Abstract
ABSTRACTInfection with human immunodeficiency virus 1 (HIV-1) remains incurable because long-lived, latently-infected cells persist during prolonged antiretroviral therapy. Attempts to pharmacologically reactivate and purge the latent reservoir with latency reactivating agents (LRAs) such as protein kinase C (PKC) agonists (e.g. ingenol A) or histone deacetylase (HDAC) inhibitors (e.g. SAHA) have shown promising but incomplete efficacy. Using the J-Lat T cell model of HIV latency, we found that the plant-derived compound harmine enhanced the efficacy of existing PKC agonist LRAs in reactivating latently-infected cells. Treatment with harmine increased not only the number of reactivated cells but also increased HIV transcription and protein expression on a per-cell basis. Importantly, we observed a synergistic effect when harmine was used in combination with ingenol A and the HDAC inhibitor SAHA. An investigation into the mechanism revealed that harmine, when used with LRAs, increased the activity of NFκB, MAPK p38, and ERK1/2. Harmine treatment also resulted in reduced expression of HEXIM1, a negative regulator of transcriptional elongation. Thus, harmine enhanced the effects of LRAs by increasing the availability of transcription factors needed for HIV reactivation and promoting transcriptional elongation. Combination therapies with harmine and LRAs could benefit patients by achieving deeper reactivation of the latent pool of HIV provirus.
Highlights
Infection with human immunodeficiency virus 1 (HIV) remains incurable because of the ability of this virus to permanently integrate its genetic material into the host genome of infected cells
In the current study, we demonstrate that the plant-derived compound harmine can boost the efficacy of latent HIV-1 reactivation mediated by latency reactivating agents (LRAs)
We found that harmine treatment results in reduced expression of HEXIM1, a negative regulator of transcription elongation mediated by pTEFb
Summary
Infection with human immunodeficiency virus 1 (HIV) remains incurable because of the ability of this virus to permanently integrate its genetic material into the host genome of infected cells. The HIV genome may enter a state of non-expression wherein viral mRNA and proteins are not expressed 2 Whether this non-expression is through neglect (lack of stimuli required to drive the HIV LTR promoter) or active suppression (binding of inhibitory proteins to the LTR or epigenetic silencing of the locus), the outcome is the same – HIV is not produced, and the virus remains hidden from host immunity. In this state, HIV endures for as long as the infected cell and all progeny from future cell divisions. If replication-competent proviral genomes are harbored, an individual is at risk for viral reactivation
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