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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 J+Virol
2014 ; 88
(19
): 11529-39
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Exosomes from human immunodeficiency virus type 1 (HIV-1)-infected cells license
quiescent CD4+ T lymphocytes to replicate HIV-1 through a Nef- and
ADAM17-dependent mechanism
#MMPMID25056899
Arenaccio C
; Chiozzini C
; Columba-Cabezas S
; Manfredi F
; Affabris E
; Baur A
; Federico M
J Virol
2014[Oct]; 88
(19
): 11529-39
PMID25056899
show ga
Resting CD4+ T lymphocytes resist human immunodeficiency virus (HIV) infection.
Here, we provide evidence that exosomes from HIV-1-infected cells render resting
human primary CD4+ T lymphocytes permissive to HIV-1 replication. These results
were obtained with transwell cocultures of HIV-1-infected cells with quiescent
CD4+ T lymphocytes in the presence of inhibitors of exosome release and were
confirmed using exosomes purified from supernatants of HIV-1-infected primary
CD4+ T lymphocytes. We found that the expression of HIV-1 Nef in
exosome-producing cells is both necessary and sufficient for cell activation as
well as HIV-1 replication in target CD4+ T lymphocytes. We also identified a Nef
domain important for the effects we observed, i.e., the 62EEEE65 acidic cluster
domain. In addition, we observed that ADAM17, i.e., a disintegrin and
metalloprotease converting pro-tumor necrosis factor alpha (TNF-?) in its mature
form, associates with exosomes from HIV-1-infected cells, and plays a key role in
the HIV-1 replication in quiescent CD4+ T lymphocytes. Treatment with an
inhibitor of ADAM17 abolished both activation and HIV-1 replication in resting
CD4+ T lymphocytes. TNF-? is the downstream effector of ADAM17 since the
treatment of resting lymphocytes with anti-TNF-? antibodies blocked the HIV-1
replication. The data presented here are consistent with a model where Nef
induces intercellular communication through exosomes to activate bystander
quiescent CD4+ T lymphocytes, thus stimulating viral spread. IMPORTANCE: Overall,
our findings support the idea that HIV evolved to usurp the exosome-based
intercellular communication network to favor its spread in infected hosts.