The role of latency reversal agents in the cure of HIV: A review of current data

Highlights

• Memory CD4⁺ T cells carrying proviral DNA are the major obstacle for HIV eradication.

• The immune system cannot recognize latently infected cells.

• Eliminating latently infected cells could be the choice to reduce the size of the HIV-1 reservoir.

• Latency reversing agents (LRA) reactivate latently infected cells and unmask the presence of the virus, allowing their recognition by immune cells.

• Histone deacetylase inhibitors may be studied also in patients with persistently low CD4+ count.

Abstract

The definitive cure for human immunodeficiency virus type-1 (HIV) infection is represented by the eradication of the virus from the patient’s body. To reach this result, cells that are infected but do not produce the virus must become recognizable to be killed by the immune system. For this purpose, drugs defined “latency reverting agents” (LRA) that reactivate viral production are under investigation. A few clinical studies have been performed in HIV-infected patients treated with LRA and combined antiretroviral therapy (cART). The strategy is thus to combine cART and LRA to reactivate the virus and unmask latently infected cells that, because of cART, cannot produce a fully competent form of the virus. Unmasked cells can present viral antigens to the immune system, that ultimately recognizes and kills such latently infected cells. This review reports and discusses recent studies that have been published on this topic.

Introduction

Combined antiretroviral therapy (cART) controls replication of the human immunodeficiency virus type-1 (HIV) by affecting different stages of the viral life cycle, including cell entry, reverse transcription, integration, and assembling of the virion [1]. The use of cART has led to a prolongation of the lifespan of HIV-positive individuals lifespan and to an improvement in the quality of life, turning the concept of HIV infection as a life-threatening disease into a chronic infectious disease [[2], [3]], characterized by a persistent activation of the immune system [4].

Even if cART puts a harness on viral replication and decreases plasma viremia in most treated patients [[5], [6]], it is unable to completely eliminate infected cells. Thus, the presence of resting, memory CD4⁺ T cells carrying proviral DNA remains a major obstacle for HIV eradication because, once re-activated, these latently infected cells are a potential source of viruses [[7], [8]]. The genome of HIV integrates into the host DNA but cannot express itself significantly, because the activation of the proviral promoter long terminal repeat (LTR) requires the intervention of several cellular transcription factors. In the absence of adequate stimuli, these latent reservoirs are stable and resistant to different treatment regimens [[9], [10], [11], [12]]. As respects, discovering integrated virus from the host’s genome and accordingly target infected but not virus-producing cells is remarkably challenging.

The immune system cannot recognize latently infected cells, and such cells escape from both the attack of the immune system, and are not touched by cART [1]. There are two main strategies for trying to eradicate the infection, of for its cure, that include “sterilizing cure” and “functional cure”. The sterilizing cure include treatments such as stem cell transplantation, genome editing, gene therapy and “shock and kill” strategy [[13], [14], [15]]. On the other hand, functional cure implies the long-term control of viral replication with the aim of preserving a normal CD4+ T cell count and undetectable level of viral replication [16].

In the last years, promising studies have identified drugs which are able to reverse latency without activating T cells and causing the production of new virions [[17], [18], [19]]. The aim of this strategy is to combine latency reverting agents (LRA) with cART so that LRA can activate the production of the virus by latentely infected cells: viral peptides are presented to the immune system that finally can recognize and kill infected cells. However, because of the presence of protease inhibitors among the drugs used in the cART, in theory the complete form of the virion does not have be produced, and thus viral load has to remain undetectable.

LRA include disulfiram and the histone deacetylase (HDAC) inhibitors, such as vorinostat (suberoylanilide hydroxamic acid or SAHA) [[20], [21], [22]]. The molecular mechanism of latency reactivation induced by disulfiram is unclear [23]. The role of HDAC is to remodel chromatin during transcription, leading to the prevention of LTR promoter expression, thereupon repressing viral replication. HDAC inhibitors disrupt the aforementioned process, so causing LTR activation [24].

Previous studies showed that three HDAC inhibitors, including vorinostat (Zolinza™), romidepsin (depsipeptide, FK228, FR901228), and panobinostat (LBH589, Farydak™) have enhanced the level of plasma viral RNA in aviremic patients on cART, indicating successful reactivation of latent cells that unfortunately produce intact virions [[25], [26], [27], [28], [29]]. Considering the performance of each inhibitor as far as the plasma level of HIV is concerned, a survey summarizing and comparing the role of each drug in treating infected patients can be of interest. Thereby, the current paper briefly reviews and assesses the clinical trials performed by using the HDAC inhibitors Vorinostat, Panobinostat and Romidepsin.