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

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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.

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

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Mark S Ladinsky

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States

Competing interests
No competing interests declared.
Wannisa Khamaikawin

School of Nursing, UCLA AIDS Institute, University of California, Los Angeles, Los Angeles, United States

Competing interests
No competing interests declared.
Yujin Jung

School of Nursing, UCLA AIDS Institute, University of California, Los Angeles, Los Angeles, United States

Competing interests
No competing interests declared.
Samantha Lin

School of Nursing, UCLA AIDS Institute,, University of California, Los Angeles, Los Angeles, United States

Competing interests
No competing interests declared.
Jennifer Lam

School of Nursing, UCLA AIDS Institute, University of California, Los Angeles, Los Angeles, United States

Competing interests
No competing interests declared.
Dong Sung An

School of Nursing, UCLA AIDS Institute, University of California, Los Angeles, Los Angeles, United States

Competing interests
No competing interests declared.
Pamela J Bjorkman

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States

Competing interests
Pamela J Bjorkman, Reviewing editor, eLife.

"This ORCID iD identifies the author of this article:" 0000-0002-2277-3990
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.

"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.

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).

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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.