MHC CLASS I ANTIHIV SPECIFIC CD8 T LYMPHOCYTE RESPONSE IN CNS OF HIV PATIENTS

申请人实验室的最新发现表明，脑脊液中HIV-1RNA浓度的降低与神经心理测试成绩的改善密切相关。这些结果为HIV-1病毒载量在艾滋病痴呆综合征(ADC)发病机制中的作用提供了进一步的证据。这项合作研究的总体目标是确定MHC I类限制性、抗HIV-1特异性CD8+细胞毒性T淋巴细胞(CTL)反应在控制中枢神经系统内HIV-1复制中的作用。有人建议进行研究，以检验工作假设，即艾滋病毒相关的认知障碍是由于失去对中枢神经系统内艾滋病毒-1复制的控制，这种失去控制是病毒逃避CTL反应的结果，以及病毒逃避免疫控制导致在ADC患者的中枢神经系统内选择独特的艾滋病毒-1毒株。该项目将在夏威夷大学和华盛顿大学的研究人员之间进行综合和协调的合作。该项目的申请者部分将侧重于确定HIV-1感染者中枢神经系统中HIV-1特异性CTL反应的特征，并确定CNS来源的HIV-1毒株表位序列的变化是否影响对此类表位的识别、认知障碍和脑脊液HIV-1病毒载量。将在这两个组成部分中检验的假设与实验设计密切相关，并将使调查的补充专门知识能够以最大限度地产生成效和互惠互利的方式应用。合作还将为夏威夷大学的学生和研究员提供充分的机会，以获得将在开展这项研究工作中实施的基本神经科学技术方面的培训。这项研究的结果将有助于理解MHC-1类限制性、抗HIV特异性的CD8+CTL在中枢神经系统内控制HIV-1RNA病毒载量中的作用，并将有助于理解脑脊液HIV-1病毒载量与AIDS痴呆复合体发病机制的关系。

Recent findings from the applicant's laboratories have demonstrated that decreases in CSF HIV-1 RNA concentration are strongly associated with improvement in neuropsychological test performance. These results provide further evidence for the role of HIV-1 viral load in the pathogenesis of AIDS dementia complex (ADC). The general goal of the collaborative research proposed is to define the role of MHC class I- restricted, anti-HIV-1 specific CD8+ cytotoxic T lymphocyte (CTL) responses in the control of HIV-1 replication within the CNS. Studies are proposed to test the working hypothesis that HIV-associated cognitive impairment is due to loss of control of HIV-1 replication within the CNS, that this loss of control is a consequence of viral escape from CTL responses, and that viral escape from immune control results in selection for unique strains of HIV-1 within the CNS of patients with ADC. The project will be conducted as an integrated and coordinated collaboration between investigators at the University of Hawaii and the University of Washington. The applicant component of the project will focus on characterizing HIV-1-specific CTL responses in the CNS of HIV-1 infected subjects, and determining whether changes in epitotic sequences of CNS-derived HIV-1 strains affect recognition of such epitopes, cognitive dysfunction, and CSF HIV-1 viral load. The hypotheses to be tested in both components are closely interrelated as are the experimental designs, and will allow for the complementary expertise of the investigations to be applied in a maximally productive and mutually beneficial way. The collaboration will also provide ample opportunities for students and fellows at the University of Hawaii to obtain training in the basic neuroscience techniques to be implemented in the conduct of this research efforts. The results of the proposed research will be relevant to understand the role of MHC class 1-restricted, anti-HIV-specific CD8+ CTL in controlling HIV-1 RNA viral load within the CNS, and will contribute to understanding the relationship between CSF HIV-1 viral load and the pathogenesis of AIDS dementia complex.