In:
PLOS Pathogens, Public Library of Science (PLoS), Vol. 18, No. 1 ( 2022-1-18), p. e1010245-
Abstract:
Activation of the NF-κB signaling pathway by Protein Kinase C (PKC) agonists is a potent mechanism for human immunodeficiency virus (HIV) latency disruption in vitro . However, significant toxicity risks and the lack of evidence supporting their activity in vivo have limited further evaluation of PKC agonists as HIV latency-reversing agents (LRA) in cure strategies. Here we evaluated whether GSK445A, a stabilized ingenol-B derivative, can induce HIV/simian immunodeficiency virus (SIV) transcription and virus production in vitro and demonstrate pharmacological activity in nonhuman primates (NHP). CD4 + T cells from people living with HIV and from SIV + rhesus macaques (RM) on antiretroviral therapy (ART) exposed in vitro to 25 nM of GSK445A produced cell-associated viral transcripts as well as viral particles at levels similar to those induced by PMA/Ionomycin, indicating that GSK445A can potently reverse HIV/SIV latency. Importantly, these concentrations of GSK445A did not impair the proliferation or survival of HIV-specific CD8 + T cells, but instead, increased their numbers and enhanced IFN-γ production in response to HIV peptides. In vivo , GSK445A tolerability was established in SIV-naïve RM at 15 μg/kg although tolerability was reduced in SIV-infected RM on ART. Increases in plasma viremia following GSK445A administration were suggestive of increased SIV transcription in vivo . Collectively, these results indicate that GSK445A is a potent HIV/SIV LRA in vitro and has a tolerable safety profile amenable for further evaluation in vivo in NHP models of HIV cure/remission.
Type of Medium:
Online Resource
ISSN:
1553-7374
DOI:
10.1371/journal.ppat.1010245
DOI:
10.1371/journal.ppat.1010245.g001
DOI:
10.1371/journal.ppat.1010245.g002
DOI:
10.1371/journal.ppat.1010245.g003
DOI:
10.1371/journal.ppat.1010245.g004
DOI:
10.1371/journal.ppat.1010245.g005
DOI:
10.1371/journal.ppat.1010245.g006
DOI:
10.1371/journal.ppat.1010245.s001
DOI:
10.1371/journal.ppat.1010245.s002
DOI:
10.1371/journal.ppat.1010245.s003
DOI:
10.1371/journal.ppat.1010245.s004
DOI:
10.1371/journal.ppat.1010245.s005
DOI:
10.1371/journal.ppat.1010245.s006
DOI:
10.1371/journal.ppat.1010245.s007
DOI:
10.1371/journal.ppat.1010245.s008
DOI:
10.1371/journal.ppat.1010245.s009
DOI:
10.1371/journal.ppat.1010245.s010
DOI:
10.1371/journal.ppat.1010245.s011
DOI:
10.1371/journal.ppat.1010245.s012
DOI:
10.1371/journal.ppat.1010245.s013
DOI:
10.1371/journal.ppat.1010245.s014
DOI:
10.1371/journal.ppat.1010245.s015
DOI:
10.1371/journal.ppat.1010245.s016
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2022
detail.hit.zdb_id:
2205412-1
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