IL-15 and N-803 for HIV Cure Approaches

Howard, J. Natalie; Bosque, Alberto

doi:10.3390/v15091912

Cited by 5 publications

(5 citation statements)

References 110 publications

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“…In vivo studies and clinical trials have indicated that IL-15 or N-803 alone are unlikely to provide sufficient latency reversal activity but have highlighted their potential as a component of combination treatments. This is supported by observations of immune restorative effects of IL-15 or N-803 treatment that may support the clearance of reservoir cells [261][262][263].…”

Section: Latency-reversing Agents In Combinationsupporting

confidence: 54%

“…A recent study combining a Smac mimetic with the IL-15 superagonist N-803 and RhmAbs reported latency reversal and a reduction in reservoir size in SIV-infected rhesus macaques upon treatment [246]. While the impact of N-803 on latency reversal in this study was modest, the use of IL-15 or N-803 as a part of cure strategies has been studied extensively (reviewed in [261]). In vivo studies and clinical trials have indicated that IL-15 or N-803 alone are unlikely to provide sufficient latency reversal activity but have highlighted their potential as a component of combination treatments.…”

Section: Latency-reversing Agents In Combinationmentioning

confidence: 75%

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Breaking the Silence: Regulation of HIV Transcription and Latency on the Road to a Cure

Duggan,

Dragic,

Chanda

et al. 2023

Viruses

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Antiretroviral therapy (ART) has brought the HIV/AIDS epidemic under control, but a curative strategy for viral eradication is still needed. The cessation of ART results in rapid viral rebound from latently infected CD4+ T cells, showing that control of viral replication alone does not fully restore immune function, nor does it eradicate viral reservoirs. With a better understanding of factors and mechanisms that promote viral latency, current approaches are primarily focused on the permanent silencing of latently infected cells (“block and lock”) or reactivating HIV-1 gene expression in latently infected cells, in combination with immune restoration strategies to eliminate HIV infected cells from the host (“shock and kill”). In this review, we provide a summary of the current, most promising approaches for HIV-1 cure strategies, including an analysis of both latency-promoting agents (LPA) and latency-reversing agents (LRA) that have shown promise in vitro, ex vivo, and in human clinical trials to reduce the HIV-1 reservoir.

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Section: Latency-reversing Agents In Combinationsupporting

confidence: 54%

Section: Latency-reversing Agents In Combinationmentioning

confidence: 75%

Breaking the Silence: Regulation of HIV Transcription and Latency on the Road to a Cure

Duggan,

Dragic,

Chanda

et al. 2023

Viruses

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“…No evidence that coronavirus disease 2019 mRNA vaccination induces detectable viremia HIV pVL testing was performed at the baseline visit, which occurred a median of 12 (IQR 3-26) days prior to vaccination, one month (a median of 31 [IQR [29][30][31][32][33] days) after the first vaccine dose, and again one month (a median of 30 [IQR 29-30] days) after the second vaccine dose (Fig. 1).…”

Section: Participant Characteristicsmentioning

confidence: 99%

“…This could theoretically occur via direct stimulation of reservoir cells that recognize the vaccine antigen, including naïve CD4 + T-cell reservoirs [ 25 , 26 ] specific for SARS-CoV-2 Spike, or existing cross-reactive memory CD4 + T-cell reservoirs specific for common cold coronavirus antigens [ 27 , 28 ]. Alternatively, reservoir stimulation could occur through a generalized inflammatory response with cytokine production [ 29 , 30 ] that could transiently promote HIV gene expression in bystander reservoir cells that are not specific to the vaccine antigen [ 31 ]. Indeed, reports of increased HIV viremia in individuals receiving ART following COVID-19 mRNA vaccination have emerged [ 31 – 33 ], though other studies have observed no such effects [ 34 – 36 ].…”

