PATHOGENESIS OF R5 HIV-1 ISOLATES

描述(摘自申请者的摘要)：这是一份由Dr。 来自弗吉尼亚大学的David Camerini研究CCR5趋向性的作用 HIV-1分离株在HIV发病机制中的作用。申请者将使用SCID-HU鼠标 人胸腺/肝移植模型的建立及其致病作用研究 这些分离物。以前从患者身上分离的R5 HIV-1毒株 将对艾滋病前期和艾滋病阶段的HIV-1感染进行分子评估 SCID-HU模型的决定因素和发病机制。R5-Pre AIDS HIV-I分离株对胸腺细胞不产生细胞病变，而R5-AIDS分离株可导致 SCID-HU模型中胸腺细胞的耗竭。具体目标1将是绘制 R5-AIDS通过发展重组的致病作用区域 传染性病毒。最初，重点将放在包膜基因上，因为它 含有细胞趋向性和细胞致病性的分子决定因素。这个 需要检验的假设是env基因的变化解释了 这些分离株的致病潜力增加。具体目标2将 检验这些基因变化可能导致亲和力增加的假设 与CCR5和/或扩大R5-AIDS分离株的共同受体使用有关。这个 重组病毒将接受受体用途测试。具体目标3 将测试HIV-1通过CCR5介导的信号将允许 静息记忆T细胞和部分胸腺细胞感染。

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.