Immunological control of a persistent viral infection

摘要 尤其是在免疫受损的情况下，控制潜伏的疱疹病毒的失败在缺乏有效的CD4T细胞功能的免疫受损的受者中尤其成问题。缺乏有效的CD4T细胞功能的个人，如艾滋病患者或移植受者。小鼠伽马疱疹病毒68(IVIHV-68)是一种天然存在的啮齿动物病原体，与人类病原体Epstein Barr病毒和卡波西肉瘤相关关系密切，与人类病原体Epstein Barr病毒和卡波西肉瘤相关疱疹病毒关系密切。MHV-68感染小鼠为研究疱疹病毒提供了一种易于处理的小动物模型。感染MHV-68的小鼠为研究伽马疱疹病毒感染的免疫控制、检测潜在感染能力和检测潜在复活个体的能力提供了易于处理的小动物模型。控制免疫受损个体病毒重新激活的治疗剂。CD4T细胞不是急性控制MHV-68复制所必需的，而是长期有效地需要的，突显了CD40-CD40L相互作用在帮助控制004T细胞中的重要性。我们早期的工作强调了CD4O-CD4OL相互作用在长期控制MHV-68方面的重要性，并表明CD4O单独刺激，使用激动剂CD40单独，抗体，病毒再激活抗体，足以防止病毒在CD4T细胞缺陷小鼠的肺部重新激活。细胞老鼠。CD40刺激上调树突状细胞表面CD8O和86，CD4O刺激上调树突状细胞表面CD80和86，树突状细胞分别与阳性和阴性共刺激分子CD28和CTLA-4相互作用。有趣的是，我们已经证明，已知的CD80和86对于MHV-68,0028的长期控制是必不可少的，尽管CD80和86对于MHV-68，CD28的长期控制是必要的，但CD80/86的唯一阳性共刺激受体并不是必需的，这表明0D80/86超家族可能需要一种新的阳性共刺激受体，该受体是什么受体。CD28、CD8O和86是CD28-B7超家族的一部分，由多个受体组成。0028，CD80成员，介导T细胞的正或负共刺激。在这一应用中，我们将介绍介导T细胞正或负共刺激的成员。在这一应用中，我们将研究CD40和CD28-B7家族成员相互作用调节的机制，研究0040和CD28-B7家族成员相互作用调节细胞应答CD8 T细胞应答的机制。在我的目标中，我们将感染。在目标1中，我们将调查为什么长期控制MHV-68需要CD4T细胞，但不需要长期控制MHV-68，但不调查为什么004 T细胞(急性)控制对于短期(急性)控制病毒至关重要。我们的数据显示有两种病毒。008 T细胞激活功能的替代途径CD8 T细胞激活功能的替代途径在急性期间，但在长期期间不在长期控制期间。在目标2中，我们将研究一种新的CD80/86(B7-1，2)受体控制的可能性。在目标2中，我们将研究一种新的0D80/86受体(B7-L)在MHV-68长期控制中发挥作用的可能性。在目标3中，我们将研究PD-1在控制MHV-68中的作用。在目标3中，我们已经证明的抑制性B7家族成员PD-I在没有抑制性B7家族成员的情况下在008细胞上表达上调，我们已经证明在MHV-68的急性和长期控制中，我们已经证明在没有CD4T细胞的情况下CD8 T细胞上表达上调。这些研究将为MHV-68的急性和长期控制提供重要的0D4T细胞。这些研究将为CD8T细胞介导持续病毒感染的急性和长期的急性和长期控制的机制提供重要的见解，并可能在设计病毒和设计免疫治疗剂或疫苗以对抗复发的伽马疱疹病毒感染方面具有重要价值 C&gt；。 �-0 3，第3页 C‘(0 弗洛伊德？ 能 0)3 CL) CSC BCD ：CUM 小野 O，-.O Vo(Q 中国 �0= E 我-- 0-0 Ii) 60岁， (00 、�- �c‘ P-0 “吃过了。

ABSTRACT is particularly problematic in immunocompromised Failure to control latent herpesviruses is particularly problematic in immunocompromised recipients who lack effective CD4 T cell function. individuals such as AIDS patients or transplant recipients who lack effective CD4 T cell function. Murine gammaherpesvirus-68 (IVIHV-68) is naturally occurring rodent pathogen, which is closely Murine gammaherpesvirus-68 (MHV-68) naturally occurring rodent which is closely related to the human pathogens Epstein Barr virus and Kaposi's sarcoma-associated related to the human pathogens Epstein virus and Kaposi's sarcoma-associated herpesvirus. Infection of mice with MHV-68 provides a tractable small animal model for studying herpesvirus. Infection mice with MHV-68 provides tractable small animal model for studying immunological control of gammaherpesvirus infection and for testing the ability of potential infection and for testing the ability of potential reactivation individuals. therapeutic agents to control viral reactivation in immunocompromised individuals. CD4 T cells are not required for acute control of replicating MHV-68, but are required for effective long-term highlighted the importance of CD40-CD40L interactions in 004 T cell help control. Our early work highlighted the importance of CD4O-CD4OL interactions in CD4 T cell help in the long-term control of MHV-68 and showed that CD4O stimulation alone, using agonistic