Section: Introductionmentioning

confidence: 99%

Effects of COVID-19 mRNA vaccination on HIV viremia and reservoir size

Duncan,

Omondi,

Kinloch

et al. 2024

Aids

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Objective: The immunogenic nature of COVID-19 mRNA vaccines led to some initial concern that these could stimulate the HIV reservoir. We analyzed changes in plasma HIV loads (pVL) and reservoir size following COVID-19 mRNA vaccination in 62 people with HIV (PWH) receiving antiretroviral therapy (ART), and analyzed province-wide trends in pVL before and after the mass vaccination campaign. Design: Longitudinal observational cohort and province-wide analysis. Methods: 62 participants were sampled pre-vaccination, and one month after their first and second COVID-19 immunizations. Vaccine-induced anti-SARS-CoV-2-Spike antibodies in serum were measured using the Roche Elecsys Anti-S assay. HIV reservoirs were quantified using the Intact Proviral DNA Assay; pVL were measured using the cobas 6800 (LLOQ:20 copies/mL). The province-wide analysis included all 290,401 pVL performed in British Columbia, Canada between 2012-2022. Results: Pre-vaccination, the median intact reservoir size was 77 (IQR:20–204) HIV copies/million CD4+ T-cells, compared to 74 (IQR:27–212) and 65 (IQR:22–174) post-first and -second dose, respectively (all comparisons p>0.07). Pre-vaccination, 82% of participants had pVL<20 copies/mL (max:110 copies/mL), compared to 79% post-first dose (max:183 copies/mL) and 85% post-second dose (max:79 copies/mL) (p > 0.4). There was no evidence that the magnitude of the vaccine-elicited anti-SARS-CoV-2-Spike immune response influenced pVL nor changes in reservoir size (p > 0.6). We found no evidence linking the COVID-19 mass vaccination campaign to population-level increases in detectable pVL frequency among all PWH in the province, nor among those who maintained pVL suppression on ART. Conclusion: We found no evidence that COVID-19 mRNA vaccines induced changes in HIV reservoir size nor plasma viremia.

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“…In research using a mouse tumor model, hematopoietic stem cell (HSC)-derived CAR-NK cells have shown exceptional anti-tumor efficacy in combination with nivolumab 50 . N-803, an IL-15 superagonist, has been shown to expand NK cells in humans after injection and to be well tolerated 51 . An ongoing clinical trial (NCT04847466) 52 is investigating the combination of N-803, pembrolizumab, and HSC CAR-NK for the treatment of GEJ and advanced HNSCC; trial completion is expected by the end of 2025.…”

Section: Traditional Icismentioning

confidence: 99%

Immune checkpoint inhibitors: breakthroughs in cancer treatment

Kong,

Zhang,

Chen

et al. 2024

Cancer Biol Med

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Over the past two decades, immunotherapies have increasingly been considered as first-line treatments for most cancers. One such treatment is immune checkpoint blockade (ICB), which has demonstrated promising results against various solid tumors in clinical trials. Monoclonal antibodies (mAbs) are currently available as immune checkpoint inhibitors (ICIs). These ICIs target specific immune checkpoints, including cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1). Clinical trial results strongly support the feasibility of this immunotherapeutic approach. However, a substantial proportion of patients with cancer develop resistance or tolerance to treatment, owing to tumor immune evasion mechanisms that counteract the host immune response. Consequently, substantial research focus has been aimed at identifying additional ICIs or synergistic inhibitory receptors to enhance the effectiveness of anti-PD-1, anti-programmed cell death ligand 1 (anti-PD-L1), and anti-CTLA-4 treatments. Recently, several immune checkpoint molecular targets have been identified, such as T cell immunoreceptor with Ig and ITIM domains (TIGIT), mucin domain containing-3 (TIM-3), lymphocyte activation gene-3 (LAG-3), V-domain immunoglobulin suppressor of T cell activation (VISTA), B and T lymphocyte attenuator (BTLA), and signal-regulatory protein α (SIRPα). Functional mAbs targeting these molecules are under development. CTLA-4, PD-1/PD-L1, and other recently discovered immune checkpoint proteins with distinct structures are at the forefront of research. This review discusses these structures, as well as clinical progress in mAbs targeting these immune checkpoint molecules and their potential applications.

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IL-15 and N-803 for HIV Cure Approaches

Cited by 5 publications

References 110 publications

Breaking the Silence: Regulation of HIV Transcription and Latency on the Road to a Cure

Breaking the Silence: Regulation of HIV Transcription and Latency on the Road to a Cure

Effects of COVID-19 mRNA vaccination on HIV viremia and reservoir size

Immune checkpoint inhibitors: breakthroughs in cancer treatment

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