HILDRETH, JAMES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我们之前的工作和其他人的工作清楚地表明了胆固醇在艾滋病毒复制中发挥的重要作用。我们已经证明，一种胆固醇隔离剂倍他环糊精作为艾滋病毒微生物剂具有重要的前景。到目前为止，胆固醇在艾滋病毒生物学中的重要性是基于这种脂质在膜生物学中所起的作用，包括生物膜的融合。在过去的一年里，我们获得了胆固醇可能对艾滋病毒转录也有直接影响的证据。我们的结果表明，与胆固醇合成相关基因的表达共同调节的转录因子直接激活HIV基因的转录。这些结果表明，细胞和组织中的胆固醇水平可能在基因转录水平上影响艾滋病毒的复制。此外，这些结果对与使用抗逆转录病毒药物相关的脂肪营养不良有重要意义，其中一些药物深刻地干扰了脂质同化。他汀类药物对HIV释放和HIV蛋白质合成的矛盾效应也可以通过这一新的观察得到部分解释。这些研究已经在细胞系和原代细胞中进行，证实了在体内观察的潜在重要性。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our previous work and that of others clearly demonstrate the important role cholesterol plays in the replication of HIV. We have shown that a cholesterol-sequestering agent betacyclodextrin holds significant promise as an HIV microbicide. The importance of cholesterol in HIV biology to this point has been based on the role this lipid plays in membrane biology, including the fusion of biological membranes. Over the last year we have obtained evidence that cholesterol may have a direct effect on HIV transcription as well. Our results indicate that a transcription factor whose expression is co-regulated with that of genes related to cholesterol synthesis directly activates HIV gene transcription. These results indicate that cholesterol levels in cells and tissues may impact HIV replication at the level of gene transcription. Furthermore, the results have significant implications for lipodystrophy associated with the use of anti-retroviral drugs some of which profoundly disturb lipid homoestasis. The paradoxical effects of statins on HIV release and HIV protein synthesis may also be explained in part by this novel observation. These studies have been carried out in both cell lines and primary cells confirming the potential importance of this observation in vivo.