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Role of TIM-4 in exosome-dependent entry of HIV-1 into human immune cells

Authors Sims B, Farrow AL, Williams SD, Bansal A, Krendelchtchikov A, Gu L, Matthews QL

Received 19 January 2017

Accepted for publication 4 April 2017

Published 6 July 2017 Volume 2017:12 Pages 4823—4833


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 3

Editor who approved publication: Dr Thomas Webster

Brian Sims,1–3,* Anitra L Farrow,4,* Sparkle D Williams,1,2 Anju Bansal,4 Alexandre Krendelchtchikov,1,2,4 Linlin Gu,5 Qiana L Matthews3,4,6

1Division of Neonatology, Department of Pediatrics, 2Department of Cell, Developmental and Integrative Biology, 3Center for AIDS Research, 4Division of Infectious Diseases, 5Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, 6Microbiology Program, Department of Biological Sciences, College of Science, Technology, Engineering and Mathematics, Alabama State University, Montgomery, AL, USA

*These authors contributed equally to this work

Abstract: Exosomes, 30–200 nm nanostructures secreted from donor cells and internalized by recipient cells, can play an important role in the cellular entry of some viruses. These microvesicles are actively secreted into various body fluids, including blood, urine, saliva, cerebrospinal fluid, and breast milk. We successfully isolated exosomes from human breast milk and plasma. The size and concentration of purified exosomes were measured by nanoparticle tracking, while Western blotting confirmed the presence of the exosomal-associated proteins CD9 and CD63, clathrin, and T cell immunoglobulin and mucin proteins (TIMs). Through viral infection assays, we determined that HIV-1 utilizes an exosome-dependent mechanism for entry into human immune cells. The virus contains high amounts of phosphatidylserine (PtdSer) and may bind PtdSer receptors, such as TIMs. This mechanism is supported by our findings that exosomes from multiple sources increased HIV-1 entry into T cells and macrophages, and viral entry was potently blocked with anti-TIM-4 antibodies.

Keywords: exosomes, HIV-1, T cell immunoglobulin and mucin proteins, phosphatidylserine, nanoparticle tracking analysis

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