ABX464: a good drug candidate instead of a magic bullet.

Ben Berkhout,Yme U Van Der Velden

doi:10.1186/s12977-015-0189-x

Ben Berkhout, Yme U Van Der Velden

Open Access

https://doi.org/10.1186/s12977-015-0189-x

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Journal: Retrovirology	Publication Date: Jul 28, 2015
Citations: 18	License type: cc-by

Affiliation: Academic Medical Center, University of Amsterdam

Abstract

Despite the significant number of antiviral drugs that are currently available in the clinics of developed countries, none of these affect the production stage of HIV-1 replication, more specifically the process of viral gene expression. For instance, several early attempts failed to generate inhibitors of the viral Tat protein, the small activator of viral transcription from the long terminal repeat (LTR) promoter. A recent study published in Retrovirology by Campos et al. presents a new small molecule inhibitor, ABX464, that targets the other small viral protein essential for viral gene expression, the Rev protein (Retrovirology 12:30, 2015). Targeting of multiple virus replication steps and silencing the generation of new progeny may be of particular value for current attempts to develop novel therapeutic strategies that provide a cure or functional cure for HIV-1 infection (Nat Rev Immunol 12: 607–614, 2012). We will briefly review some of the unique antiviral properties of ABX464, with the focus on its surprising ability to exhibit a sustained antiviral effect in a humanized mouse model. Although ABX464 may remain an important new addition to the anti-HIV arsenal, we do present a sobering alternative explanation for the long-lasting reduction in viral load after treatment cessation.

Highlights

Despite the significant number of antiviral drugs that are currently available in the clinics of developed countries, none of these affect the production stage of HIV-1 replication, the process of viral gene expression
Profound suppression of the HIV-1 YU2 strain was obtained by state of the art combined antiretroviral therapy in the humanized immune system (HIS) mouse model, but an immediate rebound of the viral load was observed after the treatment was stopped
The explanation provided is that ABX464 prevents virus replication in macrophages, thereby blocking the establishment of a viral reservoir that will cause the rebound after stopping therapy

Summary

Introduction

Despite the significant number of antiviral drugs that are currently available in the clinics of developed countries, none of these affect the production stage of HIV-1 replication, the process of viral gene expression. In the Retrovirology study [1], ABX464 was shown to block HIV-1 replication by preventing the export of unspliced viral RNA from the nucleus to the cytoplasm, a process that is regulated by the viral Rev protein. This indole drug class was originally described as targeting the splicing factor SRSF1 [2], ABX464 was found to bind directly to the cap binding complex (CBC).

Results

Conclusion