PD-1 Blockade and TLR7 Activation Lack Therapeutic Benefit in Chronic Simian Immunodeficiency Virus-Infected Macaques on Antiretroviral Therapy

Bekerman, Elena; Hesselgesser, Joseph; Carr, Brian A.; Nagel, Mark; Hung, Magdeleine; Wang, Adele; Stapleton, Lance; Gegerfelt, Agneta von; Elyard, Hanne Andersen; Lifson, Jeffrey D.; Geleziunas, Romas

doi:10.1128/aac.01163-19

Cited by 47 publications

(43 citation statements)

References 46 publications

(53 reference statements)

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“…We did observe several blips of viremia in treated RMs, but similar viral blips were also seen in the control group around the same timepoints indicating that this transient viremia was likely unrelated to GS-986 treatment (Fig 1B and 1C). Our findings conflict with Lim et al [30], but are consistent with reports by Del Prete et al, and Borducchi et al, and Bekerman et al [18,[31][32][33]. Based on the safe induction of innate immune activation we observed in infants, TLR-7 agonists remain promising for use as vaccine adjuvants or perhaps could be explored in combination with other agents to stimulate virus reactivation from latency.…”

Section: Plos Pathogenssupporting

confidence: 87%

Therapeutic vaccination of SIV-infected, ART-treated infant rhesus macaques using Ad48/MVA in combination with TLR-7 stimulation

et al. 2020

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Globally, 1.8 million children are living with HIV-1. While antiretroviral therapy (ART) has improved disease outcomes, it does not eliminate the latent HIV-1 reservoir. Interventions to delay or prevent viral rebound in the absence of ART would be highly beneficial for HIV-1-infected children who now must remain on daily ART throughout their lifespan. Here, we evaluated therapeutic Ad48-SIV prime, MVA-SIV boost immunization in combination with the TLR-7 agonist GS-986 in rhesus macaque (RM) infants orally infected with SIVmac251 at 4 weeks of age and treated with a triple ART regimen beginning 4 weeks after infection. We hypothesized immunization would enhance SIV-specific T cell responses during ART-mediated suppression of viremia. Compared to controls, vaccinated infants had greater magnitude SIV-specific T cell responses (mean of 3475 vs 69 IFN-γ spot forming cells (SFC) per 106 PBMCs, respectively, P = 0.01) with enhanced breadth of epitope recognition and increased CD8+ and CD4+ T cell polyfunctionality (P = 0.004 and P = 0.005, respectively). Additionally, SIV-specific gp120 antibodies against challenge and vaccine virus strains were significantly elevated following MVA boost (P = 0.02 and P < 0.001, respectively). GS-986 led to expected immune stimulation demonstrated by activation of monocytes and T cells 24 hours post-dose. Despite the vaccine-induced immune responses, levels of SIV DNA in peripheral and lymph node CD4+ T cells were not significantly different from controls and a similar time to viral rebound and viral load set point were observed following ART interruption in both groups. We demonstrate infant RMs mount a robust immunological response to this immunization, but vaccination alone was not sufficient to impact viral reservoir size or modulate rebound dynamics following ART release. Our findings hold promise for therapeutic vaccination as a part of a combination cure approach in children and highlight the importance of a pediatric model to evaluate HIV-1 cure interventions in this unique setting of immune development.

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Section: Plos Pathogenssupporting

confidence: 87%

Therapeutic vaccination of SIV-infected, ART-treated infant rhesus macaques using Ad48/MVA in combination with TLR-7 stimulation

et al. 2020

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“…Accordingly, several clinical studies from our group have demonstrated HIV-1 (re)activation through an IFNα-α induced CD4+ Tcell activation and increased HIV-1-specific polyfunctionality of CD8+ T cells following TLR9 stimulation (74,75,92). Similar effects have been demonstrated ex vivo and in vivo in TL7TLR7 agonist studies (51,93,94).…”

Section: Immunomodulatory Properties Of Tlr Agonistssupporting

confidence: 60%

“…Bekerman et al tested the immunomodulatory effect of a chimeric anti-PD-1 antibody and the TLR7 agonist GS-9620 in chronically SIV infected rhesus macaques (94). In a four-arm controlled design, NHPs received 0.15 mg/kg GS-9620 by oral gavage every other week for a total of 10 administrations, alone or in combination with 10 mg/kg anti-PD-1 antibody.…”

Section: Tlr Agonists and Programmed Death-1 (Pd-1) Inhibitionmentioning

confidence: 99%

The Use of Toll-Like Receptor Agonists in HIV-1 Cure Strategies

et al. 2020

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Toll-like receptors (TLRs) are a family of pattern recognition receptors and part of the first line of defense against invading microbes. In humans, we know of 10 different TLRs, which are expressed to varying degrees in immune cell subsets. Engaging TLRs through their specific ligands leads to activation of the innate immune system and secondarily priming of the adaptive immune system. Because of these unique properties, TLR agonists have been investigated as immunotherapy in cancer treatment for many years, but in recent years there has also been growing interest in the use of TLR agonists in the context of human immunodeficiency virus type 1 (HIV-1) cure research. The primary obstacle to curing HIV-1 is the presence of a latent viral reservoir in transcriptionally silent immune cells. Due to the very limited transcription of the integrated HIV-1 proviruses, latently infected cells cannot be targeted and cleared by immune effector mechanisms. TLR agonists are very interesting in this context because of their potential dual effects as latency reverting agents (LRAs) and immune modulatory compounds. Here, we review preclinical and clinical data on the impact of TLR stimulation on HIV-1 latency as well as antiviral and HIV-1-specific immunity. We also focus on the promising role of TLR agonists in combination strategies in HIV-1 cure research. Different combinations of TLR agonists and broadly neutralizing antibodies or TLRs agonists as adjuvants in HIV-1 vaccines have shown very encouraging results in non-human primate experiments and these concepts are now moving into clinical testing.

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“…However, a key distinction is that in cancer the self-immunogen is pervasive; whereas, in ART-treated HIV infection chronic antigenic stimulation arises largely from gut microbial translocation, not from viral proteins. This different in antigen source may represent a key obstacle when translating therapies between cancer and HIV models (63). In designing immunotherapy strategies, it is also important to consider that adverse event outcomes between these models have substantially different tolerances, as HIV is a manageable chronic disease and cancers are invariably fatal.…”

Section: Discussionmentioning

confidence: 99%

Editorial: HIV and Cancer Immunotherapy: Similar Challenges and Converging Approaches

et al. 2020

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PD-1 Blockade and TLR7 Activation Lack Therapeutic Benefit in Chronic Simian Immunodeficiency Virus-Infected Macaques on Antiretroviral Therapy

Cited by 47 publications

References 46 publications

Therapeutic vaccination of SIV-infected, ART-treated infant rhesus macaques using Ad48/MVA in combination with TLR-7 stimulation

Therapeutic vaccination of SIV-infected, ART-treated infant rhesus macaques using Ad48/MVA in combination with TLR-7 stimulation

The Use of Toll-Like Receptor Agonists in HIV-1 Cure Strategies

Editorial: HIV and Cancer Immunotherapy: Similar Challenges and Converging Approaches

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