Active PD-L1 incorporation within HIV virions functionally impairs T follicular helper cells

Munoz, Olivia; Banga, Riddhima; Schelling, Rachel; Procopio, Francesco A.; Mastrángelo, Andrea; Nortier, Pauline; Ohmiti, Khalid; Daraspe, Jean; Cavassini, Matthias; Fenwick, Craig; Perez, Laurent; Perreau, Matthieu

doi:10.1371/journal.ppat.1010673

Cited by 8 publications

(14 citation statements)

References 88 publications

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“…We showed that bioactive LPS loaded on CD14 + virions could activate NF-κB and IRF3 in a TLR4 reporter cell line, and in THP-1 monocytes, it triggered the secretion of TNF-α and CCL5. While others have described the impact of incorporated immunoregulatory proteins on cell signaling ( 26 – 28 ), our work highlights a pivotal role for CD14 in allowing virions to function as a shuttle for bioactive molecules like LPS and eliciting inflammatory responses.…”

Section: Discussionmentioning

confidence: 99%

“…Most interesting was the resulting activation of the transcription factors nuclear factor kappa B (NF-κB) and nuclear factor of activated T cells, which activated HIV-1 long-terminal repeat-driven gene expression ( 27 ). More recently, it was shown that HIV-1 can incorporate the immune checkpoint ligand, programmed death-ligand 1 (PD-L1) ( 28 ). Conferred with an immunoregulatory ability, HIV-1 virions with incorporated PD-L1 impaired follicular helper T cell proliferation and cytokine secretion, resulting in reduced IgG1 secretion by autologous B cells.…”

Section: Introductionmentioning

confidence: 99%

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Virion-incorporated CD14 enables HIV-1 to bind LPS and initiate TLR4 signaling in immune cells

Persaud,

Khela,

Fernandes

et al. 2024

J Virol

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HIV-1 has a broad range of nuanced interactions with the immune system, and the incorporation of cellular proteins by nascent virions continues to redefine our understanding of the virus-host relationship. Proteins located at the sites of viral egress can be selectively incorporated into the HIV-1 envelope, imparting new functions and phenotypes onto virions, and impacting viral spread and disease. Using virion capture assays and western blot, we show that HIV-1 can incorporate the myeloid antigen CD14 into its viral envelope. Virion-incorporated CD14 remained biologically active and able to bind its natural ligand, bacterial lipopolysaccharide (LPS), as demonstrated by flow virometry and immunoprecipitation assays. Using a Toll-like receptor 4 (TLR4) reporter cell line, we also demonstrated that virions with bound LPS can trigger TLR4 signaling to activate transcription factors that regulate inflammatory gene expression. Complementary assays with THP-1 monocytes demonstrated enhanced secretion of inflammatory cytokines like tumor necrosis factor alpha (TNF-α) and the C-C chemokine ligand 5 (CCL5), when exposed to LPS-loaded virus. These data highlight a new type of interplay between HIV-1 and the myeloid cell compartment, a previously well-established cellular contributor to HIV-1 pathogenesis and inflammation. Persistent gut inflammation is a hallmark of chronic HIV-1 infection, and contributing to this effect is the translocation of microbes across the gut epithelium. Our data herein provide proof of principle that virion-incorporated CD14 could be a novel mechanism through which HIV-1 can drive chronic inflammation, facilitated by HIV-1 particles binding bacterial LPS and initiating inflammatory signaling in TLR4-expressing cells. IMPORTANCE HIV-1 establishes a lifelong infection accompanied by numerous immunological changes. Inflammation of the gut epithelia, exacerbated by the loss of mucosal T cells and cytokine dysregulation, persists during HIV-1 infection. Feeding back into this loop of inflammation is the translocation of intestinal microbes across the gut epithelia, resulting in the systemic dissemination of bacterial antigens, like lipopolysaccharide (LPS). Our group previously demonstrated that the LPS receptor, CD14, can be readily incorporated by HIV-1 particles, supporting previous clinical observations of viruses derived from patient plasma. We now show that CD14 can be incorporated by several primary HIV-1 isolates and that this virion-incorporated CD14 can remain functional, enabling HIV-1 to bind to LPS. This subsequently allowed CD14 + virions to transfer LPS to monocytic cells, eliciting pro-inflammatory signaling and cytokine secretion. We posit here that virion-incorporated CD14 is a potential contributor to the dysregulated immune responses present in the setting of HIV-1 infection.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Virion-incorporated CD14 enables HIV-1 to bind LPS and initiate TLR4 signaling in immune cells

