Next Article in Journal
Proteogenomic Characterization of Pseudomonas veronii SM-20 Growing on Phenanthrene as Only Carbon and Energy Source
Previous Article in Journal
Resistome Analysis of Klebsiella pneumoniae Complex from Residential Aged Care Facilities Demonstrates Intra-facility Clonal Spread of Multidrug-Resistant Isolates
Previous Article in Special Issue
Altered Plasma microRNA Signature in Hospitalized COVID-19 Patients Requiring Oxygen Support
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Microorganisms
Volume 12
Issue 4
10.3390/microorganisms12040752
microorganisms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Targeting Viral Transcription for HIV Cure Strategies

by
Jon Izquierdo-Pujol
1,2,
Maria C. Puertas
1,2,3,
Javier Martinez-Picado
1,2,3,4,5 and
Sara Morón-López
1,2,3,*
1
IrsiCaixa, 08916 Badalona, Spain
2
Germans Trias i Pujol Research Institute (IGTP), 08916 Badalona, Spain
3
CIBERINFEC, 28029 Madrid, Spain
4
Department of Infectious Diseases and Immunity, School of Medicine, University of Vic-Central University of Catalonia (UVic-UCC), 08500 Vic, Spain
5
Catalan Institution for Research and Advanced Studies (ICREA), 08010 Barcelona, Spain
*
Author to whom correspondence should be addressed.
Microorganisms 2024, 12(4), 752; https://doi.org/10.3390/microorganisms12040752
Submission received: 21 March 2024 / Revised: 5 April 2024 / Accepted: 5 April 2024 / Published: 8 April 2024
(This article belongs to the Special Issue Molecular Mechanisms of Viral Persistence and Immune Evasion)
Browse Figures
Review Reports Versions Notes

Abstract

:
Combination antiretroviral therapy (ART) suppresses viral replication to undetectable levels, reduces mortality and morbidity, and improves the quality of life of people living with HIV (PWH). However, ART cannot cure HIV infection because it is unable to eliminate latently infected cells. HIV latency may be regulated by different HIV transcription mechanisms, such as blocks to initiation, elongation, and post-transcriptional processes. Several latency-reversing (LRA) and -promoting agents (LPA) have been investigated in clinical trials aiming to eliminate or reduce the HIV reservoir. However, none of these trials has shown a conclusive impact on the HIV reservoir. Here, we review the cellular and viral factors that regulate HIV-1 transcription, the potential pharmacological targets and genetic and epigenetic editing techniques that have been or might be evaluated to disrupt HIV-1 latency, the role of miRNA in post-transcriptional regulation of HIV-1, and the differences between the mechanisms regulating HIV-1 and HIV-2 expression.

1. Introduction

An estimated 39 million people worldwide are living with HIV, 1.7 million of them being children from 0 to 14 years old and 2 million of them living with HIV-2. With an incidence of 1.3 million new infections in 2022, the HIV pandemic remains an important global health problem [1]. Since the introduction of antiretroviral therapy (ART), the infection has transitioned from a lethal to a chronic disease, and the incidence has been gradually decreasing [2]. Although ART controls HIV replication and dramatically reduces the chance of developing AIDS, the availability of a universal cure for HIV seems a little bit far. This is mainly due to the rapid establishment of viral reservoirs that escape the immune response and, therefore, remain latent. Due to these viral reservoirs, most ART-suppressed people living with HIV (PWH) after ART discontinuation would experience viral rebound, forcing them to be on ART indefinitely.
Understanding the mechanisms that control HIV expression will provide insights into how HIV latency, pathogenesis, and persistence are regulated. In particular, HIV latency, which is a major barrier to a cure, is maintained by combinatorial mechanisms at transcriptional and post-transcriptional levels.
The disruption of viral transcription is postulated as a potential target for therapeutic intervention, among the different strategies aimed at curing HIV [3]. Specifically, by activating the expression of latent proviruses, known as “shock and kill”, or by promoting the silencing of HIV transcription, known as “block and lock”. On the one hand, pharmacological induction of latent HIV transcription began with the use of epigenetic modulators, with the hope of generating viral proteins that could activate specific cytotoxic responses to reduce the viral reservoir [4,5]. Subsequently, many other pharmacological compounds with different mechanisms of action have been proposed using the same strategy as pharmacological latency-reversing agents (LRAs) [6]. However, they mainly differ in the stage of HIV transcription that they target to reactivate the latently infected cell. On the other hand, the mechanistically opposite strategy, which pursues the definitive silencing of HIV transcription, includes a more limited number of latency-promoting agents (LPAs) with a lower diversity in their mechanisms of action [7,8,9,10,11,12,13,14,15].
In conclusion, HIV cure strategies based on the disruption of viral transcription are in constant evolution and represent the scientific focus of multiple experimental interventions addressed to impact HIV latency. Here, we review the cellular and viral factors that regulate HIV transcription and post-transcription mechanisms, their pharmacological interference using novel approaches to tackle viral latency, and their parallels with HIV-2.

2. Cellular and Viral Factors Regulating HIV Transcription and Nuclear Export

A summary of the cellular and viral factors regulating HIV transcription stages (initiation, elongation, polyadenylation, and multiple splicing) and nuclear export are described in the following sections and represented in Figure 1.

2.1. Initiation

HIV-1 transcription initiation starts in the trans-activator response element (TAR) of the 5′ long terminal repeat region (LTR) and is dependent on different cellular host factors. Transcription initiation is mainly controlled by cis-regulatory elements along 5′LTR. These cis-regulatory elements are recognized by either constitutively expressed transcription factors such as specificity protein 1 (Sp1) [16,17] and o-binding protein 1 (Oct1) [18], and inducible transcription factors such as nuclear factor-kappa B (NF-κB) [19,20], activator protein 1 (AP-1) [16,17], and the nuclear factor of activated T cells (NFAT) [16,17]. Therefore, the initiation of viral transcription depends on the balance between transcription factors that are activators or repressors and their binding to the 5′LTR loop. This way, only when activator transcription factors are bound to the viral cis-regulatory elements will the cellular RNA polymerase II (RNAPII) machinery be recruited and halted until the elongation step begins [21].

2.2. Elongation

The elongation process is mainly driven by human positive transcriptional elongation factor b (P-TEFb) and the viral transactivator Tat. Tat and P-TEFb, through many different steps (reviewed in [21]), are responsible for the phosphorylation of the carboxy terminal domain (CTD) of RNAPII, thereby switching the pausing state of RNAPII to an active elongation [22]. Moreover, P-TEFb and Tat undergo multiple cycles of association/dissociation, allowing potent expression of the HIV-1 genome by repeating their function in a loop [23].

2.3. Polyadenylation

HIV mRNA follows the same polyadenylation process as other cellular mRNAs. The polyadenylation process starts with an endonucleolytic cleavage by CPSF3. Then, the poly(A) polymerase (PAP) finishes the process by adding 100 to 250 adenylate residues (reviewed in [24]). In order for this process to start, CPSF3 needs to recognize the cleavage site of the mRNA. This cleavage site consists of an AAUAAA or similar hexanucleotide and a 25–30 base short U- or GU-rich zone that can be located either downstream or upstream of the hexanucleotide. Among the elements that participate in this process, there are 13 core elements and almost 80 auxiliary elements that, together with the core elements, are responsible for the polyadenylation of mRNAs [25]. Moreover, HIV has two polyadenylation sites, one at each LTR region, either 5′ or 3′ [26]. It is essential that the virus suppresses the upstream 5′ polyadenylation signal, or there will be no open reading frame for some mRNAs, constituting one of the mechanisms promoting HIV latency [27] and, therefore, an interesting therapeutic target (reviewed in [24]).

2.4. Multiple Splicing

Splicing in HIV is fundamental in order to produce competent viral particles. HIV-1 first needs to generate a 9 kb unspliced vRNA (HIV-1 US vRNA) encoding the full viral genome, which will serve as the genomic RNA that will be packaged in new virions. But still, splicing in HIV-1 is essential in order to produce both structural components of the viral particles and accessory proteins. Thus, this 9 kb long transcript is processed by the spliceosome cellular machinery and subjected to alternative splicing that will produce either the 4 kb single spliced vRNA (HIV-1 SS vRNA) or the 2 kb multiply spliced vRNA (HIV-1 MS vRNA) (reviewed in [28]). HIV-1 MS vRNAs are basically produced in the early stages of HIV transcription since they encode for Tat, which enhances HIV transcription initiation, and Rev, which will be responsible in part for the translocation of HIV-1 US vRNA from the nucleus to the cytoplasm [28]. It has been recently reported that PCID2 establishes blocks to alternative splicing during HIV-1 latency and misregulates alternative splicing in cells obtained from PWH [29]. However, there is limited knowledge of the specific cellular molecules and proteins involved in HIV splicing. In trying to better understand the host factors involved in HIV-1-splicing, a recent study showed several genes upregulated and downregulated in association with HIV splicing [30]. Among them, four were involved specifically in the minor mRNA splicing pathway [31,32,33], of which three were upregulated (RNAU4ATAC, SNRNP25, SNRPD2) and one was downregulated (RNAU4ATAC11P). These results suggested that the minor mRNA splicing pathway might be involved in HIV splicing. Therefore, disruption of the HIV-1 splicing process is also an interesting therapeutic approach for both LRAs and LPAs.

2.5. Nuclear Export

Each of the three types of vRNA resulting from splicing (HIV-1 US, SS, or MS vRNA) uses a specific mechanism for its translocation from the nucleus to the cytoplasm. During the early phases of HIV transcription, the shortest HIV-1 MS vRNA transcripts are is exported through the nuclear pores via the canonical NXF1/NXT1-mediated export [34,35]. This MS vRNA will produce Rev, a protein that will be key for the export of both SS and US HIV-1 vRNA. Rev contains a nuclear localization signal (NLS) that allows it to return to the nucleus by interacting with Importin B [36]. It will then be bound to the Rev response element (RRE) and mediate the long vRNA export via a CRM-1-dependent mechanism [37,38]. Therefore, halting the export of MS vRNA in order to abrogate Rev function or directly block the export of SS and US vRNA from the nucleus to the cytoplasm are potential therapeutic approaches.

