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Cell Rep. 2019 Mar 26;26(13):3586-3599.e7. doi: 10.1016/j.celrep.2019.02.091.

Tuberculosis Exacerbates HIV-1 Infection through IL-10/STAT3-Dependent Tunneling Nanotube Formation in Macrophages.

Author information

1
Institut de Pharmacologie et Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France; International Associated Laboratory (LIA) CNRS "IM-TB/HIV" (1167), Toulouse, France, and Buenos Aires, Argentina.
2
International Associated Laboratory (LIA) CNRS "IM-TB/HIV" (1167), Toulouse, France, and Buenos Aires, Argentina; Institute of Experimental Medicine-CONICET, National Academy of Medicine, Buenos Aires, Argentina.
3
Institut de Pharmacologie et Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France.
4
Institut de Pharmacologie et Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France; Centre for Genomic Regulation, Barcelona, Spain.
5
Centre de Physiopathologie de Toulouse Purpan, INSERM UMR 1043, CNRS UMR 5282, Université Toulouse III Paul Sabatier, Toulouse, France.
6
INSERM/UPS/ENVT-US006/CREFRE, Service d'Histopathologie, CHU Purpan, 31024 Toulouse, France.
7
Instituto de Tisioneumonologia "Raúl F. Vaccarezza," Universitad de Buenos Aires, Argentina.
8
Division de SIDA, Hospital de Infecciosas Dr. F.J. Muñiz, Buenos Aires, Argentina.
9
Tulane National Primate Research Center, Covington, LA 70433, USA; Department of Microbiology and Immunology, School of Medicine, Tulane University, New Orleans, LA 70112, USA.
10
Institut de Pharmacologie et Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France; International Associated Laboratory (LIA) CNRS "IM-TB/HIV" (1167), Toulouse, France, and Buenos Aires, Argentina. Electronic address: lugo@ipbs.fr.
11
Institut de Pharmacologie et Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France; International Associated Laboratory (LIA) CNRS "IM-TB/HIV" (1167), Toulouse, France, and Buenos Aires, Argentina. Electronic address: verollet@ipbs.fr.

Abstract

The tuberculosis (TB) bacillus, Mycobacterium tuberculosis (Mtb), and HIV-1 act synergistically; however, the mechanisms by which Mtb exacerbates HIV-1 pathogenesis are not well known. Using in vitro and ex vivo cell culture systems, we show that human M(IL-10) anti-inflammatory macrophages, present in TB-associated microenvironment, produce high levels of HIV-1. In vivo, M(IL-10) macrophages are expanded in lungs of co-infected non-human primates, which correlates with disease severity. Furthermore, HIV-1/Mtb co-infected patients display an accumulation of M(IL-10) macrophage markers (soluble CD163 and MerTK). These M(IL-10) macrophages form direct cell-to-cell bridges, which we identified as tunneling nanotubes (TNTs) involved in viral transfer. TNT formation requires the IL-10/STAT3 signaling pathway, and targeted inhibition of TNTs substantially reduces the enhancement of HIV-1 cell-to-cell transfer and overproduction in M(IL-10) macrophages. Our study reveals that TNTs facilitate viral transfer and amplification, thereby promoting TNT formation as a mechanism to be explored in TB/AIDS potential therapeutics.

KEYWORDS:

AIDS; HIV-1; IL-10; Mycobacterium tuberculosis; STAT3; biomarker; co-infection; macrophage; monocyte; tuberculosis; tunneling nanotubes; viral spread

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