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Review
. 2017 Jan;12(1):96-104.
doi: 10.1097/COH.0000000000000328.

Cancer therapies in HIV cure research

Thomas A Rasmussen  1 , Jenny L Anderson, Fiona Wightman, Sharon R Lewin
Affiliations
Review

Cancer therapies in HIV cure research

Thomas A Rasmussen et al. Curr Opin HIV AIDS. 2017 Jan.

Abstract

Purpose of review: This article provides an overview of anticancer therapies in various stages of clinical development as potential interventions to target HIV persistence.

Recent findings: Epigenetic drugs developed for cancer have been investigated in vitro, ex vivo and in clinical trials as interventions aimed at reversing HIV latency and depleting the amount of virus that persists on antiretroviral therapy. Treatment with histone deacetylase inhibitors induced HIV expression in patients on antiretroviral therapy but did not reduce the frequency of infected cells. Other interventions that may accelerate the decay of latently infected cells, in the presence or absence of latency-reversing therapy, are now being explored. These include apoptosis-promoting agents, nonhistone deacetylase inhibitor compounds to reverse HIV latency and immunotherapy interventions to enhance antiviral immunity such as immune checkpoint inhibitors and Toll-like receptor agonists.

Summary: A curative strategy in HIV will likely need to both reduce the amount of virus that persists on antiretroviral therapy and improve anti-HIV immune surveillance. Although we continue to explore advances in the field of oncology including cancer immunotherapy, there are major differences in the risk-benefit assessment between HIV-infected individuals and patients with malignancies. Drug development specifically targeting HIV persistence will be the key to developing effective interventions with an appropriate safety profile.

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Conflict of interest statement

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, Gilead and Tetralogic for investigator initiated research; Merck, Viiv and Gilead for educational activities.

Figures

Figure 1
Figure 1. Anti-cancer compounds with potential to target HIV persistence
Latency reversing agents (LRAs) that induce HIV expression in latently infected cells include histone deacetylase inhibitors (HDACi), bromodomain and extra-terminal (BET) inhibitors, methylation inhibitors and protein kinase C (PKC) agonists. HDACi promote histone acetylation and chromatin remodelling at the HIV promoter to support access for transcription initiation. Methylation inhibitors prevent deleterious hypermethylation of CpG islands near the HIV promoter to foster HIV transcription initiation. PKC agonists (eg. prostratin, bryostatin) promote the accumulation of active cellular NF-κB transcription factor in the cell nucleus to promote HIV transcription initiation. Bromodomain inhibitors (eg. JQ1) prevent PTEF-b binding to bromodomain proteins, releasing free PTEF-b to interact with HIV Tat protein for efficient HIV transcription elongation. Apoptosis-inducing compounds act on various pathways leading to caspase activation and apoptosis and could also be administered with LRAs to sensitise cells for apoptosis. For instance, acitretin triggers retinoic acid-inducible gene I (RIG-I) that in turn detects viral RNA for subsequent interferon-induced apoptosis. SMAC mimetics block inhibitor of apoptosis (IAP) proteins, preventing IAPs from inhibiting apoptosis and sensitizing cells towards apoptosis. Similarly, inhibitors of BCL-2 (eg. Venetoclax) block this BCL-2 inhibitor of apoptosis, sensitising cells towards apoptosis. Inhibitors of the PI3K/Akt pro-survival pathway both culminate in preventing Akt activation (which inhibits apoptosis), thereby also sensitising cells towards apoptosis. Immune-based therapies such as immune checkpoint (IC) inhibitors and toll-like receptor (TLR) agonists may enhance immune-mediated killing of HIV-expressing cells. IC inhibitors (e.g. anti-PD1 or anti-CTLA-4) also block negative signalling to T cells and may potentially also reverse latency. TLR 7/9 agonists bind to receptors on endolysosomes in antigen-presenting cells and other immune cells, activate dendritic cells (DCs) and natural killer (NK) cells and induce release of interferon-α. SMAC: second mitochondria-derived activator of caspase, PI3Ki: phosphoinositide 3-kinase inhibitor, Akti: Akt inhibitor, BCL-2i: B-cell lymphoma 2 inhibitor, BETi: bromodomain and extra-terminal protein inhibitor, P-TEFb: positive transcription elongation factor b, LTR: HIV long terminal repeat promoter, Ac: acetylation, Me: methylation.
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