HERPES SIMPLEX VIRUS IMMUNE EVASION IN HIV SUBJECTS

描述：（由申请人提供）在HIV感染个体中，HSV 随着CD 4 T细胞计数的减少，感染的频率和严重程度增加。这 本申请提出了一种新的策略，通过改善 抗体和补体（C）在宿主防御中的有效性。HSV-1使用 规避抗体和C攻击的隐形策略。HSV-1糖蛋白gC 在C级联的几个步骤中干扰C激活，使C 对病毒无效。然而，如果结合C3的关键gC结构域 当从病毒中删除时，C将HSV-1毒力降低50至100倍。HSV-1 糖蛋白gE通过结合IgG Fc结构域并阻断抗体， Fc介导的活性，包括C活化和抗体依赖性细胞免疫调节。 细胞毒不能结合IgG Fc结构域的HSV-1 gE突变病毒为50 由于增强的抗体， 有效性申请人构建了在gC和gC两者上都改变的突变体病毒。 gE并证明这些糖蛋白协同作用以逃避抗体 和C攻击，因为gC-gE双突变病毒的1,000- 10,000倍 比野生型病毒毒力更强。作为宾夕法尼亚大学CFAR计划的一部分， 1999年建立了患者登记和标本库， 在宾州诊所接受治疗的受试者。申请人将分析血清样本 以确定HIV受试者是否保持 足够水平的HSV抗体和C以中和突变型HSV-1菌株 在gC和gE免疫逃避中有缺陷。他们假设大多数人 的HIV/HSV-1合并感染受试者将维持足够的抗体和C 中和比野生型病毒多至少100倍的gC-gE突变体的滴度。 根据初步结果，他们假设， 天然HSV-1感染不能阻止gC和gE免疫逃避，因为 所涉及的域对主机是“隐藏的”。因此，他们建议修改 gC和gE免疫逃避结构域以提高免疫原性。他们将测试这些 在小鼠模型中作为疫苗候选物的改变的蛋白质，以确定 产生的抗体阻断gC和gE免疫逃避， 严重性。CD 4基因敲除小鼠将用于研究抗体和C 如果病毒免疫缺陷， 逃避防止病毒隐身可能会大大提高抗体和C活性 在HIV受试者中，并可能为发展HSV和其他疾病提供新的策略。 病毒疫苗

DESCRIPTION: (Provided by the Applicant) In HIV infected individuals, HSV infections increase in frequency and severity as CD4 T cells counts wane. This application proposes a novel strategy to control HSV-1 infection by improving the effectiveness of antibody and complement (C) in host defense. HSV-1 uses stealth strategies to evade antibody and C attack. HSV-1 glycoprotein gC interferes with C activation at several steps in the C cascade, rendering C ineffective against the virus. However, if a critical gC domain that binds C3 is deleted from the virus, C reduces HSV-1 virulence 50- to 100-fold. HSV-1 glycoprotein gE evades antibody by binding the IgG Fc domain and blocking Fc-mediated activities, including C activation and antibody-dependent cellular cytotoxicity. An HSV-1 gE mutant virus unable to bind the IgG Fc domain is 50 to 100-fold less virulent than wild-type virus because of enhanced antibody effectiveness. The applicants constructed a mutant virus altered in both gC and gE and demonstrate that these glycoproteins act in synergy to evade antibody and C attack, since the gC-gE double mutant virus is 1,000- to 10,000-fold less virulent than wild-type virus. As part of the CFAR initiative at Penn, an HIV patient registry and specimen repository was developed in 1999 to enroll subjects cared for at Penn clinics. The applicants will analyze serum samples obtained from the repository to determine whether HIV subjects maintain adequate levels of HSV antibodies and C to neutralize a mutant HSV-1 strain that is defective in gC and gE immune evasion. They postulate that the majority of HIV/HSV-1 co-infected subjects will maintain sufficient antibody and C titers to neutralize at least 100-fold more gC-gE mutant than wild-type virus. Based on preliminary results, they postulate that antibodies produced during natural HSV-1 infection cannot prevent gC and gE immune evasion because the domains involved are "hidden" from the host. Therefore, they propose to modify gC and gE immune evasion domains to improve immunogencity. They will test these altered proteins as vaccine candidates in murine models to determine whether the antibodies produced block gC and gE immune evasion and reduce disease severity. CD4-knockout mice will be used to investigate whether antibody and C can compensate for waning CD4 T cell immunity if virus is defective in immune evasion. Preventing viral stealth may greatly improve antibody and C activities in HIV subjects, and may offer a novel strategy for developing HSV and other viral vaccines.