些数据证明了对病毒特异性体液和细胞免疫的彻底分析。因此，在目标1中，我们将确定老年小鼠中和抗体滴度的下降是否导致体液免疫受损，以及是否存在同种型谱或病毒特异性随年龄的变化，如EBV所示。在目标2中，我们将监测7种不同裂解和潜伏性CD 4和CD 8表位的病毒特异性T细胞的数量、表型和功能，并确定老年小鼠的细胞免疫是否下降。最后，在目标3中， 我们将评估免疫系统的生理扰动如何影响老年人持久性γ-疱疹病毒的免疫控制。这些研究将是第一次系统分析衰老对控制持续性γ-疱疹病毒感染的影响。

With the increasing longevity of the human population, it is urgent that we define the consequences of aging on immunity and develop preventative or therapeutic strategies to counteract age-associated immune decline. Immune control of persistent viral infections is a problem associated with aging, as illustrated by the well-documented example of reactivation of the alpha-herpesvirus, varicella-zoster, in the elderly, causing postherpetic neuralgia (Shingles). The human garnma-herpesviruses, Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus, are important human pathogens, associated with lymphoproliferative disorders and various maligancies, including Burkitt's lymphoma, Hodgkin's disease, nasopharyngeal carcinoma and Kaposi's sarcoma. Continual immunesurveillance is required to maintain latency and prevent viral reactivation. It is therefore critical that we understand the ability of aged individuals to control these infections. In the current proposal, we will exploit a well-characterized mouse model, murine gamma-herpesvirus-68, MHV-68, to study the impact of aging on immune control of this important class of oncogenic viruses. Accumulating data suggest that CD4+ T cells, CD8+ T cells and antibodies all contribute to immune control of viral latency. Our preliminary data show that there is a progressive decline in neutralizing antibodies in aged mice, and that aged mice are compromised in their ability to control viral latency. These data justify a thorough analysis of virus-specific humoral and cellular immunity. Therefore, in Aim 1, we will determine whether the decline in neutralizing antibody titers in aged mice results in compromised humoral immunity, and whether there is a change in isotype profile or viral specificity with age, as has been shown for EBV. In Aim 2, we will monitor numbers, phenotype and function of virus-specific T cells for seven different lytic and latent CD4 and CD8 epitopes, and determine whether there is a decline in cellular immunity in aged mice. Finally, in Aim 3, we will assess how physiological perturbation of the immune system impacts immune control of persistent gamma-herpesviruses in the aged. These studies will be the first systematic analysis of the impact of aging on control of persistent gamma-herpesvirus infections.