Pegylated Interferon-α–Induced Natural Killer Cell Activation Is Associated With Human Immunodeficiency Virus-1 DNA Decline in Antiretroviral Therapy–Treated HIV-1/Hepatitis C Virus–Coinfected Patients

Hua, Stéphane; Viganó, Selena; Tse, Samantha; Ouyang, Zhengyu; Harrington, Sean; Negron, Jordi; García-Broncano, Pilar; Marchetti, Giulia; Genebat, Miguel; Leal, Manuel; Resino, Salvador; Ruiz‐Mateos, Ezequiel; Lichterfeld, Mathias; Yu, Xu G.

doi:10.1093/cid/cix1111

Cited by 33 publications

(31 citation statements)

References 46 publications

(43 reference statements)

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“…A clinical trial has already shown that treatment with IFN-␣ prolongs the time to viral rebound following the cessation of ART (60). In another study, NK cell activation was associated with a decline in cell-associated HIV-1 DNA in HIV-1/HCV-coinfected subjects treated with pegylated IFN-␣ and ribavirin (61). While a recent study in SIV-infected monkeys on ART suggested that pegylated IFN-␣2a treatment did not significantly affect the size of the viral reservoir (62), this could potentially be because there was no LRA given in conjunction with this immunomodulatory agent.…”

Section: Fig 6 Ifn-␣ Enhances the Suppressive Capacity Of Vp And Es Cd8mentioning

confidence: 98%

Interferon Alpha Enhances NK Cell Function and the Suppressive Capacity of HIV-Specific CD8⁺T Cells

Kwaa

Talana

Blankson

2019

J Virol

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Current shock-and-kill strategies for the eradication of the HIV-1 reservoir have resulted in blips of viremia but not in a decrease in the size of the latent reservoir in patients on suppressive antiretroviral therapy (ART). This discrepancy could potentially be explained by an inability of the immune system to kill HIV-1-infected cells following the reversal of latency. Furthermore, some studies have suggested that certain latency-reversing agents (LRAs) may inhibit CD8+T cell and natural killer (NK) cell responses. In this study, we tested the hypothesis that alpha interferon (IFN-α) could improve the function of NK cells from chronic progressors (CP) on ART. We show here that IFN-α treatment enhanced cytokine secretion, polyfunctionality, degranulation, and the cytotoxic potential of NK cells from healthy donors (HD) and CP. We also show that this cytokine enhanced the viral suppressive capacity of NK cells from HD and elite controllers or suppressors. Furthermore, IFN-α enhanced global CP CD8+T cell cytokine responses and the suppressive capacity of ES CD8+T cells. Our data suggest that IFN-α treatment may potentially be used as an immunomodulatory agent in HIV-1 cure strategies.IMPORTANCEData suggest that HIV+individuals unable to control infection fail to do so due to impaired cytokine production and/cytotoxic effector cell function. Consequently, the success of cure agendas such as the shock-and-kill strategy will probably depend on enhancing patient effector cell function. In this regard, NK cells are of particular interest since they complement the function of CD8+T cells. Here, we demonstrate the ability of short-course alpha interferon (IFN-α) treatments to effectively enhance such effector functions in chronic progressor NK cells without inhibiting their general CD8+T cell function. These results point to the possibility of exploring such short-course IFN-α treatments for the enhancement of effector cell function in HIV+patients in future cure strategies.

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Section: Fig 6 Ifn-␣ Enhances the Suppressive Capacity Of Vp And Es Cd8mentioning

confidence: 98%

Interferon Alpha Enhances NK Cell Function and the Suppressive Capacity of HIV-Specific CD8⁺T Cells

Kwaa

Talana

Blankson

2019

J Virol

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“…Gibbert et al ( 89 ) demonstrated that IFN-α11-activated NK cells that enabled cytolytic killing of Friend retrovirus-infected cells compared to other subtypes such as IFN-α2 and IFN-α5. Hua et al ( 90 ) recently reported that the treatment of HIV-1/HCV co-infected subjects on HAART with pegylated-IFN-α induced activation of CD56 bright CD16 − and CD56 bright CD16 + NK cells expressing NKG2D an NKp30 that significantly correlated with a decrease in level of HIV-1 viral reservoir in CD4 T cells. Song et al ( 67 ) examined that the effect of IFN-α subtypes on HBV infection and found that IFN-α4 and IFN-α5 correlated with expansion of effector NK cells in both liver and spleen that was associated with better control of HBV replication.…”

Section: Ifn-α Subtypes and Potential For Functional Curementioning

confidence: 99%

Interferon-α Subtypes As an Adjunct Therapeutic Approach for Human Immunodeficiency Virus Functional Cure

George

Mattapallil

2018

Front. Immunol.