2.6. Repressive Transcriptional Factors

There are multiple host transcriptional repressor factors known to be involved in the negative regulation of HIV transcription [21,39]. In this context, several studies have demonstrated that the restriction factor TRIM22 impairs HIV-1 transcription [40,41,42,43,44]. Specifically, it inhibits the binding of Sp1 to the HIV-1 promoter by forming protein complexes with other cellular proteins that bind and sequester Sp1 [45]. Another example is the COUP-TF interacting protein 2 (CTIP2), also known as BCL11B, which represses HIV-1 transcription initiation by establishing a repressive epigenetic environment in the LTR [46] and by repressing TAT-mediated transactivation in a complex with NuRD [47]. Another study showed that KLF2 and KLF3 repressed HIV-1 and HIV-2 transcription by direct binding to the LTR [48]. Moreover, the negative elongation factor (NELF) induces RNAP II promoter-proximal pausing, limiting HIV expression [49]. It has also been shown that ZBTB2 binds the HIV-1 promoter, recruiting histone deacetylases (HDACs) and repressing HIV-1 transcription [50]. Furthermore, it has been recently reported that PCI domain-containing 2 (PCID2) protein, a subunit of the transcription and export complex 2 (TREX2) complex, binds to the latent HIV-1 LTR as a transcriptional repressor [29]. Moreover, PCF11, a protein involved in 3′ end processing of mRNA and transcription termination of protein-encoding genes [51,52], causes premature termination of HIV-1 transcription [53]. Also, a study recently showed that WDR82 associates with PCF11 at a proximal RNAPII elongation checkpoint on the HIV-1 promoter, enforcing premature transcription termination [54]. Furthermore, another recent study observed that the epigenetic repressor TASOR, a protein of the Human Silencing Hub (HUSH) complex, cooperates with the RNA deadenylase CCR4–NOT complex scaffold CNOT1 and synergistically represses HIV-1 expression [55]. Therefore, increasing the expression of these transcriptional repressor factors may also promote HIV-1 latency.
Microorganisms 12 00752 g001
Figure 1. HIV post-transcriptional steps. HIV transcription initiation depends on the balance of certain host transcription factors (activators or repressors). Once initiated, Tat and P-TEFb are responsible for recruiting and activating RNA polymerase II (RNAPII), which will start HIV elongation. During HIV elongation, the spliceosome will be recruited around the RNA generated and start the splicing process, generating three major products: unspliced HIV vRNA (US vRNA) that serves as new HIV virion genome; singly spliced HIV vRNA (SS vRNA), used to produce structural and accessory viral proteins and multiply spliced HIV vRNA (MS vRNA), essential to produce Tat and Rev proteins. Then, the two vRNA will be capped and polyadenylated by the cell machinery. The last step is the HIV vRNA nuclear export; on the one hand, MS vRNA will be exported via the NFX1/NXT1 pathway through the nuclear pores (NPC). As MS vRNA is transported to the cytoplasm it will start the translation step in order to produce Rev and Tat. Lastly, Tat can return to the nucleus to enhance viral transcription, while Rev will also return to the nucleus via Importin B and bind to the RRE to export US vRNA to the cytoplasm via the canonical CRM1-mediated pathway.
Figure 1. HIV post-transcriptional steps. HIV transcription initiation depends on the balance of certain host transcription factors (activators or repressors). Once initiated, Tat and P-TEFb are responsible for recruiting and activating RNA polymerase II (RNAPII), which will start HIV elongation. During HIV elongation, the spliceosome will be recruited around the RNA generated and start the splicing process, generating three major products: unspliced HIV vRNA (US vRNA) that serves as new HIV virion genome; singly spliced HIV vRNA (SS vRNA), used to produce structural and accessory viral proteins and multiply spliced HIV vRNA (MS vRNA), essential to produce Tat and Rev proteins. Then, the two vRNA will be capped and polyadenylated by the cell machinery. The last step is the HIV vRNA nuclear export; on the one hand, MS vRNA will be exported via the NFX1/NXT1 pathway through the nuclear pores (NPC). As MS vRNA is transported to the cytoplasm it will start the translation step in order to produce Rev and Tat. Lastly, Tat can return to the nucleus to enhance viral transcription, while Rev will also return to the nucleus via Importin B and bind to the RRE to export US vRNA to the cytoplasm via the canonical CRM1-mediated pathway.
Microorganisms 12 00752 g001

3. Pharmacological Disruption of HIV Transcription and Nuclear Export

On the one hand, many latency-reversing agents (LRAs) have been investigated for their efficacy in inducing virus production from latently infected CD4+ T cells in vitro and in vivo [56,57,58,59,60]. Among the LRAs tested, histone deacetylase inhibitors (HDACi) induce chromatin decondensation, BET bromodomain inhibitors (BETi) release of the positive transcription elongation factor b (P-TEFb), and small-molecule antagonists of cIAP1 (SMAC mimetics) activate the non-canonical NF-κB signaling pathway, which leads in all three cases to subsequent relief of transcriptional repression in the 5′LTR and activation of HIV expression [61,62,63,64,65,66,67]. However, while LRAs such as HDACi have been shown to cause modest in vivo increases in cell-associated HIV transcripts (including initiated, 5′elongated, unspliced, and/or polyadenylated HIV transcripts) and transient increases in plasma viremia [60], they failed to increase multiply spliced HIV RNA (msRNA) in vitro or in vivo, which is a marker of productive infection [68,69,70]. Importantly, these LRAs also failed to induce a sustained reduction in the frequency of latently infected cells in vivo. These results may be explained because HIV expression is also further restricted by inefficient splicing [71] and possibly defects in the nuclear export of HIV RNA [72]. One interesting target for LRAs is Tat, essential for HIV vRNA elongation. Recent work showed a potent viral reactivation with the use of nanoparticles containing a truncated variant of the Tat protein, known as T66 [73,74]. Nanoparticles containing Tat RNA used in previous works showed that using Tat protein was not that effective, as Tat is known to become trapped in endosomes [75]. Another potential family of compounds that may act as LRAs are small molecule mimetics of the ubiquitin ligase BIRC2 (cIAP1) [76], a repressor of the noncanonical NF-kB pathway, which increased HIV-1 expression without mediating systemic T cell activation. For example, ciapavir induced activation of HIV-1 reservoirs in vivo in a humanized mouse model [67], and AZD5582 increased HIV- and SIV-RNA expression in the blood and tissues of ART-suppressed humanized mice and rhesus macaques [66].
On the other hand, novel compounds, known as latency-promoting agents (LPAs), have recently been developed to permanently shut off the transcription of HIV [7,77,78]. LPAs include different compounds that, by targeting different viral or cellular proteins, impair HIV-1 reactivation. Didehydro-Cortistatin A (dCA) [8,11,79], a Tat inhibitor, suppresses SIV replication and reactivation [80] and prevents HIV-1 reactivation from latency [81]. Unfortunately, Tat inhibitors are not clinically available, and a new generation of chemical derivatives, which bind and inhibit an active and specific Tat conformer, is needed [11]. Tyrosine kinase inhibitors [82], such as dasatinib, which, by preserving SAMHD1 activity, protected humanized mice from acute HIV-1 infection [83] and disturbed the HIV-1 reservoir reactivation and reseeding in ART-suppressed individuals [82]. Manidipine hydrochloride, a suppressor of gene expression noise, substantially reduced latent HIV-1 reactivation in vitro [12]; therefore, modulators of gene expression noise could be used in strategies to limit spontaneous reactivation of latent HIV-1. This is also the case of inhibitors of thioredoxin reductase, a protein involved in maintaining redox balance in host cells, which were discovered by screening for gene expression noise, and they promote HIV-1 latency in vitro [7]. Senexin A is an inhibitor of the cyclin-dependent protein kinases CDK8/CDK19, which are required for expression from 5′HIV-1 LTR, and suppresses proviral reactivation in vitro [84].
An interesting HIV transcription stage to be tackled by LPAs could be the polyadenylation step, although its principal regulation by the cellular machinery suggests that its approach could be cytotoxic. Nonetheless, a few studies have proposed interventions to disrupt vRNA polyadenylation. Particularly, a study showed that a mutation in the splice donor site promoted the activation of a cryptic polyadenylation site (CpA), causing decreased HIV transcriptional activity [85].
Additional targeting processes for both HIV latency reactivation and silencing is the splicing step. In this regard, few compounds have been investigated as potential LRAs or LPAs. A study showed that digoxin, a drug widely used in congestive heart failure treatment [86], suppresses HIV-1 replication by altering viral RNA processing [87], while another study suggested that Filgotinib, a Janus kinase (JAK) inhibitor, suppresses HIV-1 transcription by inhibiting T cell activation and by modulating RNA splicing [88]. In-depth investigation and high-throughput screening of potential compounds impacting RNA splicing should be performed to find novel efficient LRAs or LPAs that may modulate this HIV transcription stage.
The nuclear export step constitutes the last step of the transcription that can be perturbed. Because the adequate balance between US and SS vRNA depends on the Rev–RRE interaction, many LPAs tackle this specific step through mechanisms that involve inhibiting Rev from returning to the nucleus [89,90] or disrupting the Rev–RRE interaction [91,92,93,94]. The advantage of intervening in the Rev–RRE interaction is its viral specificity, which, in principle, would limit toxicity. Therefore, the Rev–RRE interaction or the Rev–CRM1 interaction has been widely studied, and several LPAs have been described, such as Leptomycin B [91], which targets the Rev–CRM1-mediated export, or Benfluoron and its analogs, which target the Rev–RRE interaction through binding to RRE [92,95]. Furthermore, it has been shown that Ivermectin can disrupt the nuclear import of Rev by inhibiting Importin-mediated nuclear import and thereby preventing the export of SS and US vRNA by Rev [89]. Despite the fact that the above-mentioned compounds have demonstrated effective antiviral effects in vitro, their intrinsic toxicity has hindered their use in clinical trials [92,95]. Finally, obefazimod (formerly context, the small molecule ABX464) showed important inhibition of HIV replication by binding to the Cap binding complex (CBC) and preventing Rev–RRE mediated transport of US vRNA to the cytoplasm, also altering its splicing and reducing HIV initiation and elongation [96,97,98]. Still, looking for novel compounds targeting the Rev-mediated nuclear transport is an active area of research. A summary of the LRAs and LPAs evaluated in vitro, in vivo, and in clinical trials is shown in Table 1 and Table 2, and in Figure 2.

