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

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.


Immunomodulation in the presence or absence of antigen
HIV-1 disease is a chronic condition treatable with antiretroviral therapy (ART).Due to the persistence of a stable latent virus reservoir that is unaffected by ART, lifelong treatment is needed for people with HIV-1. 1 To achieve HIV-1 remission, defined as sustained ART-free virological control, this latent HIV-1 reservoir needs to be eradicated, reduced, silenced and/or contained by potent HIV-1-specific immune responses.In this review, we will focus on two immunostimulatory homeostatic cytokines, IL-7 and IL-15, which both act on immune cells independently of the presence or absence of antigen.Other reviews focus on interventions that rely on the presence of HIV antigen like broadly neutralizing anti-HIV-1 antibodies (bNAbs) and bispecific molecules. 2,3n HIV-1 disease, immunomodulatory interventions are usually administered during suppressive ART, where the majority of HIV-1 proviruses remains in a latent state and HIV-1 antigen burden is low.However, recent studies have begun to explore immunomodulatory interventions given during the viremic state 4 or prior to and at the start of an ART interruption (ATI) period. 5[8]

Interleukin-7 and -15
[11] IL-7 and IL-15 are members of the four α-helix bundle family of cytokines, which also includes another four interleukins: IL-2, IL-4, IL-9 and IL-21.These cytokines share the common cytokine receptor γ-chain (γ c also known as CD132), while only IL-2 and IL-15 share the other part of the heterodimeric receptor, the IL-2/IL15Rβ-chain also known as CD122.IL-15 first binds to the membrane-bound IL-15Rα that is highly expressed by monocytes and dendritic cells and is then trans-presented in a cell-cell contact-dependent manner to responder cells expressing the IL-2/IL15Rβ-γ c heterodimer.IL-15 signalling can also occur by cis-presentation or through soluble IL-15Rα. 10,11IL-7 binds and signals via IL-7Rα (also known as CD127) as the last part of the heterodimeric receptor, and exists in membrane-bound and soluble forms.The IL-7Rα is mainly expressed on the least differentiated T cell subsets, while the IL-2/IL15Rβ is primarily expressed on the more differentiated ones. 10,12,13Both IL-7 and IL-15 signal downstream through Janus  49 in vitro CD4 + T cells p24 ELISA in supernatant Induced viral replication Unutmaz D. et al. 51 in vitro Resting (CD69-HLA-DR-) CD3  kinases (JAK)/signal transducer and activator of transcription proteins (STAT) pathways. 9,11odifications have improved the pharmacokinetic profile of recombinant human IL-7 and IL-15, especially cytokine half-life. 11,14,15A long-acting IL-7 was made by fusing recombinant human IL-7 with a hybrid immunoglobulins D/G4 Fc (rhIL-7-hyFc). 16Two key modifications (heterodimerization and superagonist) of IL-15 have increased binding ability to IL-2/IL15Rβ-γ c and thus immunostimulatory activity 1) A recombinant, heterodimeric form of IL-15 bound to IL-15Rα (het-IL-15) 17 ; and 2) A superagonist mutein containing amino acid substitutions, including IL-15N72D, 18 and a superagonist fusion where IL-15N72D is bound to a sushi domain of IL-15Rα fused with immunoglobulin G1 Fc, also known as N-803 (previously ALT-803). 19nder normal homeostatic conditions without lymphopenia, plasma levels of IL-7 and IL-15 are tightly regulated, being either undetectable or very low by standard assays. 10,201][22][23] In turn, elevated plasma IL-7 and IL-15 levels are associated with downregulation of their cellular receptors. 7,12The effects of homeostatic cytokines on CD4 + T cell proliferation in HIV-1 disease depends on the setting: 1) During initial untreated disease; the levels of homeostatic cytokines are high reflecting the 'lack' of consumption due to high turnover of CD4 + T cells, followed by 2) A progressively decrease of the levels of homeostatic cytokines and increase of CD4 + T cells counts after ART initiation, 13,[20][21][22][23] but the responding receptor expression on T cells is not fully restored within 2 years. 12,24In an earlier study using single structured ATI as a way to augment autologous HIV-1-immunity, individuals with delayed/absent viral rebound during ATI had significantly increased levels of plasma IL-15 prior to and during ATI compared to individuals with rapid viral rebound. 25In another study, the expression of IL-17 mRNA in and IL-15Rα on monocytes was higher among long-term non-progressors than progressors. 7In cancer therapy, repeated doses of IL-7 administration was shown to increase numbers of circulating T cells in a dose-dependent manner, 26 while the different IL-15 therapies increased proliferation and function of circulating NK and CD8 + T cells. 9Collectively, these findings suggest that there is a therapeutic rationale for investigating treatment with IL-7 and IL-15 in HIV-1. 27,28