Persaud,

Khela,

Fernandes

et al. 2024

J Virol

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“…Similarly, both virions and infected cells were recently shown to display high levels of PD-L1, an immune check point ligand that could induce exhaustion of CD8 + T cells. 118 PD-L1 expression differs at the specificity level 119 and could thus be a mechanism of preferential persistence.…”

Section: Host Cell Factors Influencing Persistencementioning

confidence: 99%

Antigen specificities of HIV-infected cells: A role in infection and persistence?

Faua,

Fafi-Kremer,

Gantner

2023

Journal of Virus Eradication

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“…Previously reported showed that KDM5A can induce PD-L1 expression [33,34] that may suppress the immune response for immune escape during HIV-1 infection [35][36][37][38][39]. The other KDM5, KDM5B, has been identified to suppress immune sensing from the STING-GAS signaling [40] and RIG-I signaling [41] to decrease innate immunity and antiviral responses.…”

Section: Introductionmentioning

confidence: 99%

“…KDM5A is one of the KDM5 demethylases (KDM5 A, B, C, and D), which catalyzes demethylation from H3K4me3 to H3K4me2 and then to the final product H3K4me1 [29-32]. Previously reported showed that KDM5A can induce PD-L1 expression [33, 34] that may suppress the immune response for immune escape during HIV-1 infection [35-39]. The other KDM5, KDM5B, has been identified to suppress immune sensing from the STING-GAS signaling [40] and RIG-I signaling [41] to decrease innate immunity and antiviral responses.…”

Section: Introductionmentioning

confidence: 99%

KDM5A/B promotes HIV-1 latency and KDM5 inhibitors promote HIV-1 lytic reactivation

Zhou

et al. 2022

Preprint

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Combinational antiretroviral therapy (cART) effectively suppresses HIV-1 infection, replication, and pathogenesis in HIV-1 patients. However, the patient's HIV-1 reservoir still cannot be eliminated by current cART or other therapies. One putative HIV-1 eradication strategy is 'shock and kill', which reactivates HIV-1 in latently-infected cells and induces their cytopathic effect or immune clearance to decrease the patients' reservoir size. KDM5A and KDM5B act as the HIV-1 latency-promoting genes, decreasing the HIV-1 viral gene transcription and reactivation in infected cells. Depletion of KDM5 A/B by siRNA knockdown (KD) increases H3K4 trimethylation (H3K4me3) in HIV-1 Tat-mediated transactivation. We also found that the KDM5-specific inhibitor JQKD82 can increase H3K4me3 at the HIV-1 LTR region during HIV-1 reactivation and induce cytopathic effects. We applied the JQKD82 in combination with the non-canonical NF-κB activator AZD5582, which synergistically induced HIV-1 reactivation and cell apoptosis in HIV-1 infected cells. These results suggested that the KDM5 inhibition can be a putative HIV-1 latency-reversing strategy for the HIV-1 'shock and kill' eradication therapy.

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Active PD-L1 incorporation within HIV virions functionally impairs T follicular helper cells

Cited by 8 publications

References 88 publications

Virion-incorporated CD14 enables HIV-1 to bind LPS and initiate TLR4 signaling in immune cells

Virion-incorporated CD14 enables HIV-1 to bind LPS and initiate TLR4 signaling in immune cells

Antigen specificities of HIV-infected cells: A role in infection and persistence?

KDM5A/B promotes HIV-1 latency and KDM5 inhibitors promote HIV-1 lytic reactivation

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