Control of the HIV-1 DNA Reservoir Is Associated<i>In Vivo</i>and<i>In Vitro</i>with NKp46/NKp30 (CD335 CD337) Inducibility and Interferon Gamma Production by Transcriptionally Unique NK Cells

Marras, Francesco; Casabianca, Anna; Bozzano, Federica; Ascierto, Maria Libera; Orlandi, Chiara; Biagio, Antonio Di; Pontali, Emanuele; Dentone, Chiara; Orofino, Giancarlo; Nicolini, Laura Ambra; Taramasso, Lucia; Magnani, Mauro; Marincola, Francesco M.; Wang, Ena; Moretta, Alessandro; Maria, Andrea De

doi:10.1128/jvi.00647-17

Cited by 41 publications

(46 citation statements)

References 78 publications

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“…We also observed a downmodulation of NKp46 upon IL-15 exposure. This is in accordance with previous reports (50) and is troublesome, given the importance of this receptor in NK cell antiviral activity (22,51,52). Therefore, and even if we observed an important improvement in NK cell function despite NKp46 downmodulation, it might be of interest to consider a complementary strategy to boost NKp46 expression, thus further increasing NK cell antiviral function.…”

Section: Discussionsupporting

confidence: 92%

“…Immunological strategies in the field of HIV eradication have focused on HIV-specific cytotoxic T lymphocytes (CTLs) (19)(20)(21), although recently, interest in NK cells has emerged. The capacity of NK cells to produce IFN-␥ and upregulate NKp30 and NKp46 has been inversely associated with viral reservoir size (22), and HIV DNA decline was correlated with NK cell frequency after panobinostat treatment in a clinical study (23), suggesting a role for NK cells in the clearance of HIV infection. Moreover, recent data suggest that NK cells might play an important role in viral clearance in the lymph node (16).…”

Section: Discussionmentioning

confidence: 97%

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

Garrido

Abad-Fernández

Tuyishime

et al. 2018

J Virol

108

106

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Current efforts toward human immunodeficiency virus (HIV) eradication include approaches to augment immune recognition and elimination of persistently infected cells following latency reversal. Natural killer (NK) cells, the main effectors of the innate immune system, recognize and clear targets using different mechanisms than CD8 T cells, offering an alternative or complementary approach for HIV clearance strategies. We assessed the impact of interleukin 15 (IL-15) treatment on NK cell function and the potential for stimulated NK cells to clear the HIV reservoir. We measured NK cell receptor expression, antibody-dependent cell-mediated cytotoxicity (ADCC), cytotoxicity, interferon gamma (IFN-γ) production, and antiviral activity in autologous HIV replication systems. All NK cell functions were uniformly improved by IL-15, and, more importantly, IL-15-treated NK cells were able to clear latently HIV-infected cells after exposure to vorinostat, a clinically relevant latency-reversing agent. We also demonstrate that NK cells from HIV-infected individuals aviremic on antiretroviral therapy can be efficiently stimulated with IL-15. Our work opens a promising line of investigation leading to future immunotherapies to clear persistent HIV infection using NK cells. In the search for an HIV cure, strategies to enhance immune function to allow recognition and clearance of HIV-infected cells following latency reversal are being evaluated. Natural killer (NK) cells possess characteristics that can be exploited for immunotherapy against persistent HIV infection. We demonstrate that NK cells from HIV-positive donors can be strongly stimulated with IL-15, improving their antiviral and cytotoxic potential and, more importantly, clearing HIV-infected cells after latency reversal with a clinically relevant drug. Our results encourage further investigation to design NK cell-based immunotherapies to achieve HIV eradication.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 97%

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

Garrido

Abad-Fernández

Tuyishime

et al. 2018

J Virol

108

106

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“…Prior studies have characterized NK cells from HIV controllers (39) or compared NK cell functionality to clinical parameters (40). In this study, we used mass cytometry to simultaneously profile 24 NK cell surface markers on the single-cell level in 93 subjects with differing degrees of HIV infection control, including both VC and EC.…”

mentioning

confidence: 99%

Identification of NK Cell Subpopulations That Differentiate HIV-Infected Subject Cohorts with Diverse Levels of Virus Control