In vitro and ex vivo effects of IL-7 or IL-15
The cell types and tissues assayed as well as the results from in vitro and ex vivo experiments of IL-7 or IL-15 are summarized in Table 1.We focus on the immune-stimulating effect of IL-7 or IL-15 administration on virus-specific CD8 + T cells as well as NK cells, and briefly describe their latency reversing potential.
Immune-modulatory effects: IL-7 stimulation of peripheral blood mononuclear cells (PBMCs) ex vivo enhanced virus-specific CD8 + T cell cytotoxicity 29 and function 30 (against influenza and cytomegalovirus).IL-15 stimulation ex vivo of isolated CD8 + T cells enhanced activation, but this was only observed in the most differentiated subsets. 31During untreated HIV-1 infection, activated CD8 + T cells are more susceptible to apoptosis 32 ex vivo, which can be inhibited by IL-15. 31IL-15 stimulation of PBMCs also increased numbers, 33 activation status 34 and functional capacity 33 of HIV-1-specific CD8 + T cells, whilst their susceptibility to apoptosis again was reduced. 34IL-15 stimulation of pre-activated PBMCs enhanced the frequency of HIV-1-specific T cells 31 and non-specific IFNγ secretion in the supernatant 34 several fold compared to IL-15 stimulation without pre-activation.Ex vivo stimulation with the IL-15 superagonist N-803 also enhanced HIV-1-specific T-cell cytotoxicity 35,36 and function. 36,370][41] After IL-15 stimulation, NK cells had higher expression of the activation receptor NKG2D and cytotoxicity receptor NKp30 39,40,42 (also seen after in vivo N-803 administration 43 ), while expression of the cytotoxicity receptor NKp46 was decreased. 40,42IL-15 stimulation and NKG2D engagement were needed for vaccine-primed-K cells to control HIV-1 in autologous CD4 + T cells. 444][55] Additionally, IL-7 stimulation of T cells resulted in a shift of subset distribution towards the memory compartment, 48,52 which supports the critical role of IL-7 for generation of long-lived memory T cells. 56IL-15 may also work as latency-reversing agent. 37,38,42More importantly, IL-7-and IL-15-primed latently infected cells to increased CD8 + T cell recognition and killing, which is an important finding since latently infected cells after stimulation with other latency-reversing agents seems to be resistant to killing. 37,40,57,58IL-15 in combination with other latency-reversing agents have been shown to abrogate each other's latency -reversing effects, although the combination of IL-15 and a protein kinase C agonist potentiated viral (re)activation and showed sustain NK cell function. 42n summary, ex vivo studies indicate that IL-7 stimulation may maintain or even expand the size of the HIV-1 reservoir due to homeostatic proliferation of infected CD4 + T cells.In contrast to IL-7, IL-15 stimulation appears to enhance cellular responses against HIV-1 in vitro and ex vivo without expanding the size of the HIV-1 reservoir.Studies are listed chronologically.Two studies are not mentioned in the text, but included in this table [111-112].Abbreviations: ADCC; antibody-dependent cellular cytotoxicity, B-LCL; lymphoblastoid B-cell line, CCR5; C-C chemokine receptor type 5, ELISA; enzyme-linked immunosorbent assay, ELISPOT; enzyme-linked absorbent spot,IFN; inteferon, IL; interleukin, LTR; long terminal repeat, NK; natural killer, PBMCs; peripheral blood mononuclear cells, PCR; polymerase chain reaction, RT; reverse transcription, 7-AAD; 7-Aminoactinomycin D.

