Interleukin-15-Stimulated Natural Killer Cells Clear HIV-1-Infected Cells following Latency Reversal
            <i>Ex Vivo</i>

Garrido, Carolina; Abad-Fernández, María; Tuyishime, Marina; Pollara, Justin; Ferrari, Guido; Soriano-Sarabia, Natalia; Margolis, David M.

doi:10.1128/jvi.00235-18

Cited by 110 publications

(115 citation statements)

References 56 publications

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“…Assays to analyze clearance of latent HIV after reactivation. These experiments are based on the latency clearance assay reported for CD8 + T cells (8) and more recently for NK cells (44). Briefly, r-CD4 + cells from HIV-infected donors were isolated as described above, and exposed to 0.5 μM VOR for 18 hours.…”

Section: Methodsmentioning

confidence: 99%

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γδ T cells: an immunotherapeutic approach for HIV cure strategies

Garrido¹,

Clohosey²,

Whitworth³

et al. 2018

JCI Insight

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Current strategies aimed to cure HIV infection are based on combined efforts to reactivate the virus from latency and improve immune effector cell function to clear infected cells. These strategies are primarily focused on CD8+ T cells and approaches are challenging due to insufficient HIV antigen production from infected cells and poor HIV-specific CD8+ T cells. γδ T cells represent a unique subset of effector T cells that can traffic to tissues, and selectively target cancer or virally infected cells without requiring MHC presentation. We analyzed whether γδ T cells represent a complementary/alternative immunotherapeutic approach towards HIV cure strategies. γδ T cells from HIV-infected virologically suppressed donors were expanded with bisphosphonate pamidronate (PAM) and cells were used in autologous cellular systems ex vivo. These cells (a) are potent cytotoxic effectors able to efficiently inhibit HIV replication ex vivo, (b) degranulate in the presence of autologous infected CD4+ T cells, and (c) specifically clear latently infected cells after latency reversal with vorinostat. This is the first proof of concept to our knowledge showing that γδ T cells target and clear autologous HIV reservoirs upon latency reversal. Our results open potentially new insights into the immunotherapeutic use of γδ T cells for current interventions in HIV eradication strategies.

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Section: Methodsmentioning

confidence: 99%

“…To further analyze the role of γδ T cells in a context more relevant to HIV eradication in vivo, we performed a modification of the previously reported latency clearance assay (8,44). In this assay, the capacity of effector cells to recognize latent HIV reactivated by LRAs was evaluated.…”

Section: Figure 5 Vδ2 Cells Degranulate In the Presence Of Autologoumentioning

confidence: 99%

γδ T cells: an immunotherapeutic approach for HIV cure strategies

Garrido¹,

Clohosey²,

Whitworth³

et al. 2018

JCI Insight

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“…The beneficial effects of IL-15 immunotherapy and IL-15 superagonist ALT-803, capable of activating both NK cells and CD8 T cells, have been highlighted in vivo in non-human primate models (Webb et al, 2018) and such an approach is currently being tested in a phase I clinical trial to facilitate clearance of latent HIV-1 reservoirs (NCT02191098). The ability of IL-15 to enhance ADCC and augment NK cell mediated killing of HIV-infected target cells ex vivo (Garrido et al, 2018) may prove vital in the development of a functional cure for HIV. Our findings together with a recent report of IL-15 mediated metabolic reprogramming improving the efficacy of HIV-specific CD8 T cells from non-controllers (Angin, 2019), highlight the complementary effects of such an approach to simultaneously re-invigorate multiple arms of the immune response.…”

Section: Discussionmentioning

confidence: 99%

IL-15 re-programming compensates for NK cell mitochondrial dysfunction in HIV-1 infection

