Cargando…

The HIV Latency Reversal Agent HODHBt Enhances NK Cell Effector and Memory-Like Functions by Increasing Interleukin-15-Mediated STAT Activation

Elimination of human immunodeficiency virus (HIV) reservoirs is a critical endpoint to eradicate HIV. One therapeutic intervention against latent HIV is “shock and kill.” This strategy is based on the transcriptional activation of latent HIV with a latency-reversing agent (LRA) with the consequent k...

Descripción completa

Detalles Bibliográficos
Autores principales: Macedo, Amanda B., Levinger, Callie, Nguyen, Bryan N., Richard, Jonathan, Gupta, Mamta, Cruz, Conrad Russell Y., Finzi, Andrés, Chiappinelli, Katherine B., Crandall, Keith A., Bosque, Alberto
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9364794/
https://www.ncbi.nlm.nih.gov/pubmed/35867565
http://dx.doi.org/10.1128/jvi.00372-22
_version_ 1784765219936927744
author Macedo, Amanda B.
Levinger, Callie
Nguyen, Bryan N.
Richard, Jonathan
Gupta, Mamta
Cruz, Conrad Russell Y.
Finzi, Andrés
Chiappinelli, Katherine B.
Crandall, Keith A.
Bosque, Alberto
author_facet Macedo, Amanda B.
Levinger, Callie
Nguyen, Bryan N.
Richard, Jonathan
Gupta, Mamta
Cruz, Conrad Russell Y.
Finzi, Andrés
Chiappinelli, Katherine B.
Crandall, Keith A.
Bosque, Alberto
author_sort Macedo, Amanda B.
collection PubMed
description Elimination of human immunodeficiency virus (HIV) reservoirs is a critical endpoint to eradicate HIV. One therapeutic intervention against latent HIV is “shock and kill.” This strategy is based on the transcriptional activation of latent HIV with a latency-reversing agent (LRA) with the consequent killing of the reactivated cell by either the cytopathic effect of HIV or the immune system. We have previously found that the small molecule 3-hydroxy-1,2,3-benzotriazin-4(3H)-one (HODHBt) acts as an LRA by increasing signal transducer and activator of transcription (STAT) factor activation mediated by interleukin-15 (IL-15) in cells isolated from aviremic participants. The IL-15 superagonist N-803 is currently under clinical investigation to eliminate latent reservoirs. IL-15 and N-803 share similar mechanisms of action by promoting the activation of STATs and have shown some promise in preclinical models directed toward HIV eradication. In this work, we evaluated the ability of HODHBt to enhance IL-15 signaling in natural killer (NK) cells and the biological consequences associated with increased STAT activation in NK cell effector and memory-like functions. We showed that HODHBt increased IL-15-mediated STAT phosphorylation in NK cells, resulting in increases in the secretion of CXCL-10 and interferon gamma (IFN-γ) and the expression of cytotoxic proteins, including granzyme B, granzyme A, perforin, granulysin, FASL, and TRAIL. This increased cytotoxic profile results in increased cytotoxicity against HIV-infected cells and different tumor cell lines. HODHBt also improved the generation of cytokine-induced memory-like NK cells. Overall, our data demonstrate that enhancing the magnitude of IL-15 signaling with HODHBt favors NK cell cytotoxicity and memory-like generation, and thus, targeting this pathway could be further explored for HIV cure interventions. IMPORTANCE Several clinical trials targeting the HIV latent reservoir with LRAs have been completed. In spite of a lack of clinical benefit, they have been crucial to elucidate hurdles that “shock and kill” strategies have to overcome to promote an effective reduction of the latent reservoir to lead to a cure. These hurdles include low reactivation potential mediated by LRAs, the negative influence of some LRAs on the activity of natural killer and effector CD8 T cells, an increased resistance to apoptosis of latently infected cells, and an exhausted immune system due to chronic inflammation. To that end, finding therapeutic strategies that can overcome some of these challenges could improve the outcome of shock and kill strategies aimed at HIV eradication. Here, we show that the LRA HODHBt also improves IL-15-mediated NK cell effector and memory-like functions. As such, pharmacological enhancement of IL-15-mediated STAT activation can open new therapeutic avenues toward an HIV cure.
