Between a shock and a hard place: challenges and developments in HIV latency reversal
Graphical abstract
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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2021, iScienceCitation Excerpt :In this treatment, cells are reactivated from latency into an active state where they can then undergo killing by cytotoxic T cells and subsequently were cleared from the patient (Figure 1A) (Dahabieh et al., 2015). Unfortunately, “shock and kill” falls short owing to incomplete reactivation and killing of the latent reservoir (Cillo et al., 2014; Zerbato et al., 2019). Furthermore, latency reversal agents (LRAs) have been shown to impair cytotoxic T cell function (Shan et al., 2012; Jones et al., 2014, 2016), and clinical trials with histone deacetylase inhibitors (HDACis) and disulfiram, two classes of candidate LRAs, produced no major reduction in the size of the latent HIV-1 reservoir in patients on antiretroviral therapy (Rasmussen and Lewin, 2016).
Multiply spliced HIV RNA is a predictive measure of virus production ex vivo and in vivo following reversal of HIV latency
2021, EBioMedicineCitation Excerpt :Others have also shown that LRAs such as HDACi are unable to induce viral elongation or splicing [18,20]. Evaluation of LRAs that modulate transcription in clinical trials of PLWH on ART have demonstrated an increase in the initiation of HIV transcription from an integrated provirus, measured as an increase in cell-associated US HIV RNA, but varying efficacy in increasing plasma HIV RNA [6]. In clinical trials of the histone deacetylase inhibitors (HDACi) vorinostat [17,21,22] and the CCR5 antagonist maraviroc [23], an increase in US HIV RNA was observed with no significant change in plasma HIV RNA.
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