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详细描述原发性人巨噬细胞中 HIV-1 复制动力学的早期特征。

Detailed Characterization of Early HIV-1 Replication Dynamics in Primary Human Macrophages.

机构信息

Department of Infectious Diseases, Virology, University of Heidelberg, 69120 Heidelberg, Germany.

AIDS Research Institute IrsiCaixa, Institut d'Investigació en Cièncias de la Salut Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, Spain.

出版信息

Viruses. 2018 Nov 10;10(11):620. doi: 10.3390/v10110620.

DOI:10.3390/v10110620
PMID:30423802
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6266216/
Abstract

Macrophages are natural target cells of human immunodeficiency virus type 1 (HIV-1). Viral replication appears to be delayed in these cells compared to lymphocytes; however, little is known about the kinetics of early post-entry events. Time-of-addition experiments using several HIV-1 inhibitors and the detection of reverse transcriptase (RT) products with droplet digital PCR (ddPCR) revealed that early replication was delayed in primary human monocyte-derived macrophages of several donors and peaked late after infection. Direct imaging of reverse-transcription and pre-integration complexes (RTC/PIC) by click-labeling of newly synthesized DNA further confirmed our findings and showed a concomitant shift to the nuclear stage over time. Altering the entry pathway enhanced infectivity but did not affect kinetics of viral replication. The addition of viral protein X (Vpx) enhanced productive infection and accelerated completion of reverse transcription and nuclear entry. We propose that sterile alpha motif (SAM) and histidine/aspartate (HD) domain-containing protein 1 (SAMHD1) activity lowering deoxyribonucleotide triphosphate (dNTP) pools is the principal factor delaying early HIV-1 replication in macrophages.

摘要

巨噬细胞是人类免疫缺陷病毒 1 型（HIV-1）的天然靶细胞。与淋巴细胞相比，病毒在这些细胞中的复制似乎被延迟；然而，关于早期进入后事件的动力学知之甚少。使用几种 HIV-1 抑制剂进行的添加时间实验和使用液滴数字 PCR（ddPCR）检测逆转录酶（RT）产物表明，几位供体的原代人单核细胞衍生巨噬细胞中的早期复制被延迟，并且在感染后很晚才达到峰值。通过新合成 DNA 的点击标记对逆转录和预整合复合物（RTC/PIC）的直接成像进一步证实了我们的发现，并显示随着时间的推移向核阶段的伴随转移。改变进入途径可增强感染性，但不影响病毒复制的动力学。病毒蛋白 X（Vpx）的添加增强了有性感染并加速了逆转录和核进入的完成。我们提出，无活性α基序（SAM）和组氨酸/天冬氨酸（HD）结构域包含蛋白 1（SAMHD1）降低脱氧核糖核苷酸三磷酸（dNTP）池的活性是延迟巨噬细胞中 HIV-1 早期复制的主要因素。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9709/6266216/27f0d7e5dd9e/viruses-10-00620-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9709/6266216/423e0dbcac54/viruses-10-00620-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9709/6266216/d62341bcf91f/viruses-10-00620-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9709/6266216/e3e65a134774/viruses-10-00620-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9709/6266216/c6b0932c7fde/viruses-10-00620-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9709/6266216/27f0d7e5dd9e/viruses-10-00620-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9709/6266216/423e0dbcac54/viruses-10-00620-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9709/6266216/2bc1ba0d6b48/viruses-10-00620-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9709/6266216/e2c83bf495e7/viruses-10-00620-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9709/6266216/d62341bcf91f/viruses-10-00620-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9709/6266216/e3e65a134774/viruses-10-00620-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9709/6266216/c6b0932c7fde/viruses-10-00620-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9709/6266216/27f0d7e5dd9e/viruses-10-00620-g007.jpg

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