Effects of IL-7 and IL-15 in HIV-1 animal models
Of note, in murine [59][60][61][62] and HNP models, [63][64][65] the use of IL-7 or IL-15 as vaccine adjuvants enhanced the immune responses to HIV/SIV/SHIV vaccines, but this vaccine adjuvant effect could not be repeated in humans. 66IL-15-adjuvanted SIV vaccination prior to SIV challenge preserved the CD4 + T cell numbers in the tissue to a greater extent than vaccination without IL-15 as adjuvant. 67Further, some non-human primates (NHPs) primed with both TLR agonists and IL-15 prior to SIV vaccination were protected again SIV infection. 68mmune-modulatory effects: IL-7 administration among simian immunodeficiency virus (SIV)-infected NHPs enhanced proliferation [69][70][71][72] and activation 69,71 of CD4 + and CD8 + T cells leading to a transient increase in numbers [69][70][71][72] (Table 2).0][71][72][73] The expression of IL-7Rα on these cells was transiently downregulated following IL-7 administration. 70,71The proliferative effects were more sustained with repeated than single IL-7 administration. 73IL-7 stimulation also enhanced HIV-1-specific CD8 + T cell cytotoxicity, 74 and lymphadenopathy occurred following subcutaneous (SC) IL-7 injection due to cell migration. 69,70-15 administration among viremic NHPs only led to modest increases in CD8 + T cell and NK numbers 6,75,76 as opposed to what was observed in SIV-uninfected NHPs (reviewed elsewhere 27 ) as well as ex vivo IL-15 stimulation of pre-activated PBMCs as described above .31,34 In one of the studies, IL-15 administration led to increased viral set-point (as seen in a HIV mice model 77 ) and accelerated disease progression.So the modest effect seen on CD8 + T and NK cells of additional exogen IL-15 administration during untreated infection could be due to already high levels of endogen IL-15 78 as well as short half-life of responder cells.27 Whether or not IL-15 stimulation during the viremic phase of HIV-1 infection might provide superior effects on T cell function remains to be determined; however, one concern would be that of excessive CD8 + T cell activation, which is known to be associated with worse outcomes in people with HIV-1.79 IL-15 administration at ART initiation among SIV-infected NHPs increased the number of CD8 + T cells. 80 Moreimportantly, following IL-15 administration, the virus-specific CD8 + T cell proliferated, 80 but no effect was observed on IFNγ cytotoxicity 75,80 or control during ATI.In non-progressors and ART-suppressed SIV-infected NHPs, IL-15 increased the proliferative activity of T cells 6,81 and enhanced frequency of T effector memory cells expressing granzyme B. 81 N-803 administration was also tested among ART-treated virally-suppressed NHPs, which generally confirmed the findings described above .82,83 Studies have also tested whether N-803 could benefit virus-specific immunity among more favourable clinical phenotypes (SIV controllers) in the absence of ART.85 After N-803 and het-IL-15 administration, there was increased proliferation of NK and CD8 + T cells.81,[83][84][85] There are conflicting findings on whether the cytotoxicity of virus-specific CD8 + T cells were increased 81 or not 85 following N-803 administration.The majority of the NK and CD8 + T cells that increased in numbers following N-803 expressed CD16 + and had effector memory phenotype, respectively.81,[83][84][85] Virological control during ATI was not observed among SIV/SHIV-infected NHPs after N-803 administration. 82,83f note, prior to N-803 administration, SIV-specific CD8 + T cells primarily localized in the extrafollicular space of lymph nodes, but after N-803 administration the numbers of SIV-specific CD8 + T cells significantly increased within B-cell follicles.84 Migration of CD8 + T cells to the lymph nodes occurred via upregulation of CXC chemokine receptor 5 (CXCR5).84 The expression of IL-2/IL15Rβ-y c on central memory CD8 + T cells transiently declined during weekly N-803 administration, but was somewhat restored by deferring administration, 85 thus spacing administrations seems optimal due to refractoriness.6,75,[85][86][87][88] Multiple administrations of N-803 led to increased PD-1 expression on CD8 + T cells, which might be due to activation rather than exhaustion.85 In two HIV mice models IL-15-primed CD8 + T cells showed enhanced in vivo activity on initial viremia when given at the day of infection, but administration of an IL-15 superagonist led to increased plasma viral setpoint. 77In the other model, N-803 administration 3 days after infection induced NK cell-mediated inhibition of acute infection.36 Thus, interventional approaches within the first days of infection in these models does not mirror what is feasible in people with HIV-1.
0][71] Following N-803 administration, plasma viral loads decreased indicating that the in vivo latency reversal effect of N-803 might be masked due to antiviral effector functions, 37,82,84,85 which also explains the diverse findings from the other studies using IL-15 therapies. 6,75,80,81,83everal studies have assessed the effect of IL-15 therapies on the size of the viral reservoir with mixed results (Table 2), as it was found to either decrease, 81,83 remain unchanged 82,84 or increase. 65n summary, in multiple studies across several animal models, IL-7 administration increased absolute T cell numbers, and N-803 administration increased the total numbers of NK and CD8 + T cells, with spaced administration of more than one week being most optimal.Despite these proliferative effects of IL-15, more information is needed on the HIV-1specific effects as well as antiviral functions of the effector cells following the interventions as there was no apparent impact of IL-15 on virological control among animals that had interrupted ART.