4. Genetic and Epigenetic Modulation to Impact HIV Transcription

On the one hand, the development of gene editing tools, including zinc finger nucleases (ZFNs) [111], transcription activator-like effector nucleases (TALENs) [112], and the CRIPSR-Cas9 system [113], has created novel strategies to tackle viral latency in the field of HIV persistence. These advancements may include (a) directly targeting the virus in its integrated or non-integrated forms, (b) modulating its transcription as a “block and lock” [114] or “shock and kill” [115] strategies by using catalytically inactive Cas9 [116,117], (c) targeting host genes involved in the viral replication cycle (such CCR5) [118], and (d) discovering novel host molecular genes involved in the viral replication cycle using CRISPR as a screening tool [119].One of the novelties brought by the CRISPR-Cas9 system is the simpleness of the model, as CRISPR-Cas9 technology uses RNA as a guide to target directly objective genes, making it easier to design than ZFNs and TALENs. CRISPR-Cas9 is being widely used in the HIV field in applications ranging from the modulation of HIV transcription [114] to the discovery of host genes involved in the viral replication cycle [119]. Currently, there are two ongoing clinical trials using CRIPSR-Cas9 in HIV. However, only one (NCT05144386) has a recorded status. In this trial, the aim is to evaluate EBT-101, which is designed to excise HIV proviral DNA using CRISPR-Cas9 and two guide RNAs (gRNAs) targeting LTRs and Gag regions and is delivered to cells as a one-time treatment via an adeno-associated virus (AAV), administrated intravenously to aviremic adults on stable antiretroviral treatment. EBT-001 (a homolog of EBT-101 to target SIV) has already been successfully used to eliminate integrated SIV DNA in non-human primates [120]. EBT-001, similar to EBT-101, consists of an adeno-associated virus serotype 9 (AAV9) encapsulated in an all-in-one CRISPR construct that simultaneously expresses the SaCa9 endonuclease and dual gRNAs that targets LTRs and the Gag regions. Therefore, both EBT-101/001 can generate three different deletions in the HIV/SIV integrated genome: 5′LTR to Gag, Gag to 3′LTR, and 5′LTR to 3′LTR. Furthermore, in a recent study, EBT-001 showed no off-target effects or abnormal pathology in non-human primates (macaques) [120]. These positive results prompted a clinical trial, which is currently ongoing (NCT05144386). Several studies have evaluated the applicability of catalytically inactive Cas9 to reactivate or silence HIV and SIV transcription [114,121,122,123,124,125,126,127,128], but all these studies are still in the pre-clinical stage.
On the other hand, the discovery of new compounds that are integrase inhibitors and contribute to HIV integration site selection has opened novel potential mechanisms to regulate HIV transcription. In this regard, LEDGINs are small-molecule integrase inhibitors that target the binding pocket of LEDGF/p75, a cellular cofactor that substantially contributes to HIV integration site selection. These compounds are potent antivirals that inhibit HIV integration and maturation, but, in addition, they lead pre-integrated HIV DNA away from transcriptionally active regions and towards a more repressive chromatin environment of the cellular genome. This modulation of the HIV integration site demonstrated the establishment of more latent and more refractory reactivation proviruses in vitro [129], supporting the use of these compounds as potential indirect LPAs.
Furthermore, microRNAs (miRNAs) are small non-coding RNAs that bind mRNAs based on sequence complementarity to regulate protein expression as a mechanism of post-transcriptional epigenetic regulation [130,131,132]. It has been extensively demonstrated that cellular RNA interference machinery, such as miRNAs, play key roles in controlling viral infections [133,134]. Several cellular miRNAs have been shown to play a direct or indirect role in modulating HIV-1 replication (reviewed in [135,136]). Specifically, focusing on HIV transcriptional and post-transcriptional regulation, there is not much research published yet. A study showed that miR-29, which directly targets the 3′UTR of viral mRNAs, can bind HIV-1 mRNA and increase its interaction with proteins involved in post-transcriptional processes, such as mRNA degradation, inhibiting translation of viral proteins and viral replication [137]. Other studies found that miR-27b, miR-29b, miR-150, miR-198, and miR-223 inhibit the expression of Cyclin T1, an important component of the eukaryotic RNA polymerase II elongation complex, and reduce its protein levels in different cell types, which decreases HIV-1 transcription [138,139]. Another study observed that the miRNA cluster miR-17/92 targets p300-CREB binding protein associated factor (PCAF), which is important for Tat acetylation and HIV-1 LTR-driven transcriptional up-regulation, thus decreasing the efficiency of HIV-1 transcription [140]. Hence, the use of specific miRNA mimics or inhibitors might be an attractive novel strategy to impact HIV-1 transcriptional and post-transcriptional regulation and impact latency.
A schematic representation of pharmacological, genetic, and epigenetic modulation of HIV transcription is shown in Figure 2.
Microorganisms 12 00752 g002
Figure 2. Graphical representation of host factors, compounds, and tools that regulate HIV transcription and their main targets.
Figure 2. Graphical representation of host factors, compounds, and tools that regulate HIV transcription and their main targets.
Microorganisms 12 00752 g002

5. What Can We Learn from HIV-2?

The two main subtypes of HIV, HIV-1 and HIV-2, are differentiated by their replicative and pathogenic capacity, virus evolution, and target of infection. HIV-1 is the most prevalent type of HIV spread worldwide, whereas HIV-2 is mostly found in West Africa. This different distribution might be explained by a lower capacity for transmission [141]. Furthermore, although both variants share similarities in transmission routes and can cause acquired immunodeficiency syndrome with comparable clinical manifestations, HIV-2 infection is generally milder and less likely to progress to AIDS. Thus, as HIV-2 is naturally less pathogenic, it might be used as a model to provide insight into alternative HIV cure strategies.
Most HIV studies are focused on the HIV-1 variant; however, HIV-2 should not be neglected as an estimated 2 million people worldwide are living with this infection, and there might be differences in the mechanisms that regulate HIV-2 persistence and latency. Recently, Koofhethile et al. observed that the HIV-2 proviral landscape is dominated by defective proviruses, similar to what happens in HIV-1 infection [142]. Nonetheless, although HIV-2 LTR is similar to HIV-1 LTR, it contains a duplicated TAR RNA stem-loop structure [143] and is less responsive to CD4+ T cell activation signals [144]. These differences in transcriptional control of HIV-2 might be due to differential regulation affecting basal transcription levels and the response to environmental transcription regulators. In that context, as previously mentioned in Section 2, TASOR is a repressive transcriptional factor of HIV-1, but interestingly, Vpx from HIV-2 induces its degradation [55], suggesting that this might be a differential mechanism of HIV-1 and HIV-2 transcription regulation. Furthermore, Pedro et al. [48] identified several transcription factors that preferentially bound HIV-2 LTRs. Interestingly, they identified PLAGL1, which was not previously described as a regulator of HIV transcription, as an HIV-2-specific transcriptional activator [48]. This transcription factor is widely expressed in immune cells, recognizes GC-rich DNA regions, has both transactivating and repressing activities [145,146,147], is involved in cell cycle regulation and oncogenesis [147,148], and interacts with other transcriptional activators of HIV, such as SP1, AP-1, and PCAF/CBP/P300 [148]. This study suggested that HIV-2 LTR is differentially regulated compared to HIV-1 and that there is a need for a more detailed transcriptional analysis of the mechanisms that control HIV-2 proviral expression [48]. In this regard, Lu et al. [149] developed a panel of novel PCR assays to investigate the mechanisms of latent infection with HIV-2, showing that HIV-2 transcription is regulated by blocks to elongation and completion in peripheral CD4+ T cells [150]. Hence, further characterization of the mechanisms regulating HIV-2 transcription in vivo is essential to find a worldwide applicable HIV cure strategy.

6. Conclusions

There is a lack of knowledge on how RNA metabolism can be used as a strategy to cure HIV. In this review, we summarize the cellular and viral factors that regulate HIV-1 transcription, the potential pharmacological targets and genetic and epigenetic editing techniques that have been or might be evaluated to disrupt HIV-1 latency, the role of miRNA in post-transcriptional regulation of HIV-1, and the differences between the mechanisms regulating HIV-1 and HIV-2 expression. The in-depth investigation of these pathways, drugs, and techniques is essential to increase our current knowledge of HIV latency and persistence and will potentially lead to novel therapeutic targets advancing to a global HIV cure strategy.

Author Contributions

J.I.-P. and S.M.-L. conceived, drafted, and designed the review. M.C.P. and J.M.-P. critically reviewed the manuscript and contributed important intellectual content. All authors have read and agreed to the published version of the manuscript.

Funding

J.I.-P. is supported by a PhD Joan Oró fellowship (2023 FI-1 00207) from the Catalan Agency for Management of University and Research Grants. S.M.-L. is supported by the EU Gilead Research Scholars Program in HIV award 2021 and the 2020 BP 00046 grant from the Catalan Agency for Management of University and Research Grants. Research in the J.M.-P. laboratory is supported by the Spanish Ministry of Science and Innovation (grants PID2022-139271OB-I00 and CB21/13/00063, Spain), NIH/NIAID (1 UM1 AI164561-01 and 1P01AI178376-01, United States of America), EU HORIZON-HLTH-2021-DISEASE-04-07 (grants 101057100 and 101095606, European Union), Fundació La Marató de TV3 (grant 202130-30-31-32, Spain), and Generalitat de Valencia (grant PROMETEO/2021/036, Spain).

Acknowledgments

Figures were created with BioRender.com.

Conflicts of Interest

J.M.-P. has received institutional grants and educational/consultancy fees from AbiVax, AstraZeneca, Gilead Sciences, Grifols, Janssen, Merck Sharp & Dohme, and ViiV Healthcare, all outside the submitted work. M.C.P. and S.M.-L. have received institutional grants from Gilead Sciences outside the submitted work. The remaining authors declare no conflicts of interest.

