Author ORCID Identifier

Mark R. Chance

John C. Tilton

Document Type

Article

Publication Date

7-3-2018

Abstract

Background: Viral reprogramming of host cells enhances replication and is initiated by viral interaction with the cell surface. Upon human immunodeficiency virus (HIV) binding to CD4+ T cells, a signal transduction cascade is initiated that reorganizes the actin cytoskeleton, activates transcription factors, and alters mRNA splicing pathways. Methods: We used a quantitative mass spectrometry-based phosphoproteomic approach to investigate signal transduction cascades initiated by CCR5-tropic HIV, which accounts for virtually all transmitted viruses and the vast majority of viruses worldwide. Results: CCR5-HIV signaling induced significant reprogramming of the actin cytoskeleton and mRNA splicing pathways, as previously described. In addition, CCR5-HIV signaling induced profound changes to the mRNA transcription, processing, translation, and post-translational modifications pathways, indicating that virtually every stage of protein production is affected. Furthermore, we identified two kinases regulated by CCR5-HIV signaling-p70-S6K1 (RPS6KB1) and MK2 (MAPKAPK2)-that were also required for optimal HIV infection of CD4+ T cells. These kinases regulate protein translation and cytoskeletal architecture, respectively, reinforcing the importance of these pathways in viral replication. Additionally, we found that blockade of CCR5 signaling by maraviroc had relatively modest effects on CCR5-HIV signaling, in agreement with reports that signaling by CCR5 is dispensable for HIV infection but in contrast to the critical effects of CXCR4 on cortical actin reorganization. Conclusions: These results demonstrate that CCR5-tropic HIV induces significant reprogramming of host CD4+ T cell protein production pathways and identifies two novel kinases induced upon viral binding to the cell surface that are critical for HIV replication in host cells.

Keywords

CCR5, HIV-1, phosphoproteomics, post-translational modifications, signaling, splicing, transcription, translation

Publication Title

Retrovirology

Volume

15

Grant

P30 AI036219; R21AI113148; R01GM117208; 4UL1TR000439

Funder

Case Western Reserve University/University Hospitals Centers for AIDS Research; National Institutes of Health (NIH); Clinical and Translation Science Collaborative of Cleveland

Creative Commons License

Creative Commons Attribution 4.0 International License
This work is licensed under a Creative Commons Attribution 4.0 International License.

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10.1186/s12977-018-0423-4" data-hide-no-mentions="true">
10.1186/s12977-018-0423-4" data-hide-zero-citations="true" data-style="small_circle">
 
 

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