HIV-1 Nef interferes with T-lymphocyte circulation through confined environments in vivo

Stolp, Bettina; Imle, Andrea; Coelho, Fernanda Matos; Hons, Miroslav; Gorina, Roser; Lyck, Ruth; Stein, Jens V; Fackler, Oliver T (2012). HIV-1 Nef interferes with T-lymphocyte circulation through confined environments in vivo. Proceedings of the National Academy of Sciences of the United States of America - PNAS, 109(45), pp. 18541-6. Washington, D.C.: National Academy of Sciences NAS 10.1073/pnas.1204322109

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HIV-1 negative factor (Nef) elevates virus replication and contributes to immune evasion in vivo. As one of its established in vitro activities, Nef interferes with T-lymphocyte chemotaxis by reducing host cell actin dynamics. To explore Nef's influence on in vivo recirculation of T lymphocytes, we assessed lymph-node homing of Nef-expressing primary murine lymphocytes and found a drastic impairment in homing to peripheral lymph nodes. Intravital imaging and 3D immunofluorescence reconstruction of lymph nodes revealed that Nef potently impaired T-lymphocyte extravasation through high endothelial venules and reduced subsequent parenchymal motility. Ex vivo analyses of transendothelial migration revealed that Nef disrupted T-lymphocyte polarization and interfered with diapedesis and migration in the narrow subendothelial space. Consistently, Nef specifically affected T-lymphocyte motility modes used in dense environments that pose high physical barriers to migration. Mechanistically, inhibition of lymph node homing, subendothelial migration and cell polarization, but not diapedesis, depended on Nef's ability to inhibit host cell actin remodeling. Nef-mediated interference with in vivo recirculation of T lymphocytes may compromise T-cell help and thus represents an important mechanism for its function as a HIV pathogenicity factor.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Theodor Kocher Institute

UniBE Contributor:

Stolp, Bettina; Hons, Miroslav; Lyck, Ruth and Stein, Jens Volker

ISSN:

0027-8424

Publisher:

National Academy of Sciences NAS

Funders:

[4] Swiss National Science Foundation
[7] Swiss Multiple Sclerosis Society

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:36

Last Modified:

17 Mar 2015 21:27

Publisher DOI:

10.1073/pnas.1204322109

PubMed ID:

23093676

Web of Science ID:

000311156700066

URI:

https://boris.unibe.ch/id/eprint/14686 (FactScience: 221785)

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