13
PLoSPathog. 2013;9(10):e1003687.
Massive depletion of bovine leukemia virus proviral clones
located ingenomic transcriptionallyactivesitesduringprimary
infection.
GilletNA, GutiérrezG, RodriguezSM, deBrogniezA, RenotteN, Alvarez I, TronoK,WillemsL.
Abstract
DeltaretrovirusessuchashumanT-lymphotropicvirus type1 (HTLV-1)andbovine leukemiavirus
(BLV) induce a persistent infection that remains generally asymptomatic but can also lead to
leukemiaor lymphoma. These viruses replicateby infectingnew lymphocytes (i.e. the infectious
cycle)orviaclonal expansionof the infectedcells (mitoticcycle).The relative importanceof these
two cycles in viral replication varies during infection. Themajority of infected clones are created
early before the onset of an efficient immune response. Later on, themain replication route is
mitotic expansion of pre-existing infected clones. Due to the paucity of available samples and
for ethical reasons, only scarce data is available on early infectionbyHTLV-1. Therefore, we ad-
dressed thisquestion inacomparativeBLVmodel.Weusedhigh-throughput sequencing tomap
andquantify the insertionsitesof theprovirus inorder tomonitor theclonalityof theBLV-infected
cellspopulation (i.e. thenumber of distinct clonesandabundanceof eachclone).We found that
BLVpropagation shifts from cell neoinfection to clonal proliferation inabout 2months from ino-
culation. Initially, BLVproviral integration significantly favors transcribed regions of the genome.
Negative selection then eliminates 97% of the clones detected at seroconversion and disfavors
BLV-infectedcellscarryingaprovirus locatedclose toapromoteroragene.Nevertheless, among
the surviving proviruses, clone abundance positively correlateswith proximity of the provirus to
a transcribed region. Two opposite forces thus operate during primary infection and dictate the
fateof long termclonal composition: (1) initial integration insidegenesor promotersand (2) host
negative selection disfavoring proviruses located next to transcribed regions. The result of this
initial responsewill contribute to theproviral loadset point valueasclonal abundancewill benefit
fromcarryingaprovirus in transcribed regions.
JClin Invest. 2013May1;123(5):2143-54.
MicroRNA-146a is a therapeutic target and biomarker for
peripartumcardiomyopathy.
HalkeinJ, TabruynSP, Ricke-HochM, HaghikiaA, NguyenNQ, ScherrM, CastermansK,Malvaux
L, Lambert V, ThiryM, SliwaK, Noel A,Martial JA, Hilfiker-KleinerD, Struman I.
Abstract
Peripartumcardiomyopathy (PPCM) isa life-threateningpregnancy-associatedcardiomyopathy
inpreviouslyhealthywomen. AlthoughPPCM isdriven inpart by the16-kDaN-terminal prolactin
fragment (16K PRL), the underlying molecular mechanisms are poorly understood. We found
that16KPRL inducedmicroRNA-146a (miR-146a) expression inECs,whichattenuatedangioge-
nesis through downregulation of NRAS. 16K PRL stimulated the release of miR-146a-loaded
exosomes from ECs. The exosomes were absorbed by cardiomyocytes, increasing miR-146a
levels, which resulted in a subsequent decrease inmetabolic activity and decreased expression
ofErbb4,Notch1, and Irak1.Micewithcardiomyocyte-restrictedStat3knockout (CKOmice) exhi-
bited a PPCM-like phenotype and displayed increased cardiacmiR-146a expressionwith coin-
cident downregulationof Erbb4, Nras, Notch1, and Irak1. BlockingmiR-146awith lockednucleic
acids or antago-miRs attenuated PPCM in CKOmice without interrupting full-length prolactin
signaling, as indicated by normal nursing activities. Finally, miR-146awas elevated in the plas-
ma andhearts of PPCMpatients, but not inpatientswithdilated cardiomyopathy. These results
demonstrate thatmiR-146a isadownstream-mediatorof16KPRL thatcouldpotentiallyserveas
abiomarker and therapeutic target for PPCM.
Schematic illustration of the role ofmiR-146a inPeripartum cardiomyopathy (PPCM). InPPCM patients, PRL
is cleaved into 16KPRL, which viaNF-
k
B increases expression ofmiR-146a in endothelial cells. By targeting
NRAS, miR-146a reduces proliferation and viability in endothelial cells and contributes to the cardiacmicro-
vasculaturedestruction.MiR-146a is released fromendothelial cellsprotectedby theexosomes that fusewith
cardiomyocyteswheremiR-146a targetsERBB4and impairsmetabolism.
