New ex vivo approaches distinguish effective and ineffective single agents for reversing HIV-1 latency in vivo

Predicting the outcomes of treatment to eradicate the latent reservoir for HIV-1

“…The dramatic reductions in reservoir size accompanying these strategies stands in stark contrast to the actions of current LRAs, which induce only a fraction of latent virus in vitro (26,27) and have not produced a measurable decrease in LR size in vivo (12,13,28). It is unclear how patient outcomes depend on reservoir reduction between these extremes, nor even whether a reduction that falls short of those achieved with stem cell transplantation will bring any clinical benefit.…”

Post-transcriptional gene silencing, transcriptional gene silencing and human immunodeficiency virus

“…The scope of this discovery may be extrapolated to the barriers to achieving reactivation of latent provirus as a therapeutic approach. Reactivation strategies to purge the latent reservoir, such as the use of histone deacetylase inhibitors (HDACis) have not been successful, despite using a variety of agents like Vorinostat and Panabinostat, with different potencies and specificities in inducing HIV specific chromatin relaxation [32] . The mechanism by which this HIV antisense lncRNA maintains latency might explain in part this difficulty, because a very robust and deep silencing may be established in a great deal of latent proviruses that make up the reservoir.…”

“…However, while viral transcripts from apparently latently infected cells have been detected, no significant change or reduction in the size of the latent reservoir-proviral integrated DNAhas been observed [30,31] . There is currently a debate as to whether these cell associated viral RNA transcripts represent transcripts driven by the endogenous HIV promoter, the 5'LTR or whether these are so called "read through transcripts" which arise from altered expression from the promoter of the parent gene into which HIV has integrated [32] . The results of further trials of these agents are awaited.…”

Multifarious immunotherapeutic approaches to cure HIV-1 infection

“…Considering the high proportion of defective provirus in the latent reservoir (88-98.5%), an agreed method to accurately measure potential latency reversal by various candidate agents is urgently needed. 59,60 The reported failures of various first generation latency reversal agents on their own resulted in modifying such approaches. To date, a number of potential latency reversal agents have failed to upregulate HIV-1 gene expression in resting CD4 C T cells from treated patients, with the exception of the protein kinase C agonist, bryostatin-1.…”

“…To date, a number of potential latency reversal agents have failed to upregulate HIV-1 gene expression in resting CD4 C T cells from treated patients, with the exception of the protein kinase C agonist, bryostatin-1. 47,59 The next generation of candidate agents will hopefully yield more promising results. Ongoing and planned trials of these interventions are incorporating the strategies we have reviewed here, including early cART, therapeutic immunization, cytokines and cART intensification ( Table 1).…”