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

Ladinsky, Mark S. and Khamaikawin, Wannisa and Jung, Yujin and Lin, Samantha and Lam, Jennifer and An, Dong Sung and Bjorkman, Pamela J. and Kieffer, Collin (2019) Mechanisms of virus dissemination in bone marrow of HIV-1-infected humanized BLT mice. eLife, 8 . Art. No. e46916. ISSN 2050-084X. PMCID PMC6839903. https://resolver.caltech.edu/CaltechAUTHORS:20191105-112449359

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.7554/elife.46916DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839903/PubMed CentralArticle
ORCID:
AuthorORCID
Ladinsky, Mark S.0000-0002-1036-3513
Bjorkman, Pamela J.0000-0002-2277-3990
Kieffer, Collin0000-0001-9051-3819
Additional Information:© 2019 eLife Sciences Publications Ltd. Subject to a Creative Commons Attribution license, except where otherwise noted. Data availability: Source data files have been provided for graphs from Figure 1. We thank Andres Collazo at the Caltech Biological Imaging Facility for use of confocal and light sheet microscopes and help with image capture and analysis, Carol Garland and the Caltech Kavli Nanoscience Institute for aid in maintaining the TF30 electron microscope, and the Gordon and Betty Moore and Beckman Foundations for gifts to Caltech to support electron microscopy. This research was supported by the Rosalind W. Alcott post-doctoral fellowship (Caltech) and startup funding from the University of Illinois at Urbana-Champaign School of Molecular and Cellular Biology (C.K.), NIAID 1R01AI100652-01A1, the UCLA AIDS Institute, and the UCLA Center for AIDS Research NIH/NIAID AI028697 (D.S.A.), and the National Institute of General Medical Sciences (2 P50 GM082545-08) and California HIV/AIDS Research Program (ID15-CT-017) (P.J.B.) The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. The opinions, findings, and conclusions herein are those of the authors and do not necessarily represent those of The Regents of the University of California, or any of its programs. The authors declare no competing interests.
Group:Kavli Nanoscience Institute
Funders:
Funding AgencyGrant Number
Gordon and Betty Moore FoundationUNSPECIFIED
Arnold and Mabel Beckman FoundationUNSPECIFIED
CaltechUNSPECIFIED
University of Illinois Urbana-ChampaignUNSPECIFIED
NIH1R01AI100652-01A1
UCLAUNSPECIFIED
NIHAI028697
NIH2 P50 GM082545-08
California HIV/AIDS Research ProgramID15-CT-017
PubMed Central ID:PMC6839903
Record Number:CaltechAUTHORS:20191105-112449359
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20191105-112449359
Official Citation:Mechanisms of virus dissemination in bone marrow of HIV-1-infected humanized BLT mice. eLife 2019; 8:e46916. DOI: 10.7554/eLife.46916
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:99678
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:05 Nov 2019 20:39
Last Modified:05 Dec 2019 21:31

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