References

  1. World Health Organization (WHO). HIV Statistics, Globally and by WHO Region, 2023; World Health Organization: Geneva, Switzerland, 2023. [Google Scholar]
  2. Joint United Nations Programme on HIV/AIDS. The Path that Ends AIDS: UNAIDS Global AIDS Update 2023; United Nations: New York, NY, USA, 2023. [Google Scholar]
  3. Crespo, R.; Rao, S.; Mahmoudi, T. HibeRNAtion: HIV-1 RNA Metabolism and Viral Latency. Front. Cell. Infect. Microbiol. 2022, 12, 855092. [Google Scholar] [CrossRef] [PubMed]
  4. Deeks, S.G. Shock and kill. Nature 2012, 487, 439–440. [Google Scholar] [CrossRef] [PubMed]
  5. Archin, N.M.; Liberty, A.L.; Kashuba, A.D.; Choudhary, S.K.; Kuruc, J.D.; Crooks, A.M.; Parker, D.C.; Anderson, E.M.; Kearney, M.F.; Strain, M.C.; et al. Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature 2012, 487, 482–485. [Google Scholar] [CrossRef]
  6. Kim, Y.; Anderson, J.L.; Lewin, S.R. Getting the “Kill” into “Shock and Kill”: Strategies to Eliminate Latent HIV. Cell Host Microbe 2018, 23, 14–26. [Google Scholar] [CrossRef]
  7. Lu, Y.; Bohn-Wippert, K.; Pazerunas, P.J.; Moy, J.M.; Singh, H.; Dar, R.D. Screening for gene expression fluctuations reveals latency-promoting agents of HIV. Proc. Natl. Acad. Sci. USA 2021, 118, e2012191118. [Google Scholar] [CrossRef]
  8. Kessing, C.F.; Nixon, C.C.; Li, C.; Tsai, P.; Takata, H.; Mousseau, G.; Ho, P.T.; Honeycutt, J.B.; Fallahi, M.; Trautmann, L.; et al. In Vivo Suppression of HIV Rebound by Didehydro-Cortistatin A, a “Block-and-Lock” Strategy for HIV-1 Treatment. Cell Rep. 2017, 21, 600–611. [Google Scholar] [CrossRef] [PubMed]
  9. Tyagi, M.; Karn, J. CBF-1 promotes transcriptional silencing during the establishment of HIV-1 latency. EMBO J. 2007, 26, 4985–4995. [Google Scholar] [CrossRef]
  10. Vargas, B.; Giacobbi, N.S.; Sanyal, A.; Venkatachari, N.J.; Han, F.; Gupta, P.; Sluis-Cremer, N. Inhibitors of Signaling Pathways That Block Reversal of HIV-1 Latency. Antimicrob. Agents Chemother. 2019, 63, e01744-18. [Google Scholar] [CrossRef] [PubMed]
  11. Mediouni, S.; Chinthalapudi, K.; Ekka, M.K.; Usui, I.; Jablonski, J.A.; Clementz, M.A.; Mousseau, G.; Nowak, J.; Macherla, V.R.; Beverage, J.N.; et al. Didehydro-Cortistatin A Inhibits HIV-1 by Specifically Binding to the Unstructured Basic Region of Tat. MBio 2019, 10, e02662-18. [Google Scholar] [CrossRef]
  12. Dar, R.D.; Hosmane, N.N.; Arkin, M.R.; Siliciano, R.F.; Weinberger, L.S. Screening for noise in gene expression identifies drug synergies. Science 2014, 344, 1392–1396. [Google Scholar] [CrossRef]
  13. Balachandran, A.; Wong, R.; Stoilov, P.; Pan, S.; Blencowe, B.; Cheung, P.; Harrigan, P.R.; Cochrane, A. Identification of small molecule modulators of HIV-1 Tat and Rev protein accumulation. Retrovirology 2017, 14, 7. [Google Scholar] [CrossRef] [PubMed]
  14. Delannoy, A.; Poirier, M.; Bell, B. Cat and Mouse: HIV Transcription in Latency, Immune Evasion and Cure/Remission Strategies. Viruses 2019, 11, 269. [Google Scholar] [CrossRef]
  15. Jean, M.J.; Fiches, G.; Hayashi, T.; Zhu, J. Current Strategies for Elimination of HIV-1 Latent Reservoirs Using Chemical Compounds Targeting Host and Viral Factors. AIDS Res. Hum. Retroviruses 2019, 35, 1–24. [Google Scholar] [CrossRef] [PubMed]
  16. el Kharroubi, A.; Verdin, E. Protein-DNA interactions within DNase I-hypersensitive sites located downstream of the HIV-1 promoter. J. Biol. Chem. 1994, 269, 19916–19924. [Google Scholar] [CrossRef]
  17. Van Lint, C.; Amella, C.A.; Emiliani, S.; John, M.; Jie, T.; Verdin, E. Transcription factor binding sites downstream of the human immunodeficiency virus type 1 transcription start site are important for virus infectivity. J. Virol. 1997, 71, 6113–6127. [Google Scholar] [CrossRef]
  18. Liu, Y.Z.; Latchman, D.S. The octamer-binding proteins Oct-1 and Oct-2 repress the HIV long terminal repeat promoter and its transactivation by Tat. Biochem. J. 1997, 322 Pt 1, 155–158. [Google Scholar] [CrossRef]
  19. Ruocco, M.R.; Chen, X.; Ambrosino, C.; Dragonetti, E.; Liu, W.; Mallardo, M.; De Falco, G.; Palmieri, C.; Franzoso, G.; Quinto, I.; et al. Regulation of HIV-1 Long Terminal Repeats by Interaction of C/EBP(NF-IL6) and NF-κB/Rel Transcription Factors. J. Biol. Chem. 1996, 271, 22479–22486. [Google Scholar] [CrossRef] [PubMed]
  20. Montano, M.A.; Kripke, K.; Norina, C.D.; Achacoso, P.; Herzenberg, L.A.; Roy, A.L.; Nolan, G.P. NF-kappa B homodimer binding within the HIV-1 initiator region and interactions with TFII-I. Proc. Natl. Acad. Sci. USA 1996, 93, 12376–12381. [Google Scholar] [CrossRef]
  21. Dutilleul, A.; Rodari, A.; Van Lint, C. Depicting HIV-1 Transcriptional Mechanisms: A Summary of What We Know. Viruses 2020, 12, 1385. [Google Scholar] [CrossRef]
  22. Parada, C.A.; Roeder, R.G. Enhanced processivity of RNA polymerase II triggered by Tat-induced phosphorylation of its carboxy-terminal domain. Nature 1996, 384, 375–378. [Google Scholar] [CrossRef]
  23. Molle, D.; Maiuri, P.; Boireau, S.; Bertrand, E.; Knezevich, A.; Marcello, A.; Basyuk, E. A real-time view of the TAR:Tat:P-TEFb complex at HIV-1 transcription sites. Retrovirology 2007, 4, 36. [Google Scholar] [CrossRef] [PubMed]
  24. Wilusz, J. Putting an “End” to HIV mRNAs: Capping and polyadenylation as potential therapeutic targets. AIDS Res. Ther. 2013, 10, 31. [Google Scholar] [CrossRef]
  25. Shi, Y.; Di Giammartino, D.C.; Taylor, D.; Sarkeshik, A.; Rice, W.J.; Yates, J.R., 3rd; Frank, J.; Manley, J.L. Molecular architecture of the human pre-mRNA 3′ processing complex. Mol. Cell 2009, 33, 365–376. [Google Scholar] [CrossRef] [PubMed]
  26. Berkhout, B. HIV-1 as RNA evolution machine. RNA Biol. 2011, 8, 225–229. [Google Scholar] [CrossRef]
  27. Telwatte, S.; Morón-López, S.; Aran, D.; Kim, P.; Hsieh, C.; Joshi, S.; Montano, M.; Greene, W.C.; Butte, A.J.; Wong, J.K.; et al. Heterogeneity in HIV and cellular transcription profiles in cell line models of latent and productive infection: Implications for HIV latency. Retrovirology 2019, 16, 32. [Google Scholar] [CrossRef]
  28. Stoltzfus, C.M. Chapter 1. Regulation of HIV-1 alternative RNA splicing and its role in virus replication. Adv. Virus Res. 2009, 74, 1–40. [Google Scholar] [CrossRef]
  29. Crespo, R.; Ne, E.; Reinders, J.; Meier, J.I.J.; Li, C.; Jansen, S.; Górska, A.; Koçer, S.; Kan, T.W.; Doff, W.; et al. PCID2 dysregulates transcription and viral RNA processing to promote HIV-1 latency. iScience 2024, 27, 109152. [Google Scholar] [CrossRef]
  30. Moron-Lopez, S.; Telwatte, S.; Sarabia, I.; Battivelli, E.; Montano, M.; Macedo, A.B.; Aran, D.; Butte, A.J.; Jones, R.B.; Bosque, A.; et al. Human splice factors contribute to latent HIV infection in primary cell models and blood CD4+ T cells from ART-treated individuals. PLoS Pathog. 2020, 16, e1009060. [Google Scholar] [CrossRef] [PubMed]
  31. Levine, A.; Durbin, R. A computational scan for U12-dependent introns in the human genome sequence. Nucleic Acids Res. 2001, 29, 4006–4013. [Google Scholar] [CrossRef]
  32. Will, C.L.; Lührmann, R. Splicing of a rare class of introns by the U12-dependent spliceosome. Biol. Chem. 2005, 386, 713–724. [Google Scholar] [CrossRef]
  33. Patel, A.A.; Steitz, J.A. Splicing double: Insights from the second spliceosome. Nat. Rev. Mol. Cell Biol. 2003, 4, 960–970. [Google Scholar] [CrossRef] [PubMed]
  34. Cullen, B.R. Nuclear mRNA export: Insights from virology. Trends Biochem. Sci. 2003, 28, 419–424. [Google Scholar] [CrossRef] [PubMed]
  35. Köhler, A.; Hurt, E. Exporting RNA from the nucleus to the cytoplasm. Nat. Rev. Mol. Cell Biol. 2007, 8, 761–773. [Google Scholar] [CrossRef] [PubMed]
