Mechanisms of virus dissemination in bone marrow of HIV-1–infected humanized BLT mice

Mark S. Ladinsky, Wannisa Khamaikawin, Yujin Jung, Samantha Lin, Jennifer Lam, Dong Sung An, Pamela J. Bjorkman, Collin Kieffer

Research output: Contribution to journalArticle

Abstract

Immune progenitor cells differentiate in bone marrow (BM) and then migrate to tissues. HIV-1 infects multiple BM cell types, but virus dissemination within BM has been poorly understood. We used light microscopy and electron tomography to elucidate mechanisms of HIV-1 dissemination within BM of HIV-1–infected BM/thymus/liver (BLT) mice. Tissue clearing combined with confocal and light sheet fluorescence microscopy revealed distinct populations of HIV-1 p24-producing cells in BM early after infection, and quantification of these populations identified macrophages as the principal subset of virus-producing cells in BM over time. Electron tomography demonstrated three modes of HIV-1 dissemination in BM: (i) semi-synchronous budding from T-cell and macrophage membranes, (ii) mature virus association with virus-producing T-cell uropods contacting putative target cells, and (iii) macrophages engulfing HIV-1–producing T-cells and producing virus within enclosed intracellular compartments that fused to invaginations with access to the extracellular space. These results illustrate mechanisms by which the specialized environment of the BM can promote virus spread locally and to distant lymphoid tissues.

Original languageEnglish (US)
Article numbere46916
JournaleLife
Volume8
DOIs
StatePublished - Oct 2019

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ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Ladinsky, M. S., Khamaikawin, W., Jung, Y., Lin, S., Lam, J., An, D. S., Bjorkman, P. J., & Kieffer, C. (2019). Mechanisms of virus dissemination in bone marrow of HIV-1–infected humanized BLT mice. eLife, 8, [e46916]. https://doi.org/10.7554/eLife.46916