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

Abstract

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.

Antigen-Independent Induction of Tim-3 Expression on Human T Cells by the Common γ-Chain Cytokines IL-2, IL-7, IL-15, and IL-21 Is Associated with Proliferation and Is Dependent on the Phosphoinositide 3-Kinase Pathway

“…IL-2 and IL-7 administered to HIV-1-infected individuals was shown to enhance the frequency of CD4 + T cells (29,(54)(55)(56). In SIV-infected macaques, IL-15 failed to improve viral loads after a therapeutic SIV vaccine, and it had no effect on SIV-specific CD8 + function (57). These studies did not examine Tim-3 or PD-1 expression on T cells.…”

IL-15 delays suppression and fails to promote immune reconstitution in virally suppressed chronically SIV-infected macaques

“…Similar to our findings, no significant increase in Ki-67 ϩ CD4 ϩ T-cell proliferation was observed in another study with ART-suppressed rhesus macaques treated with IL-15. 30 Could the complete viral suppression, as achieved in this study by potent antiviral therapy, impair the responsiveness to IL-15? Differences in inflammation and soluble IL-15R␣ chains may reduce T-cell responsiveness by affecting IL-15 transpresentation 31 or the levels of IL-2/15R␤ chain, although we recently excluded a potential role for IL-15R␣ on the surface of dendritic cells in mediating IL-15 function in vivo.…”

Immune Activation Driven by CTLA-4 Blockade Augments Viral Replication at Mucosal Sites in Simian Immunodeficiency Virus Infection

“…All animals were seronegative for SIV, simian T cell lymphotropic virus type 1, and herpes virus B. All animals were infected intrarectally with the same stock of SIV mac251 as previously described (31). Antiretroviral therapy (ART), given in condition of mild sedation, was initiated at week 14 and halted at week 37 in the second study.…”