  36. Henderson, B.R.; Percipalle, P. Interactions between HIV Rev and nuclear import and export factors: The Rev nuclear localisation signal mediates specific binding to human importin-beta. J. Mol. Biol. 1997, 274, 693–707. [Google Scholar] [CrossRef] [PubMed]
  37. Schwartz, S.; Campbell, M.; Nasioulas, G.; Harrison, J.; Felber, B.K.; Pavlakis, G.N. Mutational inactivation of an inhibitory sequence in human immunodeficiency virus type 1 results in Rev-independent gag expression. J. Virol. 1992, 66, 7176–7182. [Google Scholar] [CrossRef]
  38. Schwartz, S.; Felber, B.K.; Pavlakis, G.N. Distinct RNA sequences in the gag region of human immunodeficiency virus type 1 decrease RNA stability and inhibit expression in the absence of Rev protein. J. Virol. 1992, 66, 150–159. [Google Scholar] [CrossRef] [PubMed]
  39. Schiralli Lester, G.M.; Henderson, A.J. Mechanisms of HIV Transcriptional Regulation and Their Contribution to Latency. Mol. Biol. Int. 2012, 2012, 614120. [Google Scholar] [CrossRef]
  40. Tissot, C.; Mechti, N. Molecular cloning of a new interferon-induced factor that represses human immunodeficiency virus type 1 long terminal repeat expression. J. Biol. Chem. 1995, 270, 14891–14898. [Google Scholar] [CrossRef]
  41. Pagani, I.; Poli, G.; Vicenzi, E. TRIM22. A Multitasking Antiviral Factor. Cells 2021, 10, 1864. [Google Scholar] [CrossRef]
  42. Kajaste-Rudnitski, A.; Marelli, S.S.; Pultrone, C.; Pertel, T.; Uchil, P.D.; Mechti, N.; Mothes, W.; Poli, G.; Luban, J.; Vicenzi, E. TRIM22 inhibits HIV-1 transcription independently of its E3 ubiquitin ligase activity, Tat, and NF-kappaB-responsive long terminal repeat elements. J. Virol. 2011, 85, 5183–5196. [Google Scholar] [CrossRef]
  43. Singh, R.; Gaiha, G.; Werner, L.; McKim, K.; Mlisana, K.; Luban, J.; Walker, B.D.; Karim, S.S.A.; Brass, A.L.; Ndung’u, T. Association of TRIM22 with the type 1 interferon response and viral control during primary HIV-1 infection. J. Virol. 2011, 85, 208–216. [Google Scholar] [CrossRef]
  44. Morón-López, S.; Gómez-Mora, E.; Salgado, M.; Ouchi, D.; Puertas, M.C.; Urrea, V.; Navarro, J.; Jou, A.; Pérez, M.; Tural, C.; et al. Short-term Treatment With Interferon Alfa Diminishes Expression of HIV-1 and Reduces CD4+ T-Cell Activation in Patients Coinfected With HIV and Hepatitis C Virus and Receiving Antiretroviral Therapy. J. Infect. Dis. 2016, 213, 1008–1012. [Google Scholar] [CrossRef]
  45. Sanchez, J.G.; Okreglicka, K.; Chandrasekaran, V.; Welker, J.M.; Sundquist, W.I.; Pornillos, O. The tripartite motif coiled-coil is an elongated antiparallel hairpin dimer. Proc. Natl. Acad. Sci. USA 2014, 111, 2494–2499. [Google Scholar] [CrossRef] [PubMed]
  46. Marban, C.; Suzanne, S.; Dequiedt, F.; de Walque, S.; Redel, L.; Van Lint, C.; Aunis, D.; Rohr, O. Recruitment of chromatin-modifying enzymes by CTIP2 promotes HIV-1 transcriptional silencing. EMBO J. 2007, 26, 412–423. [Google Scholar] [CrossRef] [PubMed]
  47. Cismasiu, V.B.; Paskaleva, E.; Suman Daya, S.; Canki, M.; Duus, K.; Avram, D. BCL11B is a general transcriptional repressor of the HIV-1 long terminal repeat in T lymphocytes through recruitment of the NuRD complex. Virology 2008, 380, 173–181. [Google Scholar] [CrossRef]
  48. Pedro, K.D.; Agosto, L.M.; Sewell, J.A.; Eberenz, K.A.; He, X.; Fuxman Bass, J.I.; Henderson, A.J. A functional screen identifies transcriptional networks that regulate HIV-1 and HIV-2. Proc. Natl. Acad. Sci. USA 2021, 118, e2012835118. [Google Scholar] [CrossRef]
  49. Natarajan, M.; Schiralli Lester, G.M.; Lee, C.; Missra, A.; Wasserman, G.A.; Steffen, M.; Gilmour, D.S.; Henderson, A.J. Negative elongation factor (NELF) coordinates RNA polymerase II pausing, premature termination, and chromatin remodeling to regulate HIV transcription. J. Biol. Chem. 2013, 288, 25995–26003. [Google Scholar] [CrossRef] [PubMed]
  50. Bruce, J.W.; Bracken, M.; Evans, E.; Sherer, N.; Ahlquist, P. ZBTB2 represses HIV-1 transcription and is regulated by HIV-1 Vpr and cellular DNA damage responses. PLoS Pathog. 2021, 17, e1009364. [Google Scholar] [CrossRef]
  51. Buratowski, S. Connections between mRNA 3′ end processing and transcription termination. Curr. Opin. Cell Biol. 2005, 17, 257–261. [Google Scholar] [CrossRef] [PubMed]
  52. Rosonina, E.; Kaneko, S.; Manley, J.L. Terminating the transcript: Breaking up is hard to do. Genes Dev. 2006, 20, 1050–1056. [Google Scholar] [CrossRef]
  53. Zhang, Z.; Klatt, A.; Henderson, A.J.; Gilmour, D.S. Transcription termination factor Pcf11 limits the processivity of Pol II on an HIV provirus to repress gene expression. Genes Dev. 2007, 21, 1609–1614. [Google Scholar] [CrossRef]
  54. Ait Said, M.; Bejjani, F.; Abdouni, A.; Ségéral, E.; Emiliani, S. Premature transcription termination complex proteins PCF11 and WDR82 silence HIV-1 expression in latently infected cells. Proc. Natl. Acad. Sci. USA 2023, 120, e2313356120. [Google Scholar] [CrossRef]
  55. Matkovic, R.; Morel, M.; Lanciano, S.; Larrous, P.; Martin, B.; Bejjani, F.; Vauthier, V.; Hansen, M.M.K.; Emiliani, S.; Cristofari, G.; et al. TASOR epigenetic repressor cooperates with a CNOT1 RNA degradation pathway to repress HIV. Nat. Commun. 2022, 13, 66. [Google Scholar] [CrossRef]
  56. Archin, N.M.; Bateson, R.; Tripathy, M.K.; Crooks, A.M.; Yang, K.-H.; Dahl, N.P.; Kearney, M.F.; Anderson, E.M.; Coffin, J.M.; Strain, M.C.; et al. HIV-1 expression within resting CD4+ T cells after multiple doses of vorinostat. J. Infect. Dis. 2014, 210, 728–735. [Google Scholar] [CrossRef]
  57. Elliott, J.H.; Wightman, F.; Solomon, A.; Ghneim, K.; Ahlers, J.; Cameron, M.J.; Smith, M.Z.; Spelman, T.; McMahon, J.; Velayudham, P.; et al. Activation of HIV transcription with short-course vorinostat in HIV-infected patients on suppressive antiretroviral therapy. PLoS Pathog. 2014, 10, e1004473. [Google Scholar] [CrossRef] [PubMed]
  58. Leth, S.; Schleimann, M.H.; Nissen, S.K.; Højen, J.F.; Olesen, R.; Graversen, M.E.; Jørgensen, S.; Kjær, A.S.; Denton, P.W.; Mørk, A.; et al. Combined effect of Vacc-4x, recombinant human granulocyte macrophage colony-stimulating factor vaccination, and romidepsin on the HIV-1 reservoir (REDUC): A single-arm, phase 1B/2A trial. Lancet HIV 2016, 3, e463–e472. [Google Scholar] [CrossRef]
  59. Rasmussen, T.A.; Tolstrup, M.; Brinkmann, C.R.; Olesen, R.; Erikstrup, C.; Solomon, A.; Winckelmann, A.; Palmer, S.; Dinarello, C.; Buzon, M.; et al. Panobinostat, a histone deacetylase inhibitor, for latent-virus reactivation in HIV-infected patients on suppressive antiretroviral therapy: A phase 1/2, single group, clinical trial. Lancet HIV 2014, 1, e13–e21. [Google Scholar] [CrossRef] [PubMed]
  60. Søgaard, O.S.; Graversen, M.E.; Leth, S.; Olesen, R.; Brinkmann, C.R.; Nissen, S.K.; Kjaer, A.S.; Schleimann, M.H.; Denton, P.W.; Hey-Cunningham, W.J.; et al. The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo. PLoS Pathog. 2015, 11, e1005142. [Google Scholar] [CrossRef] [PubMed]
  61. Bartholomeeusen, K.; Xiang, Y.; Fujinaga, K.; Peterlin, B.M. Bromodomain and extra-terminal (BET) bromodomain inhibition activate transcription via transient release of positive transcription elongation factor b (P-TEFb) from 7SK small nuclear ribonucleoprotein. J. Biol. Chem. 2012, 287, 36609–36616. [Google Scholar] [CrossRef]
  62. Boehm, D.; Calvanese, V.; Dar, R.D.; Xing, S.; Schroeder, S.; Martins, L.; Aull, K.; Li, P.-C.; Planelles, V.; Bradner, J.E.; et al. BET bromodomain-targeting compounds reactivate HIV from latency via a Tat-independent mechanism. Cell Cycle 2013, 12, 452–462. [Google Scholar] [CrossRef]
  63. Contreras, X.; Schweneker, M.; Chen, C.-S.; McCune, J.M.; Deeks, S.G.; Martin, J.; Peterlin, B.M. Suberoylanilide hydroxamic acid reactivates HIV from latently infected cells. J. Biol. Chem. 2009, 284, 6782–6789. [Google Scholar] [CrossRef] [PubMed]
