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Infectious Diseases
and STD-AIDS
Journal of Transmitted Diseases and Immunity
ISSN 2573-0320
A p r i l 2 6 - 2 7 , 2 0 1 8
R o m e , I t a l y
Infectious Diseases and STD-AIDS 2018
Page 19
I
t has been shown that HIV-1 insertions targeting BACH2 and STAT5B are
enriched and persist for decades in hematopoietic cells frompatients under Anti-
Retroviral Therapy (ART), suggesting that insertional mutagenesis could provide
a selective advantage to these cell clones. However, the mechanisms used and
the physiological impact on the cells harboring these integrations are completely
unknown.
In the hematopoietic cells of 30/87 patients under ART we identified chimeric
mRNA containing viral HIV-1 sequences fused to the first protein-coding exon
of STAT5B or BACH2. By performing droplet digital PCR, we found that these
chimeric mRNAs were specifically enriched (p<0.001) in T regulatory (Treg) cells
in all patients tested (N=9). Forced expression of
STAT5B
and
BACH2
in Treg cells
purified from healthy donors did not alter their phenotype and functions
in vitro
and significantly increased their proliferative capacity in competitive proliferation
assays (p<0.0001). Co-injection in immune-deficient mice of GFP-, BACH2- and
STAT5B-transduced Treg cells with allogenic PBMCs prevented xenogeneic
graft-versus-host disease in 75% of the animals and reduced the level of human
chimerisms in the blood of mice receiving STAT5B-expressing Treg cells when
compared to mice treated with GFP-expressing Treg cells (p<0.001), suggesting
for a superior activity of STAT5B-expressing cells in controlling the expansion of
human PBMC.
These data provide evidences that HIV-1 takes advantage of insertional
mutagenesis to favor its persistence in the host by infecting long-living and
self-renewing cellular reservoir endowed with the ability to diminish the immune
surveillance against infected cells.
New targeted therapies aimed at interfering with BACH2 and STAT5B pathways
could be exploited to reduce cellular reservoirs and favor the eradication of the
infection in cART-treated patients.
Biography
Eugenio Montini obtained his Ph.D in the field of human mo-
lecular and medical genetics at the Telethon Institute of Genet-
ics and Medicine (TIGEM, Milan, Italy) and later at the Oregon
Health Science University (Portland, USA) as American Liver
Foundation Amgen and HIH Postdoctoral Research Fellowship
Awardee in the field of viral and non-viral mediated gene thera-
py. He is now Group Leader of the Vector Safety and Insertional
mutagenesis Reseach Unit and Vector Integration Core and is
a word leading expert in insertional mutagenesis and genotox-
icity by HIV-1 and derived vectors (Montini et al., 2006 Nature
Biotechnology; Ranzani et al., 2013 Nature Methods; Biffi, Mon-
tini et al., 2103 Science, Aiuti et al., 2013 Science; Cesana et al.,
2017 Nature Communications).
He authored 60 publications in peer reviewed journals with
4611 citations and an H index of 31.
montini.eugenio@hsr.itHIV-1-mediated insertional activation of
STAT5B and BACH2 trigger viral reservoir in
T regulatory cells
Eugenio Montini
IRCCS San Raffaele Scientific Institute, Italy
Eugenio Montini, J Transm Dis Immun 2018 Volume 2
DOI: 10.21767/2573-0320-C1-001