Pohlmeyer

Gonzalez

Irrinki

et al. 2019

J Virol

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HIV infection is controlled immunologically in a small subset of infected individuals without antiretroviral therapy (ART), though the mechanism of control is unclear. CD8 ϩ T cells are a critical component of HIV control in many immunological controllers. NK cells are also believed to have a role in controlling HIV infection, though their role is less well characterized. We used mass cytometry to simultaneously measure the levels of expression of 24 surface markers on peripheral NK cells from HIV-infected subjects with various degrees of HIV natural control; we then used machine learning to identify NK cell subpopulations that differentiate HIV controllers from noncontrollers. Using CITRUS (cluster identification, characterization, and regression), we identified 3 NK cell subpopulations that differentiated subjects with chronic HIV viremia (viremic noncontrollers [VNC]) from individuals with undetectable HIV viremia without ART (elite controllers [EC]). In a parallel approach, we identified 11 NK cell subpopulations that differentiated HIV-infected subject groups using k-means clustering after dimensionality reduction by t-neighbor stochastic neighbor embedding (tSNE) or linear discriminant analysis (LDA). Among these additional 11 subpopulations, the frequencies of 5 correlated with HIV DNA levels; importantly, significance was retained in 2 subpopulations in analyses that included only cohorts without detectable viremia. By comparing the surface marker expression patterns of all identified subpopulations, we revealed that the CD11b ϩ CD57 Ϫ CD161 ϩ Siglec-7 ϩ subpopulation of CD56 dim CD16 ϩ NK cells are more abundant in EC and HIV-negative controls than in VNC and that the frequency of these cells correlated with HIV DNA levels. We hypothesize that this population may have a role in immunological control of HIV infection. IMPORTANCE HIV infection results in the establishment of a stable reservoir of latently infected cells; ART is usually required to keep viral replication under control and disease progression at bay, though a small subset of HIV-infected subjects can control HIV infection without ART through immunological mechanisms. In this study, we sought to identify subpopulations of NK cells that may be involved in the natural immunological control of HIV infection. We used mass cytometry to measure surface marker expression on peripheral NK cells. Using two distinct semisupervised machine learning approaches, we identified a CD11b ϩ CD57 Ϫ CD161 ϩ Siglec-7 ϩ subpopulation of CD56 dim CD16 ϩ NK cells that differentiates HIV controllers from noncontrollers. These cells can be sorted out for future functional studies to assess their potential role in the immunological control of HIV infection.

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“…These prior data make it difficult to ascertain whether CD96 contributes to HIV control, but our observation that CD96 hi cells have improved functional activity against HIV may reflect different mechanisms of activation between HIV infection and stimulation by PMA/I. In addition, NKp30 expression is induced upon IL-2 stimulation, and is correlated with IFN-ɣ production and inversely associated with the HIV reservoir, suggesting that cells that upregulate NKp30 upon IL-2 stimulation may have improved activity against HIV (Marras et al, 2017). This is particularly relevant as our study used IL-2 activated NK cells.…”

Section: Discussionmentioning

confidence: 93%

“…IL-2 induces changes in NK receptor expression, including upregulation of the natural cytotoxicity receptors (NCRs) NKp30 and NKp46; however, the expression of most other NK receptors remains unchanged (Vendrame et al, 2017). The differences in cytokine-induced upregulation of these NCRs between the HIV+ and HIV-groups can additionally be informative, as upregulation of NCRs have been implicated in control of HIV (Marras et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Treated HIV Infection Alters Phenotype But Not HIV-specific Function of Peripheral Blood Natural Killer Cells

Zhao

Ferreira

Grant

et al. 2020

Preprint

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ABSTRACTNatural killer (NK) cells are the predominant antiviral cells of the innate immune system, and may play an important role in acquisition and disease progression of HIV. While untreated HIV infection is associated with distinct alterations in the peripheral blood NK cell repertoire, less is known about how NK phenotype is altered in the setting of long-term viral suppression with antiretroviral therapy (ART), as well as how NK memory can impact functional responses. As such, we sought to identify changes in NK cell phenotype and function using high-dimensional mass cytometry to simultaneously analyze both surface and functional marker expression of peripheral blood NK cells in a cohort of ART-suppressed, HIV+ patients and HIV-healthy controls. We found that the NK cell repertoire following IL-2 treatment was altered in individuals with treated HIV infection compared to healthy controls, with increased expression of markers including NKG2C and CD2, and decreased expression of CD244 and NKp30. Using co-culture assays with autologous, in vitro HIV-infected CD4 T cells, we identified a subset of NK cells with enhanced responsiveness to HIV-1-infected cells, but no differences in the magnitude of anti-HIV NK cell responses between the HIV+ and HIV-groups. In addition, by profiling of NK cell receptors on responding cells, we found similar phenotypes of HIV-responsive NK cell subsets in both groups. Lastly, we identified clusters of NK cells that are altered in individuals with treated HIV infection compared to healthy controls, but found that these clusters are distinct from those that respond to HIV in vitro. As such, we conclude that while chronic, treated HIV infection induces a reshaping of the IL-2-stimulated peripheral blood NK cell repertoire, it does so in a way that does not make the repertoire more HIV-specific.

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Control of the HIV-1 DNA Reservoir Is AssociatedIn VivoandIn Vitrowith NKp46/NKp30 (CD335 CD337) Inducibility and Interferon Gamma Production by Transcriptionally Unique NK Cells

Abstract: The size of lentiviral DNA reservoirs reflects the effectiveness of immune responses against lentiviruses. So far, abundant information has been gathered on

Cited by 41 publications

References 78 publications

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

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

Identification of NK Cell Subpopulations That Differentiate HIV-Infected Subject Cohorts with Diverse Levels of Virus Control

Treated HIV Infection Alters Phenotype But Not HIV-specific Function of Peripheral Blood Natural Killer Cells

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