S100A8-mediated metabolic adaptation controls HIV-1 persistence in macrophages in vivo

Abstract

HIV-1 eradication is hindered by viral persistence in cell reservoirs, established not only in circulatory CD4+T-cells but also in tissue-resident macrophages. The nature of macrophage reservoirs and mechanisms of persistence despite combined anti-retroviral therapy (cART) remain unclear. Using genital mucosa from cART-suppressed HIV-1-infected individuals, we evaluated the implication of macrophage immunometabolic pathways in HIV-1 persistence. We demonstrate that ex vivo, macrophage tissue reservoirs contain transcriptionally active HIV-1 and viral particles accumulated in virus-containing compartments, and harbor an inflammatory IL-1R+S100A8+MMP7+M4-phenotype prone to glycolysis. Reactivation of infectious virus production and release from these reservoirs in vitro are induced by the alarmin S100A8, an endogenous factor produced by M4-macrophages and implicated in “sterile” inflammation. This process metabolically depends on glycolysis. Altogether, inflammatory M4-macrophages form a major tissue reservoir of replication-competent HIV-1, which reactivate viral production upon autocrine/paracrine S100A8-mediated glycolytic stimulation. This HIV-1 persistence pathway needs to be targeted in future HIV eradication strategies.

Monocyte-derived macrophages contain persistent latent HIV reservoirs

“…https://doi.org/10.1038/s41564-023-01349-3 tissue macrophages from vsPWH, suggesting that metabolic pathways may control latency in macrophages 41 . In animal models, a myeloid-only mouse model of HIV demonstrated that monocytes and macrophages can sustain infection independently of CD4 T cells 42 and that HIV persists in tissue macrophages during ART suppression 43 .…”

Targeting HIV persistence in the tissue

“…However, in vitro latent HIV-infected macrophages may shift to glutamate as an energy source and blocking of glutamate resulted in killing of latent infected but not uninfected macrophages [117]. In urethral tissue of PWH, M4 macrophages contained the main HIV reservoir and glycolysis blocking in these cells lead to control of HIV reactivation [31 ▪▪ ]. Together, these data indicate that metabolic interventions specifically targeting latent HIV infected cells may contribute to closing in on reducing the HIV reservoir.…”

“…Macrophages can be long-lived resident immune cells and highly diverse based on their origin and tissue conditions [30]. Considering the participation and compartmentalization of myeloid cells in viral persistence, these cells represent an additional challenge to viral persistence elimination [31 ▪▪ ].…”

“…Evidence of HIV persistence in most tissues across the human body have been reported [78]. Recent literature shows detection of viral DNA and/or RNA at multiple additional tissue sites [79], including hepatocytes and liver-infiltrating CD4 + T cells [80 ▪ ], lung bronchoalveolar lavage samples [81], hematopoietic progenitor cells in bone marrow [82,83], kidney [84], urethra [10,31 ▪▪ ], testicles [85] and prostate [3]. Further, inflammation at a particular site, such as the gingival tissue [86] or the CNS [15 ▪▪ ], may act as the spark that unmasks persistent reservoirs, likely in the form of antigen-specific CD4 + T RM that remained in a particular tissue to provide long-term memory.…”

“…Beyond blood, studies considering tissue architecture and cell interactions limiting or favoring reservoirs to reactivate upon stimulation have largely been missing. Lack of data also affects other cell types beyond CD4 + T cells, such as macrophages, which may require specific targeting such as TLR4 stimulation to induce reactivation [10,31 ▪▪ ].…”