Publication Date:
2012-08-03
Description:
After host entry through mucosal surfaces, human immunodeficiency virus-1 (HIV-1) disseminates to lymphoid tissues to establish a generalized infection of the immune system. The mechanisms by which this virus spreads among permissive target cells locally during the early stages of transmission and systemically during subsequent dissemination are not known. In vitro studies suggest that the formation of virological synapses during stable contacts between infected and uninfected T cells greatly increases the efficiency of viral transfer. It is unclear, however, whether T-cell contacts are sufficiently stable in vivo to allow for functional synapse formation under the conditions of perpetual cell motility in epithelial and lymphoid tissues. Here, using multiphoton intravital microscopy, we examine the dynamic behaviour of HIV-infected T cells in the lymph nodes of humanized mice. We find that most productively infected T cells migrate robustly, resulting in their even distribution throughout the lymph node cortex. A subset of infected cells formed multinucleated syncytia through HIV envelope-dependent cell fusion. Both uncoordinated motility of syncytia and adhesion to CD4(+) lymph node cells led to the formation of long membrane tethers, increasing cell lengths to up to ten times that of migrating uninfected T cells. Blocking the egress of migratory T cells from the lymph nodes into efferent lymph vessels, and thus interrupting T-cell recirculation, limited HIV dissemination and strongly reduced plasma viraemia. Thus, we have found that HIV-infected T cells are motile, form syncytia and establish tethering interactions that may facilitate cell-to-cell transmission through virological synapses. Migration of T cells in lymph nodes therefore spreads infection locally, whereas their recirculation through tissues is important for efficient systemic viral spread, suggesting new molecular targets to antagonize HIV infection.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3470742/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3470742/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Murooka, Thomas T -- Deruaz, Maud -- Marangoni, Francesco -- Vrbanac, Vladimir D -- Seung, Edward -- von Andrian, Ulrich H -- Tager, Andrew M -- Luster, Andrew D -- Mempel, Thorsten R -- P01 AI0178897/AI/NIAID NIH HHS/ -- P30 AI060354/AI/NIAID NIH HHS/ -- P30 AR042689/AR/NIAMS NIH HHS/ -- P30 DK043351/DK/NIDDK NIH HHS/ -- P30AI060354/AI/NIAID NIH HHS/ -- R01 CA150975/CA/NCI NIH HHS/ -- R56 AI097052/AI/NIAID NIH HHS/ -- T32 AI007387/AI/NIAID NIH HHS/ -- England -- Nature. 2012 Oct 11;490(7419):283-7. doi: 10.1038/nature11398. Epub 2012 Aug 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22854780" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
CD4-Positive T-Lymphocytes/*virology
;
Cell Movement
;
Cells, Cultured
;
Disease Models, Animal
;
Female
;
Giant Cells
;
HIV/*immunology
;
HIV Infections/*immunology/transmission/*virology
;
Humans
;
Lymph Nodes/virology
;
Mice
;
Mice, Inbred NOD
;
Mice, SCID
;
Mice, Transgenic
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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