Do Thao, Murphy Gavin, Earl Lesley A, Del Prete Gregory Q, Grandinetti Giovanna, Li Guan-Han, Estes Jacob D, Rao Prashant, Trubey Charles M, Thomas James, Spector Jeffrey, Bliss Donald, Nath Avindra, Lifson Jeffrey D, Subramaniam Sriram
Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, Maryland, USA.
J Virol. 2014 Sep;88(18):10327-39. doi: 10.1128/JVI.00788-14. Epub 2014 Jun 25.
HIV transmission efficiency is greatly increased when viruses are transmitted at virological synapses formed between infected and uninfected cells. We have previously shown that virological synapses formed between HIV-pulsed mature dendritic cells (DCs) and uninfected T cells contain interdigitated membrane surfaces, with T cell filopodia extending toward virions sequestered deep inside invaginations formed on the DC membrane. To explore membrane structural changes relevant to HIV transmission across other types of intercellular conjugates, we used a combination of light and focused ion beam scanning electron microscopy (FIB-SEM) to determine the three-dimensional (3D) architectures of contact regions between HIV-1-infected CD4(+) T cells and either uninfected human CD4(+) T cells or human fetal astrocytes. We present evidence that in each case, membrane extensions that originate from the uninfected cells, either as membrane sheets or filopodial bridges, are present and may be involved in HIV transmission from infected to uninfected cells. We show that individual virions are distributed along the length of astrocyte filopodia, suggesting that virus transfer to the astrocytes is mediated, at least in part, by processes originating from the astrocyte itself. Mechanisms that selectively disrupt the polarization and formation of such membrane extensions could thus represent a possible target for reducing viral spread.
Our findings lead to new insights into unique aspects of HIV transmission in the brain and at T cell-T cell synapses, which are thought to be a predominant mode of rapid HIV transmission early in the infection process.
当病毒在受感染细胞与未受感染细胞之间形成的病毒学突触处传播时，HIV传播效率会大大提高。我们之前已经表明，在HIV脉冲成熟树突状细胞（DC）与未受感染T细胞之间形成的病毒学突触包含相互交错的膜表面，T细胞丝状伪足向隔离在DC膜上形成的内陷深处的病毒粒子延伸。为了探索与HIV跨其他类型细胞间结合物传播相关的膜结构变化，我们结合使用了光学显微镜和聚焦离子束扫描电子显微镜（FIB-SEM）来确定HIV-1感染的CD4(+) T细胞与未受感染的人类CD4(+) T细胞或人类胎儿星形胶质细胞之间接触区域的三维（3D）结构。我们提供的证据表明，在每种情况下，源自未受感染细胞的膜延伸，无论是作为膜片还是丝状伪足桥，都存在并且可能参与HIV从受感染细胞向未受感染细胞的传播。我们表明，单个病毒粒子沿着星形胶质细胞丝状伪足的长度分布，这表明病毒向星形胶质细胞的转移至少部分是由源自星形胶质细胞本身的过程介导的。因此，选择性破坏这种膜延伸的极化和形成的机制可能代表了减少病毒传播的一个可能靶点。
我们的发现为HIV在大脑和T细胞 - T细胞突触中的独特传播方面带来了新的见解，而T细胞 - T细胞突触被认为是感染早期快速HIV传播的主要模式。
