HIV-1-mediated insertional activation of STAT5B and BACH2 trigger viral reservoir in T regulatory cells

Daniela Cesana (), Francesca R. Santoni de Sio, Laura Rudilosso, Pierangela Gallina, Andrea Calabria, Stefano Beretta, Ivan Merelli, Elena Bruzzesi, Laura Passerini, Silvia Nozza, Elisa Vicenzi, Guido Poli, Silvia Gregori, Giuseppe Tambussi and Eugenio Montini ()
Additional contact information
Daniela Cesana: IRCCS, San Raffaele Scientific Institute
Francesca R. Santoni de Sio: IRCCS, San Raffaele Scientific Institute
Laura Rudilosso: IRCCS, San Raffaele Scientific Institute
Pierangela Gallina: IRCCS, San Raffaele Scientific Institute
Andrea Calabria: IRCCS, San Raffaele Scientific Institute
Stefano Beretta: University of Milano—Bicocca
Ivan Merelli: Institute for Biomedical Technologies
Elena Bruzzesi: IRCCS, San Raffaele Scientific Institute
Laura Passerini: IRCCS, San Raffaele Scientific Institute
Silvia Nozza: IRCCS, San Raffaele Scientific Institute
Elisa Vicenzi: IRCCS, San Raffaele Scientific Institute
Guido Poli: IRCCS, San Raffaele Scientific Institute
Silvia Gregori: IRCCS, San Raffaele Scientific Institute
Giuseppe Tambussi: IRCCS, San Raffaele Scientific Institute
Eugenio Montini: IRCCS, San Raffaele Scientific Institute

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: Abstract HIV-1 insertions targeting BACH2 or MLK2 are enriched and persist for decades in hematopoietic cells from patients under combination antiretroviral therapy. However, it is unclear how these insertions provide such selective advantage to infected cell clones. Here, we show that in 30/87 (34%) patients under combination antiretroviral therapy, BACH2, and STAT5B are activated by insertions triggering the formation of mRNAs that contain viral sequences fused by splicing to their first protein-coding exon. These chimeric mRNAs, predicted to express full-length proteins, are enriched in T regulatory and T central memory cells, but not in other T lymphocyte subsets or monocytes. Overexpression of BACH2 or STAT5B in primary T regulatory cells increases their proliferation and survival without compromising their function. Hence, we provide evidence that HIV-1-mediated insertional activation of BACH2 and STAT5B favor the persistence of a viral reservoir in T regulatory cells in patients under combination antiretroviral therapy.

Date: 2017
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DOI: 10.1038/s41467-017-00609-1

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