Journal Article

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

Poli, Guido, Passerini, Laura, Santoni de Sio, Francesca R., Tambussi, Giuseppe, Cesana, Daniela, Gallina, Pierangela, Rudilosso, Laura, Vicenzi, Elisa, Beretta, Stefano, Gregori, Silvia, Calabria, Andrea, Nozza, Silvia, Merelli, Ivan, Bruzzesi, Elena, Montini, Eugenio

2017

Overview

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. HIV insertions in hematopoietic cells are enriched in BACH2 or MLK2 genes, but the selective advantages conferred are unknown. Here, the authors show that BACH2 and additionally STAT5B are activated by viral insertions, generating chimeric mRNAs specifically enriched in T regulatory cells favoring their persistence.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/326/596/2557 / 631/326/596/2564 / 631/337/572/2102 / 692/699/255/1901 / Activation / Anti-HIV Agents - therapeutic use / Antiretroviral agents / Antiretroviral drugs / Antiretroviral therapy / Basic-Leucine Zipper Transcription Factors - genetics / Cell proliferation / Cells, Cultured / Computer memory / Disease Reservoirs - virology / Drug therapy / Enrichment / Gene Expression Regulation / HEK293 Cells / HIV / HIV Infections - drug therapy / HIV Infections - genetics / HIV Infections - virology / HIV-1 - drug effects / HIV-1 - genetics / HIV-1 - physiology / Human immunodeficiency virus / Humanities and Social Sciences / Humans / Immunoregulation / Lymphocytes / Lymphocytes T / Memory cells / Monocytes / multidisciplinary / Mutagenesis, Insertional / Patients / Proteins / Reverse Transcriptase Polymerase Chain Reaction / Science / Science (multidisciplinary) / Splicing / STAT5 Transcription Factor - genetics / T-Lymphocytes, Regulatory - drug effects / T-Lymphocytes, Regulatory - metabolism / T-Lymphocytes, Regulatory - virology / Therapy / Virus Integration