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.
Highlights
Infection with human immunodeficiency virus (HIV) almost invariably causes severe damage to the host immune system, leading to the development of acquired immunodeficiency syndrome (AIDS)
We address the activities of these bryologs as required for their preclinical advancement with a focus on their comparative ability to alter HIV entry receptor levels and induce proinflammatory cytokines in primary peripheral blood mononuclear cells (PBMC), affect HIV spread in activated CD4 + T cells, and synergize with Histone deacetylase inhibitors (HDACi) to reverse HIV latency
We previously demonstrated that a panel of Protein kinase C (PKC) modulators induced expression of CD69 at the same concentrations as that required to induce HIV from latency (Marsden et al, 2017), their effects on HIV receptor expression have not been defined
Summary
Infection with human immunodeficiency virus (HIV) almost invariably causes severe damage to the host immune system, leading to the development of acquired immunodeficiency syndrome (AIDS). While multiple factors might contribute to the persistence of HIV during ART, one important source of replication-competent HIV in treated patients is latently-infected CD4 + T cells (Chun et al, 1995; Finzi et al, 1999; Finzi et al, 1997; Wong et al, 1997) These long-lived latently-infected cells harbor integrated proviruses that express little or no viral RNA and no viral proteins, but episodically produce infectious virions upon appropriate stimulation of the host cell (Chun et al, 1997; Finzi et al, 1997). Elimination of these reservoir cells, the chronic source of re-infection, is critical for HIV eradication from infected individuals
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