Fighting HIV-1 Persistence: At the Crossroads of “Shoc-K and B-Lock”

Abstract

Despite the success of highly active antiretroviral therapy (HAART), integrated HIV-1 proviral DNA cannot be eradicated from an infected individual. HAART is not able to eliminate latently infected cells that remain invisible to the immune system. Viral sanctuaries in specific tissues and immune-privileged sites may cause residual viral replication that contributes to HIV-1 persistence. The “Shock or Kick, and Kill” approach uses latency reversing agents (LRAs) in the presence of HAART, followed by cell-killing due to viral cytopathic effects and immune-mediated clearance. Different LRAs may be required for the in vivo reactivation of HIV-1 in different CD4+ T cell reservoirs, leading to the activation of cellular transcription factors acting on the integrated proviral HIV-1 LTR. An important requirement for LRA drugs is the reactivation of viral transcription and replication without causing a generalized immune activation. Toll-like receptors, RIG-I like receptors, and STING agonists have emerged recently as a new class of LRAs that augment selective apoptosis in reactivated T lymphocytes. The challenge is to extend in vitro observations to HIV-1 positive patients. Further studies are also needed to overcome the mechanisms that protect latently infected cells from reactivation and/or elimination by the immune system. The Block and Lock alternative strategy aims at using latency promoting/inducing agents (LPAs/LIAs) to block the ability of latent proviruses to reactivate transcription in order to achieve a long term lock down of potential residual virus replication. The Shock and Kill and the Block and Lock approaches may not be only alternative to each other, but, if combined together (one after the other), or given all at once [namely “Shoc-K(kill) and B(block)-Lock”], they may represent a better approach to a functional cure.

Anomalous HIV-1 RNA, How Cap-Methylation Segregates Viral Transcripts by Form and Function

“…Redox homeostasis has been a pillar in the construction of HIV Cure strategies to manipulate latently infected cells in aviremic patients [ 171 , 172 , 173 ]. Oxidative stress has been proposed to send proviruses into deep latency [ 173 ].…”

“…Redox homeostasis has been a pillar in the construction of HIV Cure strategies to manipulate latently infected cells in aviremic patients [ 171 , 172 , 173 ]. Oxidative stress has been proposed to send proviruses into deep latency [ 173 ]. Until the identification of the CBP80/NCPB3-specialized translation pathway that is licensed by TMG-cap on selected mRNAs [ 20 , 139 ], host translation during oxidative stress was attributed largely to cap-independent initiation [ 143 ].…”

Targeted Nanocarrier Delivery of RNA Therapeutics to Control HIV Infection

“…Epigenetic modifiers, such as Histone Deacetylase Inhibitors (HDACi) and histone methyltransferase inhibitors (HMTi), inhibit the activity of enzymes involved in the post-translational modifications of histones that maintain HIV latency [ 42 ]. HDACi are the most studied class of LRAs, with several drugs studied in clinical trials, such as valproate, Panobinostat, Vorinostat and Romidepsin [ 43 ]. Although some increments in the levels of cell-associated unspliced HIV-RNA have been observed, they have not resulted in a reduction in the size of the viral reservoir [ 43 ].…”

“…HDACi are the most studied class of LRAs, with several drugs studied in clinical trials, such as valproate, Panobinostat, Vorinostat and Romidepsin [ 43 ]. Although some increments in the levels of cell-associated unspliced HIV-RNA have been observed, they have not resulted in a reduction in the size of the viral reservoir [ 43 ]. Besides epigenetic modifiers, key factors in the signal transduction pathway, such as Protein kinase C, which induces signalling via the transcription factor NF-κB, have also been tested for reversing HIV latency, including PKC agonists, Bryostatin, Prostratin and Ingenol [ 40 ].…”

Accuracy of real-time PCR and digital PCR for the monitoring of total HIV DNA under prolonged antiretroviral therapy

“…Human immunodeficiency virus (HIV) provirus persists in the genome of latently infected cells despite suppression of viral replication by current antiretroviral therapies 1 . HIV reservoir is therefore considered a major obstacle to HIV cure.…”