format Online
Article
Text
id pubmed-9364794
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher American Society for Microbiology
record_format MEDLINE/PubMed
spelling pubmed-93647942022-08-11 The HIV Latency Reversal Agent HODHBt Enhances NK Cell Effector and Memory-Like Functions by Increasing Interleukin-15-Mediated STAT Activation Macedo, Amanda B. Levinger, Callie Nguyen, Bryan N. Richard, Jonathan Gupta, Mamta Cruz, Conrad Russell Y. Finzi, Andrés Chiappinelli, Katherine B. Crandall, Keith A. Bosque, Alberto J Virol Pathogenesis and Immunity Elimination of human immunodeficiency virus (HIV) reservoirs is a critical endpoint to eradicate HIV. One therapeutic intervention against latent HIV is “shock and kill.” This strategy is based on the transcriptional activation of latent HIV with a latency-reversing agent (LRA) with the consequent killing of the reactivated cell by either the cytopathic effect of HIV or the immune system. We have previously found that the small molecule 3-hydroxy-1,2,3-benzotriazin-4(3H)-one (HODHBt) acts as an LRA by increasing signal transducer and activator of transcription (STAT) factor activation mediated by interleukin-15 (IL-15) in cells isolated from aviremic participants. The IL-15 superagonist N-803 is currently under clinical investigation to eliminate latent reservoirs. IL-15 and N-803 share similar mechanisms of action by promoting the activation of STATs and have shown some promise in preclinical models directed toward HIV eradication. In this work, we evaluated the ability of HODHBt to enhance IL-15 signaling in natural killer (NK) cells and the biological consequences associated with increased STAT activation in NK cell effector and memory-like functions. We showed that HODHBt increased IL-15-mediated STAT phosphorylation in NK cells, resulting in increases in the secretion of CXCL-10 and interferon gamma (IFN-γ) and the expression of cytotoxic proteins, including granzyme B, granzyme A, perforin, granulysin, FASL, and TRAIL. This increased cytotoxic profile results in increased cytotoxicity against HIV-infected cells and different tumor cell lines. HODHBt also improved the generation of cytokine-induced memory-like NK cells. Overall, our data demonstrate that enhancing the magnitude of IL-15 signaling with HODHBt favors NK cell cytotoxicity and memory-like generation, and thus, targeting this pathway could be further explored for HIV cure interventions. IMPORTANCE Several clinical trials targeting the HIV latent reservoir with LRAs have been completed. In spite of a lack of clinical benefit, they have been crucial to elucidate hurdles that “shock and kill” strategies have to overcome to promote an effective reduction of the latent reservoir to lead to a cure. These hurdles include low reactivation potential mediated by LRAs, the negative influence of some LRAs on the activity of natural killer and effector CD8 T cells, an increased resistance to apoptosis of latently infected cells, and an exhausted immune system due to chronic inflammation. To that end, finding therapeutic strategies that can overcome some of these challenges could improve the outcome of shock and kill strategies aimed at HIV eradication. Here, we show that the LRA HODHBt also improves IL-15-mediated NK cell effector and memory-like functions. As such, pharmacological enhancement of IL-15-mediated STAT activation can open new therapeutic avenues toward an HIV cure. American Society for Microbiology 2022-07-14 /pmc/articles/PMC9364794/ /pubmed/35867565 http://dx.doi.org/10.1128/jvi.00372-22 Text en Copyright © 2022 Macedo et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Pathogenesis and Immunity
Macedo, Amanda B.
Levinger, Callie
Nguyen, Bryan N.
Richard, Jonathan
Gupta, Mamta
Cruz, Conrad Russell Y.
Finzi, Andrés
Chiappinelli, Katherine B.
Crandall, Keith A.