Cubero

Balint

Alrubayyi³

et al. 2019

Preprint

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16Dynamic regulation of cellular metabolism is important for maintaining homeostasis and can directly 17 influence immune cell function and differentiation including Natural Killer (NK) cell responses. 18Persistent HIV-1 infection leads to a state of chronic activation, subset redistribution and progressive 45 et al., 2015) (Lee et al., 2015). The adaptive reconfiguration of NK cells during HIV-1 infection is further 46 delineated by loss of the transcription factor promyelocytic leukaemia zinc finger protein (PLZF), and 47 downstream signalling molecules such as FcεRI-γ (Peppa et al., 2018), which partly overlap with 48 NKG2C expression. While these attributes are considered important in the functional specialisation of 49 2 these NK cells, the development of these features under conditions of continuous 50 stimulation/persistent inflammation during HIV-1 infection could lead to the establishment of 51 functionally and metabolically exhausted NK cells akin to exhausted CD8 T cells. In keeping with this 52 notion, chronic stimulation of adaptive NK cells through NKG2C ligation was recently found to lead to 53 a molecular programme of exhaustion that is shared between NK cells and CD8 T cells (Merino et al., 54 2019). Exhausted CD8 T cells are characterised by a number of metabolic defects, however, to date it 55 remains unexplored how persistent HIV-1 infection contributes to the metabolic remodelling of NK 56 cell subsets. NK cell exhaustion could influence responses to CD16 engagement linked to vaccine-57 induced protective immunity against HIV-1 infection and phenotypes of viral control (Scully and Alter, 58 2016). Such knowledge represents a critical first step in our understanding of the metabolic machinery 59 of NK cell subsets with distinct immunologic features that can be potentially targeted for developing 60 new or complementary antiviral approaches aimed at enhancing ADCC responses. 61 62 Whereas metabolic regulation of T cell function is well characterised, evidence of the importance of 63 immunometabolism in facilitating robust NK cell functions is gradually emerging. Notably, impaired 64 NK cell cellular metabolism has been implicated in obesity and cancer, providing a new framework for 65 understanding NK cell functionality (Michelet et al., 2018) (Cong et al., 2018). Studies from both 66 human and murine models have demonstrated that NK cells activated through cytokine stimulation 67 exhibit substantial increases in the rates of both glycolysis and oxidative phosphorylation (OXPHOS) 68 pathways (Marcais et al., 2014) (Donnelly et al., 2014) (Keating et al., 2016; O'Brien and Finlay, 2019). 69However, the metabolic requirement of NK cells for optimal effector function, in terms of IFN- 70 production, depends on the specific activation stimuli. In particular, receptor mediated activation 71 through anti-NK1.1 and anti-Ly49D in mice appears to require OXPHOS as an essential second signal 72 for IFN- production and appears more susceptible to metabolic inhibition compared to cytokine 73 stimulation ...

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“…70 Because this agonist is capable of activating both CD8+ T and NK cells, there is substantial interest in utilizing ALT-803 in SIV/HIV infection. 72 34 As IL-15 treatment enhances ADCC and can sometimes be used in concert with other cytokines, this approach may also be able to elicit adaptive ΔG NK or cytokine-induced NK cells, though this remains to be shown. This approach may prove pivotal for the development of functional cure therapies for HIV.…”

Section: Blocking Inhibitory Nk Cell Receptors During Infectionmentioning

confidence: 99%

“…Interestingly, NK cells from HIV-positive donors can be strongly stimulated with IL-15 in order to improve their antiviral and cytotoxic potential and, more importantly, enhance their ability to clear HIV-infected cells. 34 The first demonstration that primates mobilize adaptive NK cells against HIV/SIV antigens was provided by our group. 11 In this study our group showed that purified NK cells from the spleens and livers of rhesus macaques infected with simian-HIV (SHIV) demonstrated antigen-specific NK cell responses against viral proteins.…”

Section: Introductionmentioning

confidence: 99%

Adaptive NK cell responses in HIV/SIV infections: A roadmap to cell-based therapeutics?

Ram

Manickam

Lucar

et al. 2019

Journal of Leukocyte Biology

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NK cells play a critical role in antiviral and antitumor responses. Although current NK cell immune therapies have focused primarily on cancer biology, many of these advances can be readily applied to target HIV/simian immunodeficiency virus (SIV)‐infected cells. Promising developments include recent reports that CAR NK cells are capable of targeted responses while producing less off‐target and toxic side effects than are associated with CAR T cell therapies. Further, CAR NK cells derived from inducible pluripotent stem cells or cell lines may allow for more rapid “off‐the‐shelf” access. Other work investigating the IL‐15 superagonist ALT‐803 (now N803) may also provide a recourse for enhancing NK cell responses in the context of the immunosuppressive and inflammatory environment of chronic HIV/SIV infections, leading to enhanced control of viremia. With a broader acceptance of research supporting adaptive functions in NK cells it is likely that novel immunotherapeutics and vaccine modalities will aim to generate virus‐specific memory NK cells. In doing so, better targeted NK cell responses against virus‐infected cells may usher in a new era of NK cell‐tuned immune therapy.

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Interleukin-15-Stimulated Natural Killer Cells Clear HIV-1-Infected Cells following Latency Reversal Ex Vivo

Cited by 110 publications

References 56 publications

γδ T cells: an immunotherapeutic approach for HIV cure strategies

γδ T cells: an immunotherapeutic approach for HIV cure strategies

IL-15 re-programming compensates for NK cell mitochondrial dysfunction in HIV-1 infection

Adaptive NK cell responses in HIV/SIV infections: A roadmap to cell-based therapeutics?

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