Abstract
Latent HIV reservoirs in infected individuals prevent current treatment from eradicating infection. Treatment strategies against latency involve adjuvants for viral reactivation which exposes viral particles to antiretroviral drugs. In this study, the effect of novel triterpenoids isolated from Ocimum labiatum on HIV-1 expression was measured through HIV-1 p24 antigen capture in the U1 latency model of HIV-1 infection and in peripheral blood mononuclear cells (PBMCs) of infected patients on combination antiretroviral therapy (cART). The mechanism of viral reactivation was determined through the compound’s effect on cytokine production, histone deacetylase (HDAC) inhibition, and protein kinase C (PKC) activation. Cytotoxicity of the triterpenoids was determined using a tetrazolium dye and flow cytometry. The isolated triterpene isomers, 3-hydroxy-4,6a,6b,11,12,14b-hexamethyl-1,2,3,4,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-octadecahydropicene-4,8a-dicarboxylic acid (HHODC), significantly (p < 0.05) induced HIV-1 expression in a dose-dependent manner in U1 cells at non-cytotoxic concentrations. HHODC also induced viral expression in PBMCs of HIV-1 infected patients on cART. In addition, the compound up-regulated the production of interleukin (IL)-2, IL-6, tumour necrosis factor (TNF)-α, and interferon (IFN)-γ but had no effect on HDAC and PKC activity, suggesting cytokine upregulation as being involved in latency activation. The observed in vitro reactivation of HIV-1 introduces the adjuvant potential of HHODC for the first time here.
Highlights
The current HIV-1 regimen has the ability to reduce viral load to an undetectable level, complete eradication of the virus cannot be achieved due to the inability of combination antiretroviral therapy (cART) in affecting latent HIV [1]
Column chromatography of the ethyl acetate fraction of O. labiatum leaves on silica gel followed by purification with Sephadex LH-20 led to the isolation of two triterpenes
A known triterpene that is common in nature, amyrin [28] was identified as compound 1 while compound 2, the second triterpene,3-hydroxy-4,6a,6b,11,12,14b-hexamethyl-1,2,3,4,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-octade cahydropicene-4,8a-dicarboxylic acid isolated appeared as a mixture of isomers
Summary
The current HIV-1 regimen has the ability to reduce viral load to an undetectable level, complete eradication of the virus cannot be achieved due to the inability of cART in affecting latent HIV [1]. Therapeutic targeting of latent HIV-1 is crucial for viral eradication [5,6,7]. A number of clinical trials were conducted with the aim of targeting latent viral reservoirs and the drugs used in these trials were unable to completely purge the highly stable viral reservoirs [2,8]. Treating latent virus would require viral reactivation. Potential drugs tested in clinical trials for reactivation of latent HIV-1 include panobinostat, romidepsin, and vorinostat [9]
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