NK Response Correlates with HIV Decrease in Pegylated IFN-α2a–Treated Antiretroviral Therapy–Suppressed Subjects

Papasavvas, Emmanouil; Azzoni, Livio; Kossenkov, Andrew V.; Dawany, Noor; Morales, Knashawn H.; Fair, Matthew; Ross, Brian N.; Lynn, Kenneth; Mackiewicz, Agnieszka; Mounzer, Karam; Tebas, Pablo; Jacobson, Jeffrey M.; Kostman, Jay R.; Showe, Louise C.; Montaner, Luis J.

doi:10.4049/jimmunol.1801511

Cited by 22 publications

(18 citation statements)

References 80 publications

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“…CD8 + T and NK cell functions are important for the antiviral effect of IFNα treatment [38] and the impact of IFNα on levels of integrated HIV DNA was associated with NK activation and cytotoxic response to K562 target cells [39] . To examine the links between IFNα-mediated alterations in IgG glycosylation, inflammatory markers, and immune functions, we evaluated CD8 + T cell (without stimulation) and NK cell (upon K562 stimulation) phenotypes using flow cytometry (green and blue arcs in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Our observations that IFNα induces sialic acid on the NK surface and that this induction correlates negatively with NK functions warrant further investigation. IFNα is an activator of NK cell functions [75 , 76] , and the positive impact of IFNα on levels of integrated HIV DNA was associated with NK activation and cytotoxic response to K562 target cells [39] . However, IFNα-mediated induction of sialic acid may exert a negative effect that hampers taking full advantage of the positive impact of IFNα on NK cells.…”

Section: Discussionmentioning

confidence: 99%

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Interferon-α alters host glycosylation machinery during treated HIV infection

et al. 2020

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Background A comprehensive understanding of host factors modulated by the antiviral cytokine interferon-α (IFNα) is imperative for harnessing its beneficial effects while avoiding its detrimental side-effects during HIV infection. Cytokines modulate host glycosylation which plays a critical role in mediating immunological functions. However, the impact of IFNα on host glycosylation has never been characterized. Methods We assessed the impact of pegylated IFNα2a on IgG glycome, as well as CD8 + T and NK cell-surface glycomes, of 18 HIV-infected individuals on suppressive antiretroviral therapy. We linked these glycomic signatures to changes in inflammation, CD8 + T and NK cell phenotypes, and HIV DNA. Findings We identified significant interactions that support a model in which a) IFNα increases the proportion of pro-inflammatory, bisecting GlcNAc glycans (known to enhance FcγR binding) within the IgG glycome, which in turn b) increases inflammation, which c) leads to poor CD8 + T cell phenotypes and poor IFNα-mediated reduction of HIV DNA. Examining cell-surface glycomes, IFNα increases levels of the immunosuppressive GalNAc-containing glycans (T/Tn antigens) on CD8 + T cells. This induction is associated with lower HIV-gag-specific CD8 + T cell functions. Last, IFNα increases levels of fucose on NK cells. This induction is associated with higher NK functions upon K562 stimulation. Interpretation IFNα causes host glycomic alterations that are known to modulate immunological responses. These alterations are associated with both detrimental and beneficial consequences of IFNα. Manipulating host glycomic interactions may represent a strategy for enhancing the positive effects of IFNα while avoiding its detrimental side-effects. Funding NIH grants R21AI143385, U01AI110434.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Interferon-α alters host glycosylation machinery during treated HIV infection

et al. 2020

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“…The fact that ART cessation likely induces near-maximal IFN-I responses at the sites of virus recrudescence will need to be factored into the design of these strategies. Consistent with this, a recent study found that activation of NK cell cytotoxicity, and not the induction of interferon stimulated genes, correlated with exogenous IFNα2-mediated HIV-1 control ( 85 ).…”

Section: Discussionmentioning

confidence: 55%

“…1C). ART was initiated in eight participants between 85 and 323 weeks post onset of symptoms based on the standard-of-care at the time (shaded in Fig. 1).…”

Section: Generation Of Plasma Isolates From Longitudinally Sampled Inmentioning

confidence: 99%

Heightened resistance to type 1 interferons characterizes HIV-1 at transmission and following analytical treatment interruption

