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

  1. Mark S Ladinsky
  2. Wannisa Khamaikawin
  3. Yujin Jung
  4. Samantha Lin
  5. Jennifer Lam
  6. Dong Sung An
  7. Pamela J Bjorkman
  8. Collin Kieffer  Is a corresponding author
  1. California Institute of Technology, United States
  2. University of California, Los Angeles, United States
  3. University of Illinois at Urbana-Champaign, United States

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.

Data availability

Source data files have been provided for graphs from Figure 1.

Article and author information

Author details

  1. Mark S Ladinsky

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    Competing interests
    No competing interests declared.
  2. Wannisa Khamaikawin

    School of Nursing, UCLA AIDS Institute, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.
  3. Yujin Jung

    School of Nursing, UCLA AIDS Institute, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.
  4. Samantha Lin

    School of Nursing, UCLA AIDS Institute,, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.
  5. Jennifer Lam

    School of Nursing, UCLA AIDS Institute, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.
  6. Dong Sung An

    School of Nursing, UCLA AIDS Institute, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.
  7. Pamela J Bjorkman

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    Competing interests
    Pamela J Bjorkman, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2277-3990
  8. Collin Kieffer

    Department of Microbiology, University of Illinois at Urbana-Champaign, Urbana, United States
    For correspondence
    collink@illinois.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9051-3819

Funding

National Institute of Allergy and Infectious Diseases (1R01AI100652-01A1)

  • Dong Sung An

National Institute of Allergy and Infectious Diseases (AI028697)

  • Dong Sung An

National Institute of General Medical Sciences (2 P50 GM082545-08)

  • Pamela J Bjorkman

California HIV/AIDS Research Program (ID15-CT-017)

  • Pamela J Bjorkman

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Julie Overbaugh, Fred Hutchinson Cancer Research Center, United States

Ethics

Animal experimentation: Animals were maintained at the UCLA CFAR Humanized Mouse Core laboratory in accordance with a protocol approved by the UCLA Animal Research Committee. Experiments conformed to all relevant regulatory standards.(UCLA ARC # 2007-092-41A).

Version history

  1. Received: March 15, 2019
  2. Accepted: October 27, 2019
  3. Accepted Manuscript published: October 28, 2019 (version 1)
  4. Version of Record published: November 8, 2019 (version 2)

Copyright

© 2019, Ladinsky et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Mark S Ladinsky
  2. Wannisa Khamaikawin
  3. Yujin Jung
  4. Samantha Lin
  5. Jennifer Lam
  6. Dong Sung An
  7. Pamela J Bjorkman
  8. Collin Kieffer
(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

Share this article

https://doi.org/10.7554/eLife.46916

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