Abstract
BackgroundViral 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.MethodsWe 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.ResultsCCR5-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.ConclusionsThese 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.
Highlights
Viral reprogramming of host cells enhances replication and is initiated by viral interaction with the cell surface
Phosphoproteomics of CCR5‐tropic human immunodeficiency virus (HIV) signaling in primary memory CD4+ T cells HIV-1 binding to the cell surface induces signals within CD4+ T cells that have been characterized primarily using biochemical approaches [18,19,20,21,22,23,24,25,26]
CXCR4 is expressed on the majority of CD4+ T cells [29]; CXCR4-tropic HIV-1 variants account for only a fraction of viruses worldwide and almost none that are involved in transmission and early infection [2,3,4,5,6,7]
Summary
Viral reprogramming of host cells enhances replication and is initiated by viral interaction with the cell surface. HIV-1 enters cells via the interactions of gp120 with its primary receptor, CD4, and a coreceptor, typically CCR5 or CXCR4 for most clinical isolates. These events lead to conformational changes in gp120 that expose the fusion peptide of gp and lead to host and viral membrane fusion via the formation of an energetically favorable sixhelix bundle conformation (reviewed in [1]). Rac and cofilin activation by HIV enhances viral entry into cells [22, 26], indicating that signaling through CD4 and coreceptor can induce rapid changes in cells that promote viral replication. Signaling by HIV can have longer-acting effects on the cellular environment: PI3 K activation by HIV was found to enhance infection via a post-entry step prior to integration [19] and, more recently, a phosphoproteomic screen demonstrated that CXCR4-tropic HIV causes extensive alterations to the cellular microenvironment including to the splicing factor SRm300 (SRRM2) that enhances viral production by regulating alternative splicing of HIV mRNAs [27]
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