There is considerable evidence that macrophages present in tissues such as genital tissues infected early with HIV-1 constitute a new type of reservoir, in addition to the well-characterized reservoir established in CD4+ T lymphocytes. These reservoirs are an obstacle to the eradication of the virus in infected people living with HIV-1 because it is from these reservoirs that as soon as the combined anti-retroviral treatments (cART) are stopped, the production of virus restarts.
Scientists have isolated resident macrophages from the urethral mucosa of HIV-positive men on cART treatment for several years (sometimes 20 years) no longer showing detectable virus in the blood, and have characterized their ability to produce infectious virus. The results show that macrophages of a new type called M4 (characterized by the presence on their surface of the CD206, IL-1-R, IL-4-R receptors, and expressing the S100A8 and MMP-7 proteins) constitute one of the main reservoirs likely to relaunch the infection. This type of macrophage reservoir had been neglected until now, the attention being mainly focused on CD4+ T lymphocytes. The expression and then the secretion of the "alarmin" protein S100A8 allows their activation via a self-stimulation loop by binding to the Toll like 4 (TLR4) membrane receptor present on their surface. This activation induces an inflammatory state accompanied by a metabolic change: an increase in the breakdown of glucose (glycolysis). Activation of this metabolic pathway then triggers the production of infectious viral particles.
Figure legend: M4 macrophage in urethral tissue from an HIV+ subject under effective antiretroviral treatment (3D isosurface reconstruction). In blue: cell nuclei. In green: CD68 macrophage marker (immunolabelling). In purple: alarmin S100A8 (immunolabeling) M4 macrophage marker. In red: HIV RNA (in situ hybridization)
The pharmacological activation of glycolysis or the stimulation of the surface molecule TLR4 could make it possible to reach these reservoir macrophages during a first stage of the “shock-and-kill” type, i.e. to stimulate the production virus from these hidden reservoir cells to be able to make them visible to the immune system, which can then destroy them. These results show the importance of taking into account, in addition to T lymphocytes, M4 macrophages as HIV-1 reservoirs, and open the way to potential therapeutic strategies.
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Fernando Real, Aiwei Zhu, Boxin Huang, Ania Belmellat, Alexis Sennepin, Thomas Vogl, Céline Ransy, Marc Revol, Riccardo Arrigucci, Anne Lombès, Johannes Roth, Maria Laura Gennaro, Frédéric Bouillaud, Sarra Cristofari, Morgane Bomsel. S100A8-mediated metabolic adaptation controls HIV-1 persistence 1 in macrophages in vivo. Nature Communications, 13, 5956 (2022). doi.org/10.1038/s41467-022-33401-x