that CD40 in the alone, antibodies, viral reactivation antibodies, was sufficient to prevent viral reactivation in the lungs of CD4 T cell deficient mice. cell mice. CD40 stimulation upregulates CD8O and 86 on dendritic cells, which interact with CD4O stimulation upregulates CD80 and 86 on dendritic cells, which interact with positive and and negative costimulators CD28 and CTLA-4, respectively. Interestingly, we have shown that, Interestingly, we have shown that, known CD80 and 86 are essential for long-term control of MHV-68, 0028, the although CD8O and 86 are essential for long-term control of MHV-68, CD28, the only known positive costimulatory receptor for CD80/86 is not required, suggesting the possibility of a novel required, positive costimulatory receptor for 0D80/86 superfamily, which receptor. CD28, CD8O and 86 are part of the CD28-B7 superfamily, which comprises several receptor. 0028, CD80 members that mediate positive or negative costimulation of T cells. In this application, we will members that mediate positive or negative costimulation of T cells. In this application, we will investigate the mechanisms by which CD40 and CD28-B7 family members interact to regulate investigate the mechanisms by which 0040 and CD28-B7 family members interact to regulate cell response CD8 T cell responses during the response to gammaherpesvirus infection . In Aim I we will infection. In Aim 1 we will investigate why CD4 T cells are required for the long-term control of MHV-68 , but are not required long-term control MHV-68, but are not investigate why 004 T cells (acute) control essential for short-term (acute) control of the virus. Our data suggests that two virus. alternative pathways of 008 T cell activation function alternative pathways of CD8 T cell activation function during acute, but not during long-term during long-term control. In Aim 2 we will investigate the possibility that a novel receptor for CD80/86 (B7-1, 2) control. In Aim 2 we will investigate the possibility that a novel receptor for 0D80/86 (B7-l, functions in the long-term control of MHV-68. In Aim 3, we will investigate the role of PD-1, an in control MHV-68. In Aim 3, will role PD-I, an inhibitory B7 family member that we have shown is upregulated on 008 cells in the absence of inhibitory B7 family member that we have shown is upregulated on CD8 T cells in the absence of CD4 T cells, in acute and long-term control of MHV-68. These studies will provide important 0D4 T cells, in acute and long-term control of MHV-68. These studies will provide important insight into differences in the mechanisms by which CD8 T cells mediate acute and long-term which acute and control control of persistent viral infections and may be of significant value in designing viral and in designing immunotherapeutic agents or vaccines to combat recurrent gammaherpesvirus infections Sarawar, Sally 1 c>. �-0 3,p C'(0 fl? can 0)3 CL) CSC BCD :cum ono o,-.o vo(Q chi �0= E I-- 0-0 II) 60, (00 ,�- �c' p-0 `ate.