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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Aged
  • Animals
  • Cells, Cultured
  • Coinfection / pathology
  • Coinfection / virology
  • Female
  • HIV Infections / complications*
  • HIV Infections / immunology
  • HIV Infections / pathology
  • HIV Infections / virology
  • Humans
  • Interleukin-10 / metabolism*
  • Macaca mulatta
  • Macrophage Activation
  • Macrophages / pathology*
  • Macrophages / virology
  • Male
  • Middle Aged
  • Mycobacterium tuberculosis
  • Nanotubes*
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction
  • Tuberculosis, Pulmonary / complications*
  • Tuberculosis, Pulmonary / immunology
  • Tuberculosis, Pulmonary / pathology
  • Virus Replication
  • Young Adult


  • IL10 protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Interleukin-10