PATHOGENESIS OF R5 HIV-1 ISOLATES

描述（来自申请人的摘要）：这是一份由Dr. 来自弗吉尼亚大学的大卫·卡梅里尼研究了CCR 5的作用--热带 HIV-1在HIV发病机制中的作用申请人将使用SCID-hu小鼠 人胸腺/肝移植模型，以研究 这些隔离物。既往表征的R5 HIV-1分离株来自于 艾滋病前和艾滋病阶段的HIV-1感染将被评估的分子 SCID-hu模型发病的决定因素和机制。R5-艾滋病前 HIV-I分离株对胸腺细胞无细胞病变，而R5-AIDS分离株引起 SCID-hu模型中胸腺细胞的耗竭。具体目标1是绘制 R5-AIDS的区域，其通过发展重组体而赋予致病性， 传染性病毒最初，重点将放在包膜基因上，因为它 具有细胞嗜性和细胞病变的分子决定因素。的 有待检验的假设是，env基因的变化解释了 增加这些分离株的致病潜力。具体目标2将 测试这些基因变化可能导致亲和力增加的假设， CCR 5和/或R5-AIDS分离株扩大的共受体使用。的 将测试重组病毒的受体使用。具体目标3 将测试HIV-1通过CCR 5介导的信号传导将允许 静息记忆T细胞和一些胸腺细胞的感染。

DESCRIPTION (from applicant's abstract): This is a revised application by Dr. David Camerini from the University of Virginia to study the role of CCR5-tropic HIV-1 isolates in HIV pathogenesis. The applicant will use the SCID-hu mouse model bearing human thymus/liver grafts to study the pathogenic effects of these isolates. Previously characterized R5 HIV-1 isolates from patients during pre-AIDS and AIDS stages of HIV-1 infection will be evaluated for the molecular determinants and mechanisms of pathogenesis in SCID-hu model. The R5-pre AIDS HIV-I isolates are not cytopathic to thymocytes whereas R5-AIDs isolates cause depletion of thymocytes in the SCID-hu model. The Specific aim 1 will be to map the regions of R5-AIDS which confer pathogenicity by developing recombinant infectious viruses. Initially, the focus will be on the envelope gene since it harbors molecular determinants for cell tropism and cytopathicity. The hypothesis to be tested is that changes in the env gene account for the increase in pathogenic potential of these isolates. The Specific aim 2 will test the hypothesis that these genetic changes could lead to increased affinity to CCR5 and/or broadened co-receptor usage by the R5-AIDs isolates. The recombinant viruses will be tested for the receptor usage. The Specific aim 3 will test the hypothesis that HIV-1 mediated signaling through CCR5 will allow infection of resting memory T cells and some thymocytes.