Elsevier

Current Opinion in Virology

Volume 38, October 2019, Pages 1-9
Current Opinion in Virology

Between a shock and a hard place: challenges and developments in HIV latency reversal

https://doi.org/10.1016/j.coviro.2019.03.004Get rights and content

Highlights

  • HIV latency persists in long-lived and proliferating CD4+ T cells.

  • Latency is maintained through mechanisms that suppress viral transcription and translation.

  • Transcription-activating LRAs activate HIV transcription in vivo but there is no elimination of latently infected cells.

  • Immunomodulatory LRAs have dual effects on latency reversal and immune activation.

  • Clinical trials of immunomodulatory LRAs look promising in animal models.

Latently infected cells that persist in HIV-infected individuals on antiretroviral therapy (ART) are a major barrier to cure. One strategy to eliminate latency is by activating viral transcription, commonly called latency reversal. Several small non-randomised clinical trials of latency reversing agents (LRAs) in HIV-infected individuals on ART increased viral production, but disappointingly did not reduce the number of latently infected cells or delay time to viral rebound following cessation of ART. More recent approaches aimed at reversing latency include compounds that both activate virus and also modulate immunity to enhance clearance of infected cells. These immunomodulatory LRAs include toll-like receptor agonists, immune checkpoint inhibitors and some cytokines. Here, we provide a brief review of the rationale for transcription-activating and immunomodulatory LRAs, discuss recent clinical trials and some suggestions for combination approaches and research priorities for the future.

Section snippets

Introduction: HIV persistence and latency

Antiretroviral therapy (ART) can suppress HIV replication but treatment is required lifelong due to the persistence of long-lived and replicating CD4+ T cells that contain integrated HIV DNA, termed a provirus. Although the majority of integrated HIV DNA that persists on ART is defective, 2–5% of proviruses are intact and potentially replication-competent [1, 2, 3]. HIV DNA and replication competent virus has been detected in essentially every CD4+ T cell subset analysed in HIV-infected

Latency reversal and intracellular blocks

Reversing HIV latency to eliminate latently infected cells has been an actively pursued strategy in HIV cure research for the last 10 years. This approach, known as ‘shock and kill’, involves activating latent HIV through administration of a latency reversing agent (LRA) with the aim of facilitating cell death by viral cytopathic effects or immune-mediated killing [21,22]. This is done in the presence of ART so there are no further rounds of HIV replication.

HIV latency is defined as cells that

Transcription-activating LRAs

Multiple classes of drugs have been shown to activate HIV transcription in vitro, including epigenetic modifiers (such as histone deacetylase inhibitors (HDACi), methyl transferase inhibitors, methylation inhibitors and bromodomain inhibitors), protein kinase C agonists, activators of the PI3K pathway (including disulfiram and mTOR inhibitors), NFkB agonists (including SMAC mimetics and maraviroc) [reviewed in Ref. [37]]. Multiple early non-randomised clinical trials of HDACi and disulfiram in

Immunomodulatory latency reversing agents

Newer approaches to target latent HIV that appear to be more promising, at least in animal models, include compounds that activate immune function in combination with induction of viral expression. These include toll-like receptor (TLR) agonists, immune checkpoint (IC) inhibitors and cytokine-based therapy such as interleukin (IL)-15.

Combination LRAs

Several in vitro and ex vivo studies have shown that combinations of LRAs can act synergistically to enhance latency reversal [40,90, 91, 92, 93, 94, 95, 96], particularly when combining a PKC agonist with either a bromodomain inhibitor or an HDACi [91,93,96]. It is therefore possible that combining LRAs with different mechanisms of action will significantly enhance latency reversal, although safety remains a limiting factor for advancing this approach. Other combination approaches include

Areas for future research

Work to date has showed evidence of latency reversal in vivo in both blood and tissue-derived CD4+ T cells, however it is unclear if LRAs have different effects in clonally expanded infected cells; different T cell subsets; in transcriptionally silent or actively transcribing cells; or on intact or defective proviruses [3,106]. These are all important sources of latent virus to understand. Given that a fraction of latently infected cells contain full-length intact proviruses that are not easily

Conclusion

Overall, we believe that LRAs play a key role in HIV cure strategies as a component of a combination approach and to provide a mechanism to ‘expose’ virus. The potency of LRAs can be potentially enhanced through development of compounds with increased specificity for infected cells, ideally through an HIV-specific mode of action; by improving delivery to key tissue sites, potentially through nanoparticle technology; or by using LRAs in conjunction with other interventions to enhance killing of

Financial support and sponsorship

This work was partly supported by funding from the National Health and Medical Research Council (NHMRC) of Australia and the National Institutes of Health, (UM1AI126611, Delaney AIDS Research Enterprise (DARE) to find a cure) and the American Foundation for AIDS Research (amfAR 109226-58-RGRL). S.R.L. is an NHMRC Practitioner Fellow.

Conflict of interest

SRL’s institution has received funding from the National Health and Medical Research Council (NHMRC) of Australia, National Institutes for Health, American Foundation for AIDS Research; Merck, Viiv and Gilead for investigator-initiated research; Merck, Viiv and Gilead for educational activities. She is on the advisory board of Abivax and Innivirax.

Acknowledgement

None.

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