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Journal of Cell Communication and Signaling

, Volume 13, Issue 2, pp 209–224 | Cite as

Myosin-X is essential to the intercellular spread of HIV-1 Nef through tunneling nanotubes

  • Jaime Uhl
  • Shivalee Gujarathi
  • Abdul A. Waheed
  • Ana Gordon
  • Eric O. Freed
  • Karine GoussetEmail author
Research Article
  • 268 Downloads

Abstract

Tunneling nanotubes (TNTs) are intercellular structures that allow for the passage of vesicles, organelles, genomic material, pathogenic proteins and pathogens. The unconventional actin molecular motor protein Myosin-X (Myo10) is a known inducer of TNTs in neuronal cells, yet its role in other cell types has not been examined. The Nef HIV-1 accessory protein is critical for HIV-1 pathogenesis and can self-disseminate in culture via TNTs. Understanding its intercellular spreading mechanism could reveal ways to control its damaging effects during HIV-1 infection. Our goal in this study was to characterize the intercellular transport mechanism of Nef from macrophages to T cells. We demonstrate that Nef increases TNTs in a Myo10-dependent manner in macrophages and observed the transfer of Nef via TNTs from macrophages to T cells. To quantify this transfer mechanism, we established an indirect flow cytometry assay. Since Nef expression in T cells down-regulates the surface receptor CD4, we correlated the decrease in CD4 to the transfer of Nef between these cells. Thus, we co-cultured macrophages expressing varying levels of Nef with a T cell line expressing high levels of CD4 and quantified the changes in CD4 surface expression resulting from Nef transfer. We demonstrate that Nef transfer occurs via a cell-to-cell dependent mechanism that directly correlates with the presence of Myo10-dependent TNTs. Thus, we show that Nef can regulate Myo10 expression, thereby inducing TNT formation, resulting in its own transfer from macrophages to T cells. In addition, we demonstrate that up-regulation of Myo10 induced by Nef also occurs in human monocyte derived macrophages during HIV-1 infection.

Keywords

Tunneling nanotubes TNTs Myosin-X Myo10 HIV-1 Nef Intercellular transfer 

Abbreviations

TNTs

Tunneling nanotubes

Myo10

Myosin-X

Notes

Acknowledgments

N5 Raw cells from Dr. D.A. Mann were obtained through the Centre for AIDS Reagents in the UK. CEM-T4 cells from Dr. J.P. Jacobs and HeLa cells from Dr. R. Axel were obtained through the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH. The Nef-GFP plasmid was a gift from Dr. Jimmy D. Dikeakos (Department of Microbiology and Immunology, Western University, London, Ontario, Canada). This work was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number SC2GM111144. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. AG was supported by the Fundación Alfonso Martín Escudero.

Supplementary material

12079_2018_493_MOESM1_ESM.pdf (1.8 mb)
Supplementary Fig. 1 (PDF 1843 kb)

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Copyright information

© The International CCN Society 2018

Authors and Affiliations

  1. 1.Biology DepartmentCalifornia State University FresnoFresnoUSA
  2. 2.HIV Dynamics and Replication ProgramNational Cancer Institute–FrederickFrederickUSA

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