  64. Rasmussen, T.A.; Tolstrup, M.; Winckelmann, A.; Østergaard, L.; Søgaard, O.S. Eliminating the latent HIV reservoir by reactivation strategies: Advancing to clinical trials. Hum. Vaccines Immunother. 2013, 9, 790–799. [Google Scholar] [CrossRef] [PubMed]
  65. Wei, D.G.; Chiang, V.; Fyne, E.; Balakrishnan, M.; Barnes, T.; Graupe, M.; Hesselgesser, J.; Irrinki, A.; Murry, J.P.; Stepan, G.; et al. Histone deacetylase inhibitor romidepsin induces HIV expression in CD4 T cells from patients on suppressive antiretroviral therapy at concentrations achieved by clinical dosing. PLoS Pathog. 2014, 10, e1004071. [Google Scholar] [CrossRef] [PubMed]
  66. Nixon, C.C.; Mavigner, M.; Sampey, G.C.; Brooks, A.D.; Spagnuolo, R.A.; Irlbeck, D.M.; Mattingly, C.; Ho, P.T.; Schoof, N.; Cammon, C.G.; et al. Systemic HIV and SIV latency reversal via non-canonical NF-κB signalling in vivo. Nature 2020, 578, 160–165. [Google Scholar] [CrossRef] [PubMed]
  67. Pache, L.; Marsden, M.D.; Teriete, P.; Portillo, A.J.; Heimann, D.; Kim, J.T.; Soliman, M.S.A.; Dimapasoc, M.; Carmona, C.; Celeridad, M.; et al. Pharmacological Activation of Non-canonical NF-κB Signaling Activates Latent HIV-1 Reservoirs In Vivo. Cell Rep. Med. 2020, 1, 100037. [Google Scholar] [CrossRef] [PubMed]
  68. Blazkova, J.; Chun, T.-W.; Belay, B.W.; Murray, D.; Justement, J.S.; Funk, E.K.; Nelson, A.; Hallahan, C.W.; Moir, S.; Wender, P.A.; et al. Effect of histone deacetylase inhibitors on HIV production in latently infected, resting CD4(+) T cells from infected individuals receiving effective antiretroviral therapy. J. Infect. Dis. 2012, 206, 765–769. [Google Scholar] [CrossRef] [PubMed]
  69. Bullen, C.K.; Laird, G.M.; Durand, C.M.; Siliciano, J.D.; Siliciano, R.F. New ex vivo approaches distinguish effective and ineffective single agents for reversing HIV-1 latency in vivo. Nat. Med. 2014, 20, 425–429. [Google Scholar] [CrossRef] [PubMed]
  70. Moron-Lopez, S.; Kim, P.; Søgaard, O.S.; Tolstrup, M.; Wong, J.K.; Yukl, S.A. Characterization of the HIV-1 transcription profile after romidepsin administration in ART-suppressed individuals. AIDS 2019, 33, 425–431. [Google Scholar] [CrossRef]
  71. Yukl, S.A.; Kaiser, P.; Kim, P.; Telwatte, S.; Joshi, S.K.; Vu, M.; Lampiris, H.; Wong, J.K. HIV latency in isolated patient CD4(+) T cells may be due to blocks in HIV transcriptional elongation, completion, and splicing. Sci. Transl. Med. 2018, 10, eaap9927. [Google Scholar] [CrossRef]
  72. Lassen, K.G.; Ramyar, K.X.; Bailey, J.R.; Zhou, Y.; Siliciano, R.F. Nuclear Retention of Multiply Spliced HIV-1 RNA in Resting CD4+ T Cells. PLoS Pathog. 2006, 2, e68. [Google Scholar] [CrossRef]
  73. Pardons, M.; Cole, B.; Lambrechts, L.; van Snippenberg, W.; Rutsaert, S.; Noppe, Y.; De Langhe, N.; Dhondt, A.; Vega, J.; Eyassu, F.; et al. Potent latency reversal by Tat RNA-containing nanoparticle enables multi-omic analysis of the HIV-1 reservoir. Nat. Commun. 2023, 14, 8397. [Google Scholar] [CrossRef] [PubMed]
  74. Van Gulck, E.; Pardons, M.; Nijs, E.; Verheyen, N.; Dockx, K.; Van Den Eynde, C.; Battivelli, E.; Vega, J.; Florence, E.; Autran, B.; et al. A truncated HIV Tat demonstrates potent and specific latency reversal activity. Antimicrob. Agents Chemother. 2023, 67, e0041723. [Google Scholar] [CrossRef] [PubMed]
  75. Kaplan, I.M.; Wadia, J.S.; Dowdy, S.F. Cationic TAT peptide transduction domain enters cells by macropinocytosis. J. Control. Release 2005, 102, 247–253. [Google Scholar] [CrossRef] [PubMed]
  76. Molyer, B.; Kumar, A.; Angel, J.B. SMAC Mimetics as Therapeutic Agents in HIV Infection. Front. Immunol. 2021, 12, 780400. [Google Scholar] [CrossRef] [PubMed]
  77. Mori, L.; Valente, S.T. Key Players in HIV-1 Transcriptional Regulation: Targets for a Functional Cure. Viruses 2020, 12, 529. [Google Scholar] [CrossRef] [PubMed]
  78. Moranguinho, I.; Valente, S.T. Block-And-Lock: New Horizons for a Cure for HIV-1. Viruses 2020, 12, 1443. [Google Scholar] [CrossRef] [PubMed]
  79. Jin, H.; Li, D.; Lin, M.-H.; Li, L.; Harrich, D. Tat-Based Therapies as an Adjuvant for an HIV-1 Functional Cure. Viruses 2020, 12, 415. [Google Scholar] [CrossRef]
  80. Mediouni, S.; Kessing, C.F.; Jablonski, J.A.; Thenin-Houssier, S.; Clementz, M.; Kovach, M.D.; Mousseau, G.; de Vera, I.M.S.; Li, C.; Kojetin, D.J.; et al. The Tat inhibitor didehydro-cortistatin A suppresses SIV replication and reactivation. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. 2019, 33, 8280–8293. [Google Scholar] [CrossRef] [PubMed]
  81. Mousseau, G.; Kessing, C.F.; Fromentin, R.; Trautmann, L.; Chomont, N.; Valente, S.T. The Tat Inhibitor Didehydro-Cortistatin A Prevents HIV-1 Reactivation from Latency. MBio 2015, 6, e00465. [Google Scholar] [CrossRef]
  82. Vigón, L.; Martínez-Román, P.; Rodríguez-Mora, S.; Torres, M.; Puertas, M.C.; Mateos, E.; Salgado, M.; Navarro, A.; Sánchez-Conde, M.; Ambrosioni, J.; et al. Provirus reactivation is impaired in HIV-1 infected individuals on treatment with dasatinib and antiretroviral therapy. Biochem. Pharmacol. 2021, 192, 114666. [Google Scholar] [CrossRef]
  83. Salgado, M.; Martinez-Picado, J.; Gálvez, C.; Rodríguez-Mora, S.; Rivaya, B.; Urrea, V.; Mateos, E.; Alcamí, J.; Coiras, M. Dasatinib protects humanized mice from acute HIV-1 infection. Biochem. Pharmacol. 2020, 174, 113625. [Google Scholar] [CrossRef] [PubMed]
  84. Horvath, R.M.; Brumme, Z.L.; Sadowski, I. Small molecule inhibitors of transcriptional cyclin-dependent kinases impose HIV-1 latency, presenting “block and lock” treatment strategies. Antimicrob. Agents Chemother. 2024, 68, e0107223. [Google Scholar] [CrossRef] [PubMed]
  85. Andersen, P.K.; Lykke-Andersen, S.; Jensen, T.H. Promoter-proximal polyadenylation sites reduce transcription activity. Genes Dev. 2012, 26, 2169–2179. [Google Scholar] [CrossRef] [PubMed]
  86. Hauptman, P.J.; Kelly, R.A. Digitalis. Circulation 1999, 99, 1265–1270. [Google Scholar] [CrossRef] [PubMed]
  87. Zhang, G.; Luk, B.T.; Hamidy, M.; Zhang, L.; Spector, S.A. Induction of a Na(+)/K(+)-ATPase-dependent form of autophagy triggers preferential cell death of human immunodeficiency virus type-1-infected macrophages. Autophagy 2018, 14, 1359–1375. [Google Scholar] [CrossRef] [PubMed]
  88. Yeh, Y.-H.J.; Jenike, K.M.; Calvi, R.M.; Chiarella, J.; Hoh, R.; Deeks, S.G.; Ho, Y.-C. Filgotinib suppresses HIV-1-driven gene transcription by inhibiting HIV-1 splicing and T cell activation. J. Clin. Investig. 2020, 130, 4969–4984. [Google Scholar] [CrossRef]
  89. Wagstaff, K.M.; Sivakumaran, H.; Heaton, S.M.; Harrich, D.; Jans, D.A. Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus. Biochem. J. 2012, 443, 851–856. [Google Scholar] [CrossRef] [PubMed]
  90. Wong, R.W.; Balachandran, A.; Haaland, M.; Stoilov, P.; Cochrane, A. Characterization of novel inhibitors of HIV-1 replication that function via alteration of viral RNA processing and rev function. Nucleic Acids Res. 2013, 41, 9471–9483. [Google Scholar] [CrossRef]
  91. Wolff, B.; Sanglier, J.J.; Wang, Y. Leptomycin B is an inhibitor of nuclear export: Inhibition of nucleo-cytoplasmic translocation of the human immunodeficiency virus type 1 (HIV-1) Rev protein and Rev-dependent mRNA. Chem. Biol. 1997, 4, 139–147. [Google Scholar] [CrossRef]
  92. Prado, S.; Beltrán, M.; Moreno, Á.; Bedoya, L.M.; Alcamí, J.; Gallego, J. A small-molecule inhibitor of HIV-1 Rev function detected by a diversity screen based on RRE-Rev interference. Biochem. Pharmacol. 2018, 156, 68–77. [Google Scholar] [CrossRef]
