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