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Human immunodeficiency virus (HIV) establishes life-long latency in infected individuals. Although highly active antiretroviral therapy (HAART) has had a significant impact on the course of HIV infection leading to a better long-term outcome, the pool of latent reservoir remains substantial even under HAART. Numerous approaches have been under development with the goal of eradicating the latent HIV reservoir though with limited success. Approaches that combine immune-mediated control of HIV to activate both the innate and the adaptive immune system under suppressive therapy along with “shock and kill” drugs may lead to a better control of the reactivated virus. Interferon-α (IFN-α) is an innate cytokine that has been shown to activate intracellular defenses capable of restricting and controlling HIV. IFN-α, however, harbors numerous functional subtypes that have been reported to display different binding affinities and potency. Recent studies have suggested that certain subtypes such as IFN-α8 and IFN-α14 have potent anti-HIV activity with little or no immune activation, whereas other subtypes such as IFN-α4, IFN-α5, and IFN-α14 activate NK cells. Could these subtypes be used in combination with other strategies to reduce the latent viral reservoir? Here, we review the role of IFN-α subtypes in HIV infection and discuss the possibility that certain subtypes could be potential adjuncts to a “shock and kill” or therapeutic vaccination strategy leading to better control of the latent reservoir and subsequent functional cure.

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“…Interestingly, HIV + individuals with this favorable outcome had higher frequencies of cytotoxic CD56 dim NK cells (Olesen et al 2015), and the authors speculate that this may have resulted from LRA-induced alteration in expression of NK receptor ligands on infected CD4 + T cells. In another study, PEG-IFNα induced NK cell activation in Hepatitis C/HIV-1 coinfected individuals on long-term suppressive cART; there was a significant correlation between CD56 bright NK cell levels and decreases in cell-associated proviral DNA (Hua et al 2017). These results indicate that both types of NK cells may play a role in cytolysis of infected cell targets upon HIV-1 induction.…”

Section: Directing the Immune Response To Effectively Target The Resementioning

confidence: 99%

Targeting the Latent Reservoir for HIV-1

2018

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Antiretroviral therapy can effectively block HIV-1 viral replication and prevent or reverse immunodeficiency in HIV-1-infected individuals. However, viral replication resumes within weeks of treatment interruption. The major barrier to cure is a small pool of resting memory CD4+ T cells that harbor latent HIV-1 proviruses. This latent reservoir is now the focus of an intense international research effort. We describe how the reservoir is established, challenges involved in eliminating it, and pharmacologic and immunologic strategies for targeting this reservoir. The development of a successful cure strategy will likely require understanding the mechanisms that maintain HIV-1 proviruses in a latent state and pathways that drive the proliferation of infected cells, which slows reservoir decay. In addition, cure will require the development of effective immunologic approaches to eliminating infected cells. There is renewed optimism about the prospect of a cure, and the interventions discussed here may pave the way.

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Pegylated Interferon-α–Induced Natural Killer Cell Activation Is Associated With Human Immunodeficiency Virus-1 DNA Decline in Antiretroviral Therapy–Treated HIV-1/Hepatitis C Virus–Coinfected Patients

Abstract: These data suggest that the reduction of viral reservoir cells during treatment with IFN-α is primarily attributable to antiviral activities of NK cells.

Cited by 33 publications

References 46 publications

Interferon Alpha Enhances NK Cell Function and the Suppressive Capacity of HIV-Specific CD8⁺T Cells

Interferon Alpha Enhances NK Cell Function and the Suppressive Capacity of HIV-Specific CD8⁺T Cells

Interferon-α Subtypes As an Adjunct Therapeutic Approach for Human Immunodeficiency Virus Functional Cure

Targeting the Latent Reservoir for HIV-1

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Pegylated Interferon-α–Induced Natural Killer Cell Activation Is Associated With Human Immunodeficiency Virus-1 DNA Decline in Antiretroviral Therapy–Treated HIV-1/Hepatitis C Virus–Coinfected Patients

Abstract: These data suggest that the reduction of viral reservoir cells during treatment with IFN-α is primarily attributable to antiviral activities of NK cells.

Cited by 33 publications

References 46 publications

Interferon Alpha Enhances NK Cell Function and the Suppressive Capacity of HIV-Specific CD8+T Cells

Interferon Alpha Enhances NK Cell Function and the Suppressive Capacity of HIV-Specific CD8+T Cells

Interferon-α Subtypes As an Adjunct Therapeutic Approach for Human Immunodeficiency Virus Functional Cure

Targeting the Latent Reservoir for HIV-1

Contact Info

Product

Resources

About

Interferon Alpha Enhances NK Cell Function and the Suppressive Capacity of HIV-Specific CD8⁺T Cells

Interferon Alpha Enhances NK Cell Function and the Suppressive Capacity of HIV-Specific CD8⁺T Cells