  93. Daelemans, D.; Afonina, E.; Nilsson, J.; Werner, G.; Kjems, J.; De Clercq, E.; Pavlakis, G.N.; Vandamme, A.-M. A synthetic HIV-1 Rev inhibitor interfering with the CRM1-mediated nuclear export. Proc. Natl. Acad. Sci. USA 2002, 99, 14440–14445. [Google Scholar] [CrossRef]
  94. Boons, E.; Vanstreels, E.; Jacquemyn, M.; Nogueira, T.C.; Neggers, J.E.; Vercruysse, T.; van den Oord, J.; Tamir, S.; Shacham, S.; Landesman, Y.; et al. Human Exportin-1 is a Target for Combined Therapy of HIV and AIDS Related Lymphoma. EBioMedicine 2015, 2, 1102–1113. [Google Scholar] [CrossRef]
  95. Chumillas, S.; Loharch, S.; Beltrán, M.; Szewczyk, M.P.; Bernal, S.; Puertas, M.C.; Martinez-Picado, J.; Alcamí, J.; Bedoya, L.M.; Marchán, V.; et al. Exploring the HIV-1 Rev Recognition Element (RRE)–Rev Inhibitory Capacity and Antiretroviral Action of Benfluron Analogs. Molecules 2023, 28, 7031. [Google Scholar] [CrossRef] [PubMed]
  96. Campos, N.; Myburgh, R.; Garcel, A.; Vautrin, A.; Lapasset, L.; Nadal, E.S.; Mahuteau-Betzer, F.; Najman, R.; Fornarelli, P.; Tantale, K.; et al. Long lasting control of viral rebound with a new drug ABX464 targeting Rev—Mediated viral RNA biogenesis. Retrovirology 2015, 12, 30. [Google Scholar] [CrossRef] [PubMed]
  97. Vautrin, A.; Manchon, L.; Garcel, A.; Campos, N.; Lapasset, L.; Laaref, A.M.; Bruno, R.; Gislard, M.; Dubois, E.; Scherrer, D.; et al. Both anti-inflammatory and antiviral properties of novel drug candidate ABX464 are mediated by modulation of RNA splicing. Sci. Rep. 2019, 9, 792. [Google Scholar] [CrossRef] [PubMed]
  98. Moron-Lopez, S.; Bernal, S.; Wong, J.K.; Martinez-Picado, J.; Yukl, S.A. ABX464 Decreases the Total Human Immunodeficiency Virus (HIV) Reservoir and HIV Transcription Initiation in CD4+ T Cells From Antiretroviral Therapy–Suppressed Individuals Living With HIV. Clin. Infect. Dis. 2022, 74, 2044–2049. [Google Scholar] [CrossRef] [PubMed]
  99. Yoon, S.; Eom, G.H. HDAC and HDAC Inhibitor: From Cancer to Cardiovascular Diseases. Chonnam Med. J. 2016, 52, 1–11. [Google Scholar] [CrossRef] [PubMed]
  100. Lu, P.; Shen, Y.; Yang, H.; Wang, Y.; Jiang, Z.; Yang, X.; Zhong, Y.; Pan, H.; Xu, J.; Lu, H.; et al. BET inhibitors RVX-208 and PFI-1 reactivate HIV-1 from latency. Sci. Rep. 2017, 7, 16646. [Google Scholar] [CrossRef]
  101. Zhang, X.-X.; Lin, J.; Liang, T.-Z.; Duan, H.; Tan, X.-H.; Xi, B.-M.; Li, L.; Liu, S.-W. The BET bromodomain inhibitor apabetalone induces apoptosis of latent HIV-1 reservoir cells following viral reactivation. Acta Pharmacol. Sin. 2019, 40, 98–110. [Google Scholar] [CrossRef]
  102. Picaud, S.; Wells, C.; Felletar, I.; Brotherton, D.; Martin, S.; Savitsky, P.; Diez-Dacal, B.; Philpott, M.; Bountra, C.; Lingard, H.; et al. RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain. Proc. Natl. Acad. Sci. USA 2013, 110, 19754–19759. [Google Scholar] [CrossRef]
  103. Liang, T.; Zhang, X.; Lai, F.; Lin, J.; Zhou, C.; Xu, X.; Tan, X.; Liu, S.; Li, L. A novel bromodomain inhibitor, CPI-203, serves as an HIV-1 latency-reversing agent by activating positive transcription elongation factor b. Biochem. Pharmacol. 2019, 164, 237–251. [Google Scholar] [CrossRef] [PubMed]
  104. Li, G.; Zhang, Z.; Reszka-Blanco, N.; Li, F.; Chi, L.; Ma, J.; Jeffrey, J.; Cheng, L.; Su, L. Specific Activation In Vivo of HIV-1 by a Bromodomain Inhibitor from Monocytic Cells in Humanized Mice under Antiretroviral Therapy. J. Virol. 2019, 93, e00233-19. [Google Scholar] [CrossRef]
  105. Abner, E.; Stoszko, M.; Zeng, L.; Chen, H.-C.; Izquierdo-Bouldstridge, A.; Konuma, T.; Zorita, E.; Fanunza, E.; Zhang, Q.; Mahmoudi, T.; et al. A New Quinoline BRD4 Inhibitor Targets a Distinct Latent HIV-1 Reservoir for Reactivation from Other “Shock” Drugs. J. Virol. 2018, 92, e02056-17. [Google Scholar] [CrossRef]
  106. Lu, P.; Qu, X.; Shen, Y.; Jiang, Z.; Wang, P.; Zeng, H.; Ji, H.; Deng, J.; Yang, X.; Li, X.; et al. The BET inhibitor OTX015 reactivates latent HIV-1 through P-TEFb. Sci. Rep. 2016, 6, 24100. [Google Scholar] [CrossRef]
  107. Zhao, M.; De Crignis, E.; Rokx, C.; Verbon, A.; van Gelder, T.; Mahmoudi, T.; Katsikis, P.D.; Mueller, Y.M. T cell toxicity of HIV latency reversing agents. Pharmacol. Res. 2019, 139, 524–534. [Google Scholar] [CrossRef] [PubMed]
  108. Huang, H.; Liu, S.; Jean, M.; Simpson, S.; Huang, H.; Merkley, M.; Hayashi, T.; Kong, W.; Rodríguez-Sánchez, I.; Zhang, X.; et al. A Novel Bromodomain Inhibitor Reverses HIV-1 Latency through Specific Binding with BRD4 to Promote Tat and P-TEFb Association. Front. Microbiol. 2017, 8, 1035. [Google Scholar] [CrossRef]
  109. Rodríguez-Mora, S.; Spivak, A.M.; Szaniawski, M.A.; López-Huertas, M.R.; Alcamí, J.; Planelles, V.; Coiras, M. Tyrosine Kinase Inhibition: A New Perspective in the Fight against HIV. Curr. HIV/AIDS Rep. 2019, 16, 414–422. [Google Scholar] [CrossRef] [PubMed]
  110. Reiser, K.; Mathys, L.; Curbo, S.; Pannecouque, C.; Noppen, S.; Liekens, S.; Engman, L.; Lundberg, M.; Balzarini, J.; Karlsson, A. The Cellular Thioredoxin-1/Thioredoxin Reductase-1 Driven Oxidoreduction Represents a Chemotherapeutic Target for HIV-1 Entry Inhibition. PLoS ONE 2016, 11, e0147773. [Google Scholar] [CrossRef]
  111. Didigu, C.A.; Wilen, C.B.; Wang, J.; Duong, J.; Secreto, A.J.; Danet-Desnoyers, G.A.; Riley, J.L.; Gregory, P.D.; June, C.H.; Holmes, M.C.; et al. Simultaneous zinc-finger nuclease editing of the HIV coreceptors ccr5 and cxcr4 protects CD4+ T cells from HIV-1 infection. Blood 2014, 123, 61–69. [Google Scholar] [CrossRef]
  112. Benjamin, R.; Berges, B.K.; Solis-Leal, A.; Igbinedion, O.; Strong, C.L.; Schiller, M.R. TALEN gene editing takes aim on HIV. Hum. Genet. 2016, 135, 1059–1070. [Google Scholar] [CrossRef]
  113. Magro, G.; Calistri, A.; Parolin, C. Targeting and Understanding HIV Latency: The CRISPR System against the Provirus. Pathogens 2021, 10, 1257. [Google Scholar] [CrossRef] [PubMed]
  114. Olson, A.; Basukala, B.; Lee, S.; Gagne, M.; Wong, W.W.; Henderson, A.J. Targeted Chromatinization and Repression of HIV-1 Provirus Transcription with Repurposed CRISPR/Cas9. Viruses 2020, 12, 1154. [Google Scholar] [CrossRef] [PubMed]
  115. Darcis, G.; Das, A.T.; Berkhout, B. Tackling HIV Persistence: Pharmacological versus CRISPR-Based Shock Strategies. Viruses 2018, 10, 157. [Google Scholar] [CrossRef] [PubMed]
  116. Qi, L.S.; Larson, M.H.; Gilbert, L.A.; Doudna, J.A.; Weissman, J.S.; Arkin, A.P.; Lim, W.A. Repurposing CRISPR as an RNA-guided platform for sequence-specific control of gene expression. Cell 2013, 152, 1173–1183. [Google Scholar] [CrossRef] [PubMed]
  117. Larson, M.H.; Gilbert, L.A.; Wang, X.; Lim, W.A.; Weissman, J.S.; Qi, L.S. CRISPR interference (CRISPRi) for sequence-specific control of gene expression. Nat. Protoc. 2013, 8, 2180–2196. [Google Scholar] [CrossRef] [PubMed]
  118. Allen, A.G.; Chung, C.-H.; Atkins, A.; Dampier, W.; Khalili, K.; Nonnemacher, M.R.; Wigdahl, B. Gene Editing of HIV-1 Co-receptors to Prevent and/or Cure Virus Infection. Front. Microbiol. 2018, 9, 2940. [Google Scholar] [CrossRef] [PubMed]
  119. Puschnik, A.S.; Majzoub, K.; Ooi, Y.S.; Carette, J.E. A CRISPR toolbox to study virus-host interactions. Nat. Rev. Microbiol. 2017, 15, 351–364. [Google Scholar] [CrossRef] [PubMed]
  120. Burdo, T.H.; Chen, C.; Kaminski, R.; Sariyer, I.K.; Mancuso, P.; Donadoni, M.; Smith, M.D.; Sariyer, R.; Caocci, M.; Liao, S.; et al. Preclinical safety and biodistribution of CRISPR targeting SIV in non-human primates. Gene Ther. 2023; online ahead of print. [Google Scholar] [CrossRef]
  121. Zhang, Y.; Yin, C.; Zhang, T.; Li, F.; Yang, W.; Kaminski, R.; Fagan, P.R.; Putatunda, R.; Young, W.-B.; Khalili, K.; et al. CRISPR/gRNA-directed synergistic activation mediator (SAM) induces specific, persistent and robust reactivation of the HIV-1 latent reservoirs. Sci. Rep. 2015, 5, 16277. [Google Scholar] [CrossRef]
