CD8+ T cells promote HIV latency by remodeling CD4+ T cell metabolism to enhance their survival, quiescence, and stemness

Mutascio, Simona; Mota, Talia M.; Franchitti, Lavinia; Sharma, Ashish; Willemse, Abigail; Bergstresser, Sydney N; Wang, Hong; Statzu, Maura; Tharp, Gregory K.; Weiler, Jared; Sékaly, Rafick‐Pierre; Bosinger, Steven E.; Paiardini, Mirko; Silvestri, Guido; Jones, R. Brad; Kulpa, Deanna A.

doi:10.1016/j.immuni.2023.03.010

Cited by 15 publications

(17 citation statements)

References 101 publications

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“…In addition, the TGF-SMAD pathway, reported to support HIV-1 latency (48, 49), was upregulated. Importantly, a decrease in T cell activation, OXPHOS and glycolysis has also been associated with the establishment of HIV-1 latency (47, 74–76), supporting our hypothesis. Interestingly, we observed that cell apoptosis is downmodulated in TB-PE-treated activated cells, indicating that this microenvironment may promote the survival of latently infected cells contributing to the persistence of HIV-1.…”

Section: Discussionsupporting

confidence: 86%

“…The NF-κB and type I/II IFN pathways were also downmodulated by TB-PE in non-activated CD4+ T cells (Supplementary Figure 1). Furthermore, we observed upregulation of pathways associated with transforming growth factor beta (TGFβ)-SMAD response, which is known to support HIV-1 latency (47–49), in the cells exposed to TB-PE (Figure 4 A-B). Of note, regulation of the ERK cascade signaling did not show consistent modulation patterns (Figure 4A).…”

Section: Resultsmentioning

confidence: 96%

“…Based on our RNAseq data obtained from activated CD4+ T cells, we analyzed cellular pathways necessary for efficient HIV-1 transcription and viral reactivation of latently HIV-1-infected cells (40–47). These cellular pathways include the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), Janus kinase/signal transducer and activator of transcription (JAK-STAT), tumor necrosis factor (TNF), extracellular signal-regulated kinases (ERK) and type I/II interferon (IFN) pathways(40–47). We found that NF-κB, JAK-STAT and type I/II IFN pathways were downmodulated in activated cells treated with TB-PE (Figure 4A-B).…”

Section: Resultsmentioning

confidence: 99%

“…Of note, regulation of the ERK cascade signaling did not show consistent modulation patterns (Figure 4A). We also analyzed the expression of genes and pathways associated with programmed cell death, since previous studies indicate that intrinsic resistance to cell death of CD4+ T cells that compose the long-lived latent viral reservoir may contribute to HIV-1 persistence (47, 50–53). Our analysis revealed that programmed cell death pathways are inhibited by TB-PE (Supplementary Figure 2).…”

Section: Resultsmentioning

confidence: 99%

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The immunosuppressive Tuberculosis-associated microenvironment inhibits viral replication and promotes HIV-1 latency in CD4+ T cells

Cronin,

de Vries-Egan,

Vahlas

et al. 2023

Preprint

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Author SummaryMycobacterium tuberculosis(Mtb), the causative agent of tuberculosis (TB), is the most common coinfection among people living with HIV-1. This coinfection alters the efficacy of the immune response against both HIV-1 andMtb, and is associated with accelerated HIV-1 disease progression and reduced survival. Enhanced HIV-1 replication in macrophages induced byMtbcoinfection may contribute to the worsened clinical outcomes observed in HIV-1/TB coinfected individuals. However, the impact of the HIV-1/TB coinfection on HIV-1 replication and latency in CD4+ T cells remains poorly studied.In this study, we used the acellular fraction of tuberculous pleural effusion (TB-PE) as a proxy for the microenvironment generated byMtbinfection. Using this physiologically relevant fluid, we investigated whether viral replication and HIV-1 latency in CD4+ T cells are affected by a TB-associated microenvironment. Interestingly, our results revealed that TB-PE shaped the transcriptional profile of CD4+ T cells impairing T cell receptor-dependent cell activation and decreased HIV-1 replication. Moreover, this immunosuppressive TB microenvironment promoted viral latency and inhibited HIV-1 reactivation in CD4+ T cells from people living with HIV-1. This study indicates that the immune response induced by TB may contribute to the persistence of the viral reservoir by silencing HIV-1 expression in individuals coinfected with both pathogens, allowing the virus to persist undetected by the immune system and increasing the size of the HIV-1 latent reservoir in cells at the site of the coinfection.

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Section: Discussionsupporting

confidence: 86%

Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

The immunosuppressive Tuberculosis-associated microenvironment inhibits viral replication and promotes HIV-1 latency in CD4+ T cells

Cronin,

de Vries-Egan,

Vahlas

et al. 2023

Preprint

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“…While loss of CD8 + T cell function in controllers has been shown to precede resurgence of viremia [17], no single factor likely determines initial protection, suggesting that control might require an optimal combination of both a highly functional immune response and targeting of ‘networked’ epitopes. Complicating the role of CD8 + T cells in HIV control, it was recently observed that HIV-infected CD4 + T cells surviving co-culture with autologous CD8 + T cells show enrichment of genes associated with quiescence, suggesting that CD8 + T cells may play a role in promoting latency [18 ▪ ]. With these challenges in mind, we will discuss strategies to improve CTL-mediated control of HIV.…”

Section: Introductionmentioning

confidence: 99%

Harnessing immune cells to eliminate HIV reservoirs

Grasberger,

Sondrini,

Clayton

2024

Current Opinion in HIV and AIDS

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Purpose of review Despite decades of insights about how CD8+ T cells and natural killer (NK) cells contribute to natural control of infection, additional hurdles (mutational escape from cellular immunity, sequence diversity, and hard-to-access tissue reservoirs) will need to be overcome to develop a cure. In this review, we highlight recent findings of novel mechanisms of antiviral cellular immunity and discuss current strategies for therapeutic deisgn. Recent findings Of note are the apparent converging roles of viral antigen-specific MHC-E-restricted CD8+ T cells and NK cells, interleukin (IL)-15 biologics to boost cytotoxicity, and broadly neutralizing antibodies in their native form or as anitbody fragments to neutralize virus and engage cellular immunity, respectively. Finally, renewed interest in myeloid cells as relevant viral reservoirs is an encouraging sign for designing inclusive therapeutic strategies. Summary Several studies have shown promise in many preclinical models of disease, including simian immunodeficiency virus (SIV)/SHIV infection in nonhuman primates and HIV infection in humanized mice. However, each model comes with its own limitations and may not fully predict human responses. We eagerly await the results of clinical trails assessing the efficacy of these strategies to achieve reductions in viral reservoirs, delay viral rebound, or ultimately elicit immune based control of infection without combination antiretroviral therapy (cART).

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