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Characterization of designed, synthetically accessible bryostatin analog HIV latency reversing agents.

  • Author(s): Marsden, Matthew D
  • Wu, Xiaomeng
  • Navab, Sara M
  • Loy, Brian A
  • Schrier, Adam J
  • DeChristopher, Brian A
  • Shimizu, Akira J
  • Hardman, Clayton T
  • Ho, Stephen
  • Ramirez, Christina M
  • Wender, Paul A
  • Zack, Jerome A
  • et al.
Abstract

HIV latency in resting CD4+ T cell represents a key barrier preventing cure of the infection with antiretroviral drugs alone. Latency reversing agents (LRAs) can activate HIV expression in latently infected cells, potentially leading to their elimination through virus-mediated cytopathic effects, host immune responses, and/or therapeutic strategies targeting cells actively expressing virus. We have recently described several structurally simplified analogs of the PKC modulator LRA bryostatin (termed bryologs) designed to improve synthetic accessibility, tolerability in vivo, and efficacy in inducing HIV latency reversal. Here we report the comparative performance of lead bryologs, including their effects in reducing cell surface expression of HIV entry receptors, inducing proinflammatory cytokines, inhibiting short-term HIV replication, and synergizing with histone deacetylase inhibitors to reverse HIV latency. These data provide unique insights into structure-function relationships between A- and B-ring bryolog modifications and activities in primary cells, and suggest that bryologs represent promising leads for preclinical advancement.

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