  122. Saayman, S.M.; Lazar, D.C.; Scott, T.A.; Hart, J.R.; Takahashi, M.; Burnett, J.C.; Planelles, V.; Morris, K.V.; Weinberg, M.S. Potent and Targeted Activation of Latent HIV-1 Using the CRISPR/dCas9 Activator Complex. Mol. Ther. 2016, 24, 488–498. [Google Scholar] [CrossRef]
  123. Ji, H.; Jiang, Z.; Lu, P.; Ma, L.; Li, C.; Pan, H.; Fu, Z.; Qu, X.; Wang, P.; Deng, J.; et al. Specific Reactivation of Latent HIV-1 by dCas9-SunTag-VP64-mediated Guide RNA Targeting the HIV-1 Promoter. Mol. Ther. 2016, 24, 508–521. [Google Scholar] [CrossRef]
  124. Smith, L.M.; Hodara, V.L.; Parodi, L.M.; Callery, J.E.; Giavedoni, L.D. Silencing integrated SIV proviral DNA with TAR-specific CRISPR tools. J. Med. Primatol. 2020, 49, 269–279. [Google Scholar] [CrossRef] [PubMed]
  125. Klinnert, S.; Chemnitzer, A.; Rusert, P.; Metzner, K.J. Systematic HIV-1 promoter targeting with CRISPR/dCas9-VPR reveals optimal region for activation of the latent provirus. J. Gen. Virol. 2022, 103, 1754. [Google Scholar] [CrossRef]
  126. da Costa, L.C.; Bomfim, L.M.; Dittz, U.V.T.; de Velozo, C.A.; da Cunha, R.D.; Tanuri, A. Repression of HIV-1 reactivation mediated by CRISPR/dCas9-KRAB in lymphoid and myeloid cell models. Retrovirology 2022, 19, 12. [Google Scholar] [CrossRef] [PubMed]
  127. Klinnert, S.; Schenkel, C.D.; Freitag, P.C.; Günthard, H.F.; Plückthun, A.; Metzner, K.J. Targeted shock-and-kill HIV-1 gene therapy approach combining CRISPR activation, suicide gene tBid and retargeted adenovirus delivery. Gene Ther. 2024, 31, 74–84. [Google Scholar] [CrossRef] [PubMed]
  128. Fisher, M.A.; Chaudhry, W.; Campbell, L.A. Gesicles packaging dCas9-VPR ribonucleoprotein complexes can combine with vorinostat and promote HIV proviral transcription. Mol. Ther. Methods Clin. Dev. 2024, 32, 101203. [Google Scholar] [CrossRef] [PubMed]
  129. Bruggemans, A.; Vansant, G.; Balakrishnan, M.; Mitchell, M.L.; Cai, R.; Christ, F.; Debyser, Z. GS-9822, a preclinical LEDGIN candidate, displays a block-and-lock phenotype in cell culture. Antimicrob. Agents Chemother. 2023, 65, e02328-20. [Google Scholar] [CrossRef] [PubMed]
  130. Graves, P.; Zeng, Y. Biogenesis of mammalian microRNAs: A global view. Genom. Proteom. Bioinform. 2012, 10, 239–245. [Google Scholar] [CrossRef]
  131. Finnegan, E.F.; Pasquinelli, A.E. MicroRNA biogenesis: Regulating the regulators. Crit. Rev. Biochem. Mol. Biol. 2013, 48, 51–68. [Google Scholar] [CrossRef] [PubMed]
  132. Chekulaeva, M.; Filipowicz, W. Mechanisms of miRNA-mediated post-transcriptional regulation in animal cells. Curr. Opin. Cell Biol. 2009, 21, 452–460. [Google Scholar] [CrossRef]
  133. Skalsky, R.L.; Cullen, B.R. Viruses, microRNAs, and host interactions. Annu. Rev. Microbiol. 2010, 64, 123–141. [Google Scholar] [CrossRef]
  134. Chinniah, R.; Adimulam, T.; Nandlal, L.; Arumugam, T.; Ramsuran, V. The Effect of miRNA Gene Regulation on HIV Disease. Front. Genet. 2022, 13, 862642. [Google Scholar] [CrossRef] [PubMed]
  135. Klase, Z.; Houzet, L.; Jeang, K.-T. MicroRNAs and HIV-1: Complex interactions. J. Biol. Chem. 2012, 287, 40884–40890. [Google Scholar] [CrossRef] [PubMed]
  136. Swaminathan, G.; Navas-Martín, S.; Martín-García, J. MicroRNAs and HIV-1 infection: Antiviral activities and beyond. J. Mol. Biol. 2014, 426, 1178–1197. [Google Scholar] [CrossRef] [PubMed]
  137. Nathans, R.; Chu, C.-Y.; Serquina, A.K.; Lu, C.-C.; Cao, H.; Rana, T.M. Cellular microRNA and P bodies modulate host-HIV-1 interactions. Mol. Cell 2009, 34, 696–709. [Google Scholar] [CrossRef] [PubMed]
  138. Sung, T.-L.; Rice, A.P. miR-198 inhibits HIV-1 gene expression and replication in monocytes and its mechanism of action appears to involve repression of cyclin T1. PLoS Pathog. 2009, 5, e1000263. [Google Scholar] [CrossRef]
  139. Chiang, K.; Sung, T.-L.; Rice, A.P. Regulation of cyclin T1 and HIV-1 Replication by microRNAs in resting CD4+ T lymphocytes. J. Virol. 2012, 86, 3244–3252. [Google Scholar] [CrossRef] [PubMed]
  140. Triboulet, R.; Mari, B.; Lin, Y.-L.; Chable-Bessia, C.; Bennasser, Y.; Lebrigand, K.; Cardinaud, B.; Maurin, T.; Barbry, P.; Baillat, V.; et al. Suppression of microRNA-silencing pathway by HIV-1 during virus replication. Science 2007, 315, 1579–1582. [Google Scholar] [CrossRef] [PubMed]
  141. Reeves, J.D.; Doms, R.W. Human immunodeficiency virus type 2. J. Gen. Virol. 2002, 83, 1253–1265. [Google Scholar] [CrossRef] [PubMed]
  142. Koofhethile, C.K.; Gao, C.; Chang, C.; Lian, X.; Shapiro, R.; Yu, X.G.; Lichterfeld, M.; Kanki, P.J. The HIV-2 proviral landscape is dominated by defective proviruses. AIDS 2024, 38, 309–316. [Google Scholar] [CrossRef] [PubMed]
  143. Saleh, S.; Vranckx, L.; Gijsbers, R.; Christ, F.; Debyser, Z. Insight into HIV-2 latency may disclose strategies for a cure for HIV-1 infection. J. Virus Erad. 2017, 3, 7–14. [Google Scholar] [CrossRef]
  144. Tong-Starksen, S.E.; Welsh, T.M.; Peterlin, B.M. Differences in transcriptional enhancers of HIV-1 and HIV-2. Response to T cell activation signals. J. Immunol. 1990, 145, 4348–4354. [Google Scholar] [CrossRef] [PubMed]
  145. Kas, K.; Voz, M.L.; Hensen, K.; Meyen, E.; Van de Ven, W.J. Transcriptional activation capacity of the novel PLAG family of zinc finger proteins. J. Biol. Chem. 1998, 273, 23026–23032. [Google Scholar] [CrossRef] [PubMed]
  146. Huang, S.M.; Stallcup, M.R. Mouse Zac1, a transcriptional coactivator and repressor for nuclear receptors. Mol. Cell. Biol. 2000, 20, 1855–1867. [Google Scholar] [CrossRef]
  147. Huang, S.M.; Schönthal, A.H.; Stallcup, M.R. Enhancement of p53-dependent gene activation by the transcriptional coactivator Zac1. Oncogene 2001, 20, 2134–2143. [Google Scholar] [CrossRef]
  148. Vega-Benedetti, A.F.; Saucedo, C.; Zavattari, P.; Vanni, R.; Zugaza, J.L.; Parada, L.A. PLAGL1: An important player in diverse pathological processes. J. Appl. Genet. 2017, 58, 71–78. [Google Scholar] [CrossRef] [PubMed]
  149. Lu, M.D.; Telwatte, S.; Kumar, N.; Ferreira, F.; Martin, H.A.; Kadiyala, G.N.; Wedrychowski, A.; Moron-Lopez, S.; Chen, T.-H.; Goecker, E.A.; et al. Novel assays to investigate the mechanisms of latent infection with HIV-2. PLoS ONE 2022, 17, e0267402. [Google Scholar] [CrossRef]
  150. Wedrychowski, A.; Janssens, J.; Kim, S.J.; Kadiyala, G.N.; Telwatte, S.; Gaudreau, S.M.; Cu-Uvin, S.; Tsibris, A.; Yukl, S.A. HIV-2 Transcription in Blood CD4+ T-Cells Is Inhibited by Blocks to Elongation and Completion. In Proceedings of the Conference on Retroviruses and Opportunistic Infections (CROI) 2024, Denver, CO, USA, 3–6 March 2024. Poster 472. [Google Scholar]
Table 1. List of LRAs evaluated in pre-clinical or approved status.
Table 1. List of LRAs evaluated in pre-clinical or approved status.
CompoundFamily of CompoundsTypeTargetClinical StatusReferences
VorinostatHistone deacetylase inhibitors (HDACi)LRAHistone deacetylaseFDA approved[56,57,63,69,99]
RomidepsinHistone deacetylase inhibitors (HDACi)LRAHistone deacetylaseFDA approved[58,60,65,70,99]
PanobinostatHistone deacetylase inhibitors (HDACi)LRAHistone deacetylaseFDA approved[10,59,65,69,99]
BelinostatHistone deacetylase inhibitors (HDACi)LRAHistone deacetylaseFDA approved[99]
Apabetalone
(RVX-208)		Bromodomain inhibitors (BETi)LRABD2/BRD4Pre-clinical[100,101,102]
CPI-203Bromodomain inhibitors (BETi)LRABRD4Pre-clinical[103]
I-BET-151Bromodomain inhibitors (BETi)LRABD1, BD2/BRD4Pre-clinical[62,104]
MMQOBromodomain inhibitors (BETi)LRABRD2-4/BRDTPre-clinical[105]
OTX-015Bromodomain inhibitors (BETi)LRABRD2-4/BRDTPre-clinical[106,107]
PFI-1Bromodomain inhibitors (BETi)LRABRD2/BRD4Pre-clinical[100]
UMB-136Bromodomain inhibitors (BETi)LRABD1/BRD