New ex vivo approaches distinguish effective and ineffective single agents for reversing HIV-1 latency in vivo

CK Bullen, GM Laird, CM Durand, JD Siliciano… - Nature medicine, 2014 - nature.com
Nature medicine, 2014nature.com
HIV-1 persists in a latent reservoir despite antiretroviral therapy (ART),,,,. This reservoir is the
major barrier to HIV-1 eradication,. Current approaches to purging the latent reservoir
involve pharmacologic induction of HIV-1 transcription and subsequent killing of infected
cells by cytolytic T lymphocytes (CTLs) or viral cytopathic effects,,. Agents that reverse
latency without activating T cells have been identified using in vitro models of latency.
However, their effects on latently infected cells from infected individuals remain largely …
Abstract
HIV-1 persists in a latent reservoir despite antiretroviral therapy (ART),,,,. This reservoir is the major barrier to HIV-1 eradication,. Current approaches to purging the latent reservoir involve pharmacologic induction of HIV-1 transcription and subsequent killing of infected cells by cytolytic T lymphocytes (CTLs) or viral cytopathic effects,,. Agents that reverse latency without activating T cells have been identified using in vitro models of latency. However, their effects on latently infected cells from infected individuals remain largely unknown. Using a new ex vivo assay, we demonstrate that none of the latency-reversing agents (LRAs) tested induced outgrowth of HIV-1 from the latent reservoir of patients on ART. Using a quantitative reverse transcription PCR assay specific for all HIV-1 mRNAs, we demonstrate that LRAs that do not cause T cell activation do not induce substantial increases in intracellular HIV-1 mRNA in patient cells; only the protein kinase C agonist bryostatin-1 caused significant increases. These findings demonstrate that current in vitro models do not fully recapitulate mechanisms governing HIV-1 latency in vivo. Further, our data indicate that non-activating LRAs are unlikely to drive the elimination of the latent reservoir in vivo when administered individually.
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