HIV-1-induced cytokines deplete homeostatic innate lymphoid cells and expand TCF7-dependent memory NK cells

Abstract

HIV-1 infection is associated with heightened inflammation and excess risk of cardiovascular disease, cancer, and other complications. These pathologies persist despite antiretroviral therapy (ART). In two independent cohorts, we found that innate lymphoid cells (ILCs) were depleted in the blood and gut of people with HIV-1, even with effective ART. ILC depletion was associated with neutrophil infiltration of the gut lamina propria, type 1 interferon activation, increased microbial translocation, and natural killer (NK) cell skewing towards an inflammatory state with chromatin structure and phenotype typical of WNT transcription factor TCF7-dependent memory T cells. Cytokines that are elevated during acute HIV-1 infection reproduced the ILC and NK cell abnormalities ex vivo . These results demonstrate that inflammatory cytokines associated with HIV-1 infection irreversibly disrupt ILCs. This results in loss of gut epithelial integrity, microbial translocation, and memory NK cells with heightened inflammatory potential, and explains the chronic inflammation in people with HIV-1.

Differential clusterization of soluble and extracellular vesicle-associated cytokines in myocardial infarction

“…Dysregulated release of cytokines is widely studied as one of the important complications of several diseases 7 . Also, dysregulated cytokine patterns were shown to be associated with HIV infection 29,30 , CAR T-cell therapy 31 , as well as with pathologies for which etiological agents have not been established, e.g. certain complicated pregnancies 3 and, in particular, atherosclerosis and acute myocardial infarction that was the focus of our current study 1,2,[8][9][10][11][12]32 .…”

Memory like NK cells display stem cell like properties after Zika virus infection

“…The top enriched pathways were associated with active cell cycle (G2M checkpoint, E2F targets, Myc targets) and HSC self-renewal (Wnt/βcatenin pathway) [30][31][32]38] ( Fig 6A). The enrichment of Wnt/β-catenin pathway, transcriptional signature of its targets (Myc, E2F) [38,39] and its role in proliferation of cells [40] suggested a dominant nature of this pathway. GSEA further confirmed enrichment of Wnt signaling genes and canonical Wnt targets in CD27 + memory like NK cells (Fig 6C and 6D).…”

Harnessing Natural Killer Cell Innate and Adaptive Traits in HIV Infection

“…In addition to the influence of CMV co-infection, a recent study demonstrated that the pro-inflammatory milieu in HIV infected patients drives the expansion of a defined NK subset with memory-like properties, characterized by CD94 + CD56 hi and high expression of the transcription factor TCF7 (Wang et al, 2020 ). A combination of IL-12 and IL-15 was able to induce the generation of CD94 + CD56 hi NK cells from CD94 − CD56 + NK cells from HIV seronegative donors (Wang et al, 2020 ). These CD94 + CD56 hi NK cells exhibited features in keeping with adaptive NK cells, including higher NKG2C expression, increased cytotoxicity and a more pronounced degranulation against HIV-infected CD4 T cells.…”

“…These CD94 + CD56 hi NK cells exhibited features in keeping with adaptive NK cells, including higher NKG2C expression, increased cytotoxicity and a more pronounced degranulation against HIV-infected CD4 T cells. The presence of NKG2C + TFC7 + CD56 hi NK cells correlated with HIV-induced inflammation and altered homeostasis of the gut resident and circulating innate lymphoid cells (ILCs) (Wang et al, 2020 ). The effect of CMV reactivation in the gut and influence on local NK cell populations was not addressed in this study but important to delineate given the pronounced contribution of CMV reactivation to loss of intestinal epithelial integrity and chronic inflammation in HIV, despite suppressive ART (Maidji et al, 2017 ).…”