Bosque, Alberto
The HIV Latency Reversal Agent HODHBt Enhances NK Cell Effector and Memory-Like Functions by Increasing Interleukin-15-Mediated STAT Activation
title The HIV Latency Reversal Agent HODHBt Enhances NK Cell Effector and Memory-Like Functions by Increasing Interleukin-15-Mediated STAT Activation
title_full The HIV Latency Reversal Agent HODHBt Enhances NK Cell Effector and Memory-Like Functions by Increasing Interleukin-15-Mediated STAT Activation
title_fullStr The HIV Latency Reversal Agent HODHBt Enhances NK Cell Effector and Memory-Like Functions by Increasing Interleukin-15-Mediated STAT Activation
title_full_unstemmed The HIV Latency Reversal Agent HODHBt Enhances NK Cell Effector and Memory-Like Functions by Increasing Interleukin-15-Mediated STAT Activation
title_short The HIV Latency Reversal Agent HODHBt Enhances NK Cell Effector and Memory-Like Functions by Increasing Interleukin-15-Mediated STAT Activation
title_sort hiv latency reversal agent hodhbt enhances nk cell effector and memory-like functions by increasing interleukin-15-mediated stat activation
topic Pathogenesis and Immunity
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9364794/
https://www.ncbi.nlm.nih.gov/pubmed/35867565
http://dx.doi.org/10.1128/jvi.00372-22
work_keys_str_mv AT macedoamandab thehivlatencyreversalagenthodhbtenhancesnkcelleffectorandmemorylikefunctionsbyincreasinginterleukin15mediatedstatactivation
AT levingercallie thehivlatencyreversalagenthodhbtenhancesnkcelleffectorandmemorylikefunctionsbyincreasinginterleukin15mediatedstatactivation
AT nguyenbryann thehivlatencyreversalagenthodhbtenhancesnkcelleffectorandmemorylikefunctionsbyincreasinginterleukin15mediatedstatactivation
AT richardjonathan thehivlatencyreversalagenthodhbtenhancesnkcelleffectorandmemorylikefunctionsbyincreasinginterleukin15mediatedstatactivation
AT guptamamta thehivlatencyreversalagenthodhbtenhancesnkcelleffectorandmemorylikefunctionsbyincreasinginterleukin15mediatedstatactivation
AT cruzconradrusselly thehivlatencyreversalagenthodhbtenhancesnkcelleffectorandmemorylikefunctionsbyincreasinginterleukin15mediatedstatactivation
AT finziandres thehivlatencyreversalagenthodhbtenhancesnkcelleffectorandmemorylikefunctionsbyincreasinginterleukin15mediatedstatactivation
AT chiappinellikatherineb thehivlatencyreversalagenthodhbtenhancesnkcelleffectorandmemorylikefunctionsbyincreasinginterleukin15mediatedstatactivation
AT crandallkeitha thehivlatencyreversalagenthodhbtenhancesnkcelleffectorandmemorylikefunctionsbyincreasinginterleukin15mediatedstatactivation
AT bosquealberto thehivlatencyreversalagenthodhbtenhancesnkcelleffectorandmemorylikefunctionsbyincreasinginterleukin15mediatedstatactivation
AT macedoamandab hivlatencyreversalagenthodhbtenhancesnkcelleffectorandmemorylikefunctionsbyincreasinginterleukin15mediatedstatactivation
AT levingercallie hivlatencyreversalagenthodhbtenhancesnkcelleffectorandmemorylikefunctionsbyincreasinginterleukin15mediatedstatactivation
AT nguyenbryann hivlatencyreversalagenthodhbtenhancesnkcelleffectorandmemorylikefunctionsbyincreasinginterleukin15mediatedstatactivation
AT richardjonathan hivlatencyreversalagenthodhbtenhancesnkcelleffectorandmemorylikefunctionsbyincreasinginterleukin15mediatedstatactivation
AT guptamamta hivlatencyreversalagenthodhbtenhancesnkcelleffectorandmemorylikefunctionsbyincreasinginterleukin15mediatedstatactivation
AT cruzconradrusselly hivlatencyreversalagenthodhbtenhancesnkcelleffectorandmemorylikefunctionsbyincreasinginterleukin15mediatedstatactivation
AT finziandres hivlatencyreversalagenthodhbtenhancesnkcelleffectorandmemorylikefunctionsbyincreasinginterleukin15mediatedstatactivation
AT chiappinellikatherineb hivlatencyreversalagenthodhbtenhancesnkcelleffectorandmemorylikefunctionsbyincreasinginterleukin15mediatedstatactivation
AT crandallkeitha hivlatencyreversalagenthodhbtenhancesnkcelleffectorandmemorylikefunctionsbyincreasinginterleukin15mediatedstatactivation
AT bosquealberto hivlatencyreversalagenthodhbtenhancesnkcelleffectorandmemorylikefunctionsbyincreasinginterleukin15mediatedstatactivation