Differential Effects of Interleukin-7 and Interleukin-15 on NK Cell Anti-Human Immunodeficiency Virus Activity

Lum, Julian J.; Schnepple, David J.; Nie, Zilin; Sanchez-Dardon, Jaime; Mbisa, Georgina; Mihowich, Jennifer; Hawley, Nanci; Narayan, Shanil; Kim, John E.; Lynch, David H.; Badley, Andrew D.

doi:10.1128/jvi.78.11.6033-6042.2004

Cited by 53 publications

(48 citation statements)

References 82 publications

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“…IL-15 is currently proposed as adjuvant immunotherapy for HIV ϩ individuals (18,53,54) and has also been shown to curtail infections by human herpesviruses (33). Our data indicate that it may also be beneficial in HCV infection, where IFN-␣ treatment is already used, and may potentially be useful in other chronic infections too.…”

Section: Cd28mentioning

confidence: 62%

Shared Alterations in NK Cell Frequency, Phenotype, and Function in Chronic Human Immunodeficiency Virus and Hepatitis C Virus Infections

Meier

Owen

Taylor

et al. 2005

J Virol

165

145

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Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) cause clinically important persistentinfections. The effects of virus persistence on innate immunity, including NK cell responses, and the underlying mechanisms are not fully understood. We examined the frequency, phenotype, and function of peripheral blood CD3 ؊ CD56 ؉ NK subsets in HIV ؉ and HCV ؉ patients and identified significantly reduced numbers of total NK cells and a striking shift in NK subsets, with a marked decrease in the CD56 dim cell fraction compared to CD56 bright cells, in both infections. This shift influenced the phenotype and functional capacity (gamma interferon production, killing) of the total NK pool. In addition, abnormalities in the functional capacity of the CD56 dim NK subset were observed in HIV ؉ patients. The shared NK alterations were found to be associated with a significant reduction in serum levels of the innate cytokine interleukin 15 (IL-15). In vitro stimulation with IL-15 rescued NK cells of HIV ؉ and HCV ؉ patients from apoptosis and enhanced proliferation and functional activity. We hypothesize that the reduced levels of IL-15 present in the serum during HIV and HCV infections might impact NK cell homeostasis, contributing to the common alterations of the NK pool observed in these unrelated infections.

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Section: Cd28mentioning

confidence: 62%

Shared Alterations in NK Cell Frequency, Phenotype, and Function in Chronic Human Immunodeficiency Virus and Hepatitis C Virus Infections

Meier

Owen

Taylor

et al. 2005

J Virol

165

145

View full text Add to dashboard Cite

show abstract

“…Currently, a number of potential immunotherapeutic agents, including cytokines such as IL-2, IL-7, and IL-15, are being investigated for their potential to increase T-cell levels in HIV patients. [42][43][44][45][46][47] Of these, IL-7 is promising because of its multiple roles in T-cell homeostasis. 16,18,41,48 Our detailed studies in SIVsminfected mangabeys, SIVmac-infected macaques, and HIV-infected humans confirm the importance of IL-7 in regulating T-cell levels during continued infection.…”

Section: Discussionmentioning

confidence: 99%

Timely triggering of homeostatic mechanisms involved in the regulation of T-cell levels in SIVsm-infected sooty mangabeys

Muthukumar

Zhou

Paiardini

et al. 2005

Blood

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Sooty mangabeys, the natural host of simian immunodeficiency virus (SIVsm), generally avoid progressive depletion of CD4 ؉ T cells and opportunistic infections associated with infection of humans (HIV) and macaques (SIVmac). The means by which the SIVsm-infected mangabeys maintain CD4 ؉ T-cell levels despite high rates of viral replication is unknown. One cytokine that has a key role in the regulation of T-cell levels is interleukin-7 (IL-7). Here, the longitudinal assessment of 6 SIVsm-infected mangabeys identified an early increase in plasma IL-7 levels at weeks 1 to 5 after infection. This IL-7 increase correlated with an early decline in CD4 ؉ T-cell levels (decline of 492-1171 cells/L) accompanying acute viremia. Elevated IL-7 levels were followed by increased T-cell proliferation (Ki67) and maintenance of lower but stable (more than 500 cells/L) CD4 ؉ T-cell levels in each mangabey through 37 weeks of infection. These data contrast with our earlier studies in SIVmac-infected macaques, in which the IL-7 increase was delayed until 20 to 40 weeks after infection, just before the onset of simian AIDS. Taken together, these data suggest that timely triggering of IL-7 is important for stabilizing healthy T-cell levels in mangabeys and that timely administration of exogenous IL-7 may show benefit during pathogenic SIVmac and HIV infection.

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“…IL-15 activates neutrophils and macrophages, promotes the survival of NK cells, and is important for the homeostatic proliferation of CD8 ϩ T cells (20). In vitro, IL-15 appears to be superior to IL-7 in enhancing HIV-specific CD8 ϩ T cell effector function (21,22) and NKmediated antiviral activity in autologous PBMCs (23).…”

Section: H Uman Immunodeficiency Virus Infection Of Humans Ifmentioning

confidence: 99%

Interleukin-15 but Not Interleukin-7 Abrogates Vaccine-Induced Decrease in Virus Level in Simian Immunodeficiency Virusmac251-Infected Macaques

Hryniewicz

Price

Moniuszko

et al. 2007

The Journal of Immunology

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The loss of CD4+ T cells and the impairment of CD8+ T cell function in HIV infection suggest that pharmacological treatment with IL-7 and IL-15, cytokines that increase the homeostatic proliferation of T cells and improve effector function, may be beneficial. However, these cytokines could also have a detrimental effect in HIV-1-infected individuals, because both cytokines increase HIV replication in vitro. We assessed the impact of IL-7 and IL-15 treatment on viral replication and the immunogenicity of live poxvirus vaccines in SIVmac251-infected macaques (Macaca mulatta). Neither cytokine augmented the frequency of vaccine-expanded CD4+ or CD8+ memory T cells, clonal recruitment to the SIV-specific CD8+ T cell pool, or CD8+ T cell function. Vaccination alone transiently decreased the viral set point following antiretroviral therapy suspension. IL-15 induced massive proliferation of CD4+ effector T cells and abrogated the ability of vaccination to decrease set point viremia. In contrast, IL-7 neither augmented nor decreased the vaccine effect and was associated with a decrease in TGF-β expression. These results underscore the importance of testing immunomodulatory approaches in vivo to assess potential risks and benefits for HIV-1-infected individuals.

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Differential Effects of Interleukin-7 and Interleukin-15 on NK Cell Anti-Human Immunodeficiency Virus Activity

Cited by 53 publications

References 82 publications

Shared Alterations in NK Cell Frequency, Phenotype, and Function in Chronic Human Immunodeficiency Virus and Hepatitis C Virus Infections

Shared Alterations in NK Cell Frequency, Phenotype, and Function in Chronic Human Immunodeficiency Virus and Hepatitis C Virus Infections

Timely triggering of homeostatic mechanisms involved in the regulation of T-cell levels in SIVsm-infected sooty mangabeys

Interleukin-15 but Not Interleukin-7 Abrogates Vaccine-Induced Decrease in Virus Level in Simian Immunodeficiency Virusmac251-Infected Macaques

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