Effects of IL-7 and IL-15 therapy in people with HIV-1
0][91][92] The maximum tolerated dose (MTD) was 30 μg/kg with single subcutaneous (SC) injections 89 and 20 μg/kg MTD of repeated injections. 91,920][91][92][93] The results were overall similar to the findings from NHPs: IL-7 administration enhanced proliferation as measured by the expression of Ki67 on CD4 + and CD8 + T cells leading to increased cell number [89][90][91] ; mainly in the central memory (CD45RA-CCR7+ 90,91,93 or CD45RA-CD62L- 89 ), but also the naïve (CD45RA + CCR7+) 90,91,93 subsets, confirming prevalent IL-7Rα expression on these subsets.Frequencies of HIV-1-specific CD8 + T cells were unchanged after IL-7 administration, but one study has observed a trend towards enhanced proliferation as measured by Ki67 expression. 89IL-7 administration did not affect T cell subset distribution, PD-1 frequencies or IL-7Rα expression. 89everal clinical cancer trials have tested the safety and effect of IL-15 therapies.Pharmacokinetics was dependent on the exact IL-15 compound that was tested as well as the route of administration.IL-15 administration SC had a longer half-life due to a slower release, 94 but intravenous (IV) administration resulted in higher plasma concentrations, which explain the difference in SC versus IV toxicity.Of note, a greater mean fold increase in circulating numbers of NK and CD8 + T cells were observed after SC compared to IV administration of N-803, 43,94 and doses up to 20 μg/kg were tested IV without significant toxicities.In 2022, a phase 1 dose-escalation study of N-803 was conducted among 16 people with HIV-1 on suppressive ART. 95Five different dosing schemes were planned with three individuals per scheme receiving three doses once weekly.Two individuals received the lowest dose of 0.3 μg/kg IV, but due to data from cancer trials showing increased risk of a cytokine release syndrome with IV administration, the following doses were given as SC administration.The MTD was found to be 6.0 μg/kg, and of note no anti-N-803 antibodies have been observed in 6.0 μg/kg cohorts. 94,96,97Every individual experienced Grade 3 injection site erythema and 22 (65%) of the 34 injections were associated with adenopathy, but none of them were Grade 1.There were differences in pharmacodynamics at 6.0 μg/kg between cancer and HIV trials (Table 3), which have been ascribed to target-mediated drug disposition. 15In the HIV trial, three N-803 administrations increased the number of circulating NK over CD8 + T cells with enhanced proliferation as measured by Ki67 expression on both cell types.N-803 also increased expression of the activation markers, CD69 and HLA-DR on both NK and CD8 + T cells but the study could not demonstrate increased HIV-1-specific T cell responses.
Latency reversing potential: Mixed results were seen on whether IL-7 could work as a latency-reversing agent, but if plasma viremia increased this was ascribed to activation of already transcriptional active cells rather than reactivation of de novo viral transcription 53,98 as observed with other latency-reversing agents. 991][92][93] In the phase 1 clinical trial using N-803, there was evidence of a latency-reversal effect, in that 91% and 100% of the individuals had detectable plasma viral loads and increased HIV-1 mRNA transcription in memory CD4 + T cells during the interventional period, respectively. 95he impact of N-803 on the latent HIV-1 reservoir was investigated using two assays.The frequency of memory CD4 + T cells that could be activated to viral transcription was significantly reduced over the 6months course of the trial (P =<0.001).By contrast, the level of intact proviral HIV-1 DNA per million CD4 + T cells measured by the intact proviral DNA assay (IPDA) actually increased over the interventional period (P = 0.098).The levels of the defective proviral HIV-1 DNA per million CD4 + T cells did not change over the interventional period, so the authors have speculated that the intact reservoir increased due to the expansion rather than the infection of new cells, but only integrationsite analyses can ultimate clarify this point.
Cancer trial 43 HIV-1 trial 95 In summary, IL-7 and N-803 have overall shown to be safe and welltolerated among people with HIV-1 on suppressive ART.Whereas the overall number of T cells increased with IL-7 therapy, including those that were latently infected, N-803 primarily led to increases in CD8 + T and NK cells.Additional trials are needed to address whether more potent cellular responses against HIV-1 are developed following the interventions and their effect on ART-free virological control during an ATI (NCT04808908, NCT04505501).

