Immunomodulation with IL-7 and IL-15 in HIV-1 infection

Abstract

Immunomodulating agents are substances that modify the host immune responses in diseases such as infections, autoimmune conditions and cancers. Immunomodulators can be divided into two main groups: 1) immunostimulators that activate the immune system such as cytokines, toll-like receptor agonists and immune checkpoint blockers; and 2) immunosuppressors that dampen an overactive immune system such as corticosteroids and cytokine-blocking antibodies. In this review, we have focussed on the two primarily T and natural killer (NK) cell homeostatic cytokines: interleukin-7 (IL-7) and -15 (IL-15). These cytokines are immunostimulators which act on immune cells independently of the presence or absence of antigen. In vivo studies have shown that IL-7 administration enhances proliferation of circulating T cells whereas IL-15 agonists enhance the proliferation and function of NK and CD8⁺ T cells. Both IL-7 and IL-15 therapies have been tested as single interventions in HIV-1 cure-related clinical trials. In this review, we explore whether IL-7 and IL-15 could be part of the therapeutic approaches towards HIV-1 remission.

Fig. 1

Effects of IL-7 and IL-15 therapies in vivo during suppressive antiretroviral threapy (ART). (a) Illustration of the effects of IL-7 administration during suppressive ART (on ART). IL-7 binds to the IL-7Rα receptor, here on the CD4⁺ and CD8⁺ T cells (mainly naïve and central memory subsets). Cells undergo homeostatic proliferation with expansion of T cell counts. In the CD4⁺ T cell compartment, both infected and uninfected cells proliferate leading to the expansion of the HIV-1 reservoir. During the proliferation of the infected CD4⁺ T cells, some degree of latency reversal occurs and a transient increase in plasma HIV-1 RNA levels can be observed. The CD8⁺ T cell compartment also proliferates, which might also expand the HIV-1-specific CD8⁺ T cells. The expression of IL-7Rα is downregulated following IL-7 stimulation of T cells.^,, (b) Illustration of the effects of IL-15 superagonist N-803 administration during suppressive ART (on ART). N-803 binds to membrane IL-15Rα on a trans-presenting cell and in a cell-cell contact-dependent manner to responder cells expressing IL-2/IL15Rβ-γ_c. Upon stimulation with N-803 the responder cells undergo homeostatic proliferation. As seen with administration of IL-7, during proliferation of the infected CD4⁺ T cells some degree of latency reversal occurs and a transient increase in plasma HIV-1 RNA levels can be observed. In the CD4⁺ T compartment, both infected and uninfected cells expand. The NK cells and CD8⁺ effector memory (EM) T cells also expand. Expansion of the CD8⁺ EM T cells might also lead to the expansion of the HIV-1-specific CD8⁺ T cells as well as upregulation of the expression of CXCR5 leading to tissue migration.

Fig. 2

Effects of IL-15 stimulation on antiretroviral therapy (ART) and in a combinatorial approach with broadly neutralizing anti-HIV-1 antibodies (bNAbs) off ART. (a) Illustration of the effects of IL-15 superagonist N-803 administration during suppressive ART (on ART) as shown in Fig. 1. (b) Illustration of the effects of N-803 in combination with bNAbs prior to (NCT04340596) and into (NCT05245292) an analytical treatment interruption (ATI; off-ART). During ATI, infected CD4⁺ T cells with inducible HIV-1 reservoir might be (re)activated to initiated transcription/translation due to immune activation, which can lead to antibody-dependent cellular cytotoxicity by the NK and CD8⁺ T cells. Viral particles produced by the (re)activated infected CD4⁺ T cells can form bNAbs-antigen complexes that bind to plasmacytoid dendritic cells (pDCs). This cross presents viral antigens leading to the development of HIV-1-specific CD8⁺ T cell and enhanced killing of infected cells – a vaccinal effect.