Immune checkpoint blockade in infectious diseases

Wykes, Michelle N.; Lewin, Sharon R.

doi:10.1038/nri.2017.112

Cited by 410 publications

(372 citation statements)

References 171 publications

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“…Each of these circuits modulates memory T cell formation (Angelosanto and Wherry, 2010, Hale et al, 2013, Youngblood et al, 2013a, Youngblood et al, 2013b). Understanding the mechanisms by which OX40, alone or in combination with other co-stimulatory (Wikenheiser et al, 2016) or co-inhibitory (Wykes and Lewin, 2017) pathways, impacts memory CD4 T cell function may be key for developing strategies to enhance protection against chronic infections or cancer.…”

Section: Discussionmentioning

confidence: 99%

Th1-like Plasmodium -Specific Memory CD4 + T Cells Support Humoral Immunity

et al. 2017

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Summary Effector T-cells exhibiting features of either T helper 1 (Th1) or T follicular helper (Tfh) populations are essential to control experimental Plasmodium infection and are believed to be critical for resistance to clinical malaria. To determine whether Plasmodium-specific Th1- and Tfh-like effector cells generate memory populations that contribute to protection, we developed transgenic parasites that enable high-resolution study of anti-malarial memory CD4 T-cells in experimental models. We found that populations of both Th1- and Tfh-like Plasmodium-specific memory CD4 T-cells persist. Unexpectedly, Th1-like memory cells exhibit phenotypic and functional features of Tfh cells during recall and provide potent B-cell help and protection following transfer, characteristics that are enhanced following ligation of the T-cell co-stimulatory receptor OX40. Our findings delineate critical functional attributes of Plasmodium-specific memory CD4 T-cells and identify a host-specific factor that can be targeted to improve resolution of acute malaria and provide durable, long-term protection against Plasmodium parasite re-exposure.

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Section: Discussionmentioning

confidence: 99%

Th1-like Plasmodium -Specific Memory CD4 + T Cells Support Humoral Immunity

et al. 2017

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“…Administration of IC blockers in HIV-infected individuals on ART may not only reverse latent infection, but could also have the added benefit of enhanced immune clearance of latently infected cells [recently reviewed in [22] ]. Blocking interactions between PD-1 and PD-L1, as well as CTLA-4 and its ligands (CD80 and CD86), has been shown to increase HIV-specific CD4 + and CD8 + T-cell function both ex vivo [23] , and in vivo in SIV-infected macaques [24] .…”

Section: Discussionmentioning

confidence: 99%

“…Second, following the administration of anti-PD-L1, ligation of PD-1 is still possible through PD-L2. PD-L2 has multiple functions in addition to binding to PD-1 and, in some settings, can enhance rather than suppress T-cell function [27, 28] . Surprisingly, we were unable to find any publications on the relative expression of PD-L1 and PD-L2 in HIV-infected individuals on ART.…”

Section: Discussionmentioning

confidence: 99%

Programmed cell death-1 contributes to the establishment and maintenance of HIV-1 latency

Evans

Sluis

Solomon

et al. 2018

Aids

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131

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Objective In HIV-infected individuals on antiretroviral therapy (ART), latent HIV is enriched in CD4+ T-cells expressing immune checkpoint molecules (ICs), in particular programmed cell death-1 (PD-1). We therefore assessed the effect of blocking PD-1 on latency, both in vitro and in vivo. Methods HIV latency was established in vitro following co-culture of resting CD4+ T-cells with myeloid dendritic cells. Expression of PD-1 was quantified by flow cytometry, and latency assessed in sorted PD-1high and PD-1low/− non-proliferating CD4+ memory T-cells. The role of PD-1 in the establishment of latency was determined by adding anti-PD-1 (pembrolizumab) to co-cultures before and after infection. Additionally, a single infusion of anti-PD-1 (nivolumab) was administered to an HIV-infected individual on ART with metastatic melanoma, and cell-associated (CA) HIV DNA and RNA, and plasma HIV RNA were quantified. Results HIV latency was significantly enriched in PD-1high compared to PD-1low/− nonproliferating, CD4+ memory T-cells. Sorting for an additional IC, T-cell immunoglobulin domain and mucin domain-3 (Tim-3), in combination with PD-1 further enriched for latency. Blocking PD-1 prior to HIV infection, in vitro, resulted in a modest but significant decrease in latently infected cells in all donors (n=6). The administration of anti-PD-1 to an HIV-infected individual on ART, resulted in a significant increase in CA HIV RNA in CD4+ T-cells, without significant changes in HIV DNA or plasma HIV RNA, consistent with reversal of HIV latency. Conclusions PD-1 contributes to the establishment and maintenance of HIV latency and should be explored as a target, in combination with other ICs, to reverse latency.

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“…To promote the turnover of reactivated cells, immune based strategies including antibodies, T-cell vaccines and immunotherapeutics that enhance T-cell function, are being investigated to kill reactivated cells following latency reversal (reviewed elsewhere (Brockman et al, 2015; Marsden & Zack, 2015; Wykes & Lewin, 2017)). Alternatively, multiple lines of evidence reveal that HIV infection can impact both pro-apoptotic and anti-apoptotic pathways, potentially favouring cell death or cell survival respectively.…”

Section: Introductionmentioning

confidence: 99%

Getting the “Kill” into “Shock and Kill”: Strategies to Eliminate Latent HIV

Kim

Anderson

Lewin

2018

Cell Host & Microbe

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296

321

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Despite the success of antiretroviral therapy (ART), there is currently no HIV cure and treatment is lifelong. HIV persists during ART due to long lived and proliferating latently infected CD4+ T-cells. One strategy to eliminate latency is to activate virus production using latency reversing agents (LRAs) with the goal of triggering cell death through virus-induced cytolysis or immune-mediated clearance. However, multiple studies have demonstrated that activation of viral transcription alone is insufficient to induce cell death and some LRAs may counteract cell death by promoting cell survival. Here, we review new approaches to induce death of latently infected cells through apoptosis and inhibition of pathways critical for cell survival, which are often hijacked by HIV proteins. Given advances in the commercial development of compounds that induce apoptosis in cancer chemotherapy, these agents could move rapidly into clinical trials, either alone or in combination with LRAs, to eliminate latent HIV infection.

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Immune checkpoint blockade in infectious diseases

Cited by 410 publications

References 171 publications

Th1-like Plasmodium -Specific Memory CD4 + T Cells Support Humoral Immunity

Th1-like Plasmodium -Specific Memory CD4 + T Cells Support Humoral Immunity

Programmed cell death-1 contributes to the establishment and maintenance of HIV-1 latency

Getting the “Kill” into “Shock and Kill”: Strategies to Eliminate Latent HIV

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