Future directions for IL-7 or IL-15 therapy in HIV-1
Modern ART regimens are highly effective at suppressing plasma viremia, achieving undetectable levels within months of treatment.However, restoration of CD4 + T cell counts takes considerably longer, in some cases years.Central to this immune reconstitution is endogenous IL-7 and IL-15 production which regulates CD4 + T cell homeostasis (Fig. 1), and thus, could interventions with IL-7 or IL-15 help restoration of CD4 + T cells?There are two issues with the homeostatic cytokines that should be considered prior to any intervention.1) The cytokineinduced CD4 + T cell expansion of the HIV-1 reservoir, 50,100 which might be overcome by making the interventional homeostatic cytokines CD8-targeted, but then the restoration of the CD4 + T cell compartment would be missed, or by simultaneously inhibiting cell-intrinsic anti-apoptosis pathways to diminish infected CD4 + T cells 101,102 ; and 2) The increased susceptibility to infection 103,104 by enhanced CCR5 expression on CD4 + T cells. 51,82,100,105Importantly, a recent study found that IL-15 stimulation in vitro and in humanized mice promoted proliferation and survival of the HIV-1 target cell (CCR5 expressing CD4 + T cells), and furthermore the life span of infected CCR5-expressing CD4 + T cells was prolonged and their virus production was increased. 100L-15 agonists could have a role in HIV-1 cure-related strategies.N-803 induced proliferation of NK and CD8 + T cells among ARTsuppressed people with HIV-1, 95 and enhanced migration of these cells to the tissues in vivo. 6,84The impact of N-803 on T cell migration and homing is important given that homeostatic proliferation of infected cells also occurs in tissues. 106Expression of IL-15Rα on responder cells .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. 22,37,42(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.
(caption on next page) J.D. Gunst et al.  are somewhat restored by ART, but inclusion of a TLR agonist could further induce IL-15Rα expression 67 and thus enhance the effect of N-803.As stated in the introduction, the timing of immunotherapies relative to viremia versus viral suppression is currently being explored, but interventions with homeostatic cytokines in this setting seems unfit since levels are already elevated.
Despite some latency reversal effect of plasma viremia by N-803, available data indicates that more effective latency reversal is needed to decrease the HIV-1 reservoir. 107One interventional strategy to overcome reversal of latency is to pause ART during an ATI to let the virus rebound: Two clinical trials are testing this strategy with administration of N-803 in combination with two broadly neutralising antibodies (bNAbs) during suppressive ART and then conducting an ATI at a later time point (NCT04340596) or N-803 in combination with two bNAbs during suppressive ART, but administered 2 days prior to an ATI (NCT05245292) (Fig. 2).The ex vivo findings of enhanced antibody-dependent cellular cytotoxicity [39][40][41] and enhanced expression of CD16 on NK cells in animal studies 81,[83][84][85] have not been confirmed among people with HIV-1, but in theory the combinatorial approach with bNAbs will result in killing of infected cells by different Fc-mediated mechanisms (Fig. 2).The presence of bNAbs at therapeutic levels will also limit the infection of new cells by direct neutralization of cell-free virions.Another interventional combination with N-803 could include an immune checkpoint inhibitor.A mathematical model based upon one of the NHP studies 85 has shown that co-administration of an immune checkpoint inhibitor may improve N-803 efficacy, 108 which has been confirmed in a phase 1b cancer trial. 97Other combinatorial approaches with N-803 being tested in cancer research are with antibodies, 109 cell110 or gene therapy (NCT05618925, NCT04847466).Notably, as for other interventions tested in HIV-1 research, 99 N-803 has also induced person-specific changes (NK cell functionality) in cancer trials moving curative interventions towards a personalized medicine approach. 43n conclusion, IL-7 has shown to be safe and well-tolerated among people with HIV-1 leading to increased absolute T cell numbers, including latently infected cells.Prior to future trials using IL-7, this expansion of the HIV-1 reservoir needs to be hindered.IL-15 therapies have also shown to be safe and well-tolerated among people with HIV-1, leading to increased total numbers of primarily CD8 + T and NK cells.Thus, IL-15 administration could be part of therapeutic approaches towards HIV-1 remission, but future trials should have broadened the immunological assessments on both the HIV-1 reservoir as well as antiviral responses: HIV-1-specific immunity and the effect on virological control during ATI.Since HIV-1 infection causes widespread dysregulation of the host immune system that is slow to recover, even after successful ART, the interventional timing is another important aspect to consider.

Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.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 cellsa vaccinal effect. 5

Fig. 1 .
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.22,37,42(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.

Table 1
Summary of the in vitro and ex vivo effects of IL-7 or IL-15 therapies.

Table 2
Summary from animal studies using IL-7 or IL-15 therapies.