Gondim

Sherrill-Mix

Bibollet-Ruche

et al. 2020

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Type 1 interferons (IFN-I) are potent innate antiviral effectors that constrain HIV-1 transmission. However, harnessing these cytokines for HIV-1 cure strategies has been hampered by an incomplete understanding of their anti-viral activities at later stages of infection. Here, we characterized the IFN-I sensitivity of 500 clonally-derived HIV-1 isolates from plasma and CD4+ T cells of 26 individuals sampled longitudinally following transmission and/or after antiretroviral therapy (ART) and analytical treatment interruption (ATI). Determining the concentration of IFNα2 and IFNβ that reduced HIV-1 replication by 50% (IC50), we found remarkably consistent changes in the sensitivity of viruses to IFN-I inhibition, both across individuals and over time. IFN-I resistance was uniformly high during acute infection, decreased in all subjects in the first year post-infection, was reacquired concomitant with CD4+ T cell loss, and remained elevated in subjects with accelerated disease. Isolates obtained by viral outgrowth during suppressive ART were relatively IFN-I sensitive, resembling viruses circulating just prior to ART initiation. However, viruses that rebounded following treatment interruption displayed the highest levels of IFNα2 and IFNβ resistance observed at any time during the infection course. These findings indicate a dynamic interplay between host innate immune responses and the evolving HIV-1 quasispecies, with the relative contribution of IFN-I to HIV-1 control impacted by both ART and ATI. Although elevated at transmission, IFN-mediated pressures are the highest during viral rebound, limiting the viruses that successfully reactivate from latency.

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“…For example, ex vivo IL-21 treatment expanded CD16 + NK cells 9 , antagonized the IL-15-dependent expansion of resting NK cells 10 , and reverses hypo-responsiveness via the STAT1 and PI3K-AKT-FOXO1 pathways 11 . Likewise, ex vivo IFNα therapy upregulates IL-15-mediated NK cell cytotoxicity 12 , including CD107a degranulation and ADCC activity 13,14 , and downregulates IL-21R expression 15 ; furthermore, in vivo IFNα-induced NK cell cytotoxicity correlates with reductions in HIV-DNA during antiretroviral therapy (ART) 16 . In SIVagm infection, systemic IL-15 was associated with NK cell proliferation in lymph node (LN), while systemic IFNα correlated with NK cell cytotoxicity in LN 17 .…”

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confidence: 99%

IL-21 and IFNα therapy rescues terminally differentiated NK cells and limits SIV reservoir in ART-treated macaques

et al. 2021

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Unlike HIV infection, which progresses to AIDS absent suppressive anti-retroviral therapy, nonpathogenic infections in natural hosts, such African green monkeys, are characterized by a lack of gut microbial translocation and robust secondary lymphoid natural killer cell responses resulting in an absence of chronic inflammation and limited SIV dissemination in lymph node B-cell follicles. Here we report, using the pathogenic model of antiretroviral therapy-treated, SIV-infected rhesus macaques that sequential interleukin-21 and interferon alpha therapy generate terminally differentiated blood natural killer cells (NKG2a/clowCD16+) with potent human leukocyte antigen-E-restricted activity in response to SIV envelope peptides. This is in contrast to control macaques, where less differentiated, interferon gamma-producing natural killer cells predominate. The frequency and activity of terminally differentiated NKG2a/clowCD16+ natural killer cells correlates with a reduction of replication-competent SIV in lymph node during antiretroviral therapy and time to viral rebound following analytical treatment interruption. These data demonstrate that African green monkey-like natural killer cell differentiation profiles can be rescued in rhesus macaques to promote viral clearance in tissues.

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NK Response Correlates with HIV Decrease in Pegylated IFN-α2a–Treated Antiretroviral Therapy–Suppressed Subjects

Cited by 22 publications

References 80 publications

Interferon-α alters host glycosylation machinery during treated HIV infection

Interferon-α alters host glycosylation machinery during treated HIV infection

Heightened resistance to type 1 interferons characterizes HIV-1 at transmission and following analytical treatment interruption

IL-21 and IFNα therapy rescues terminally differentiated NK cells and limits SIV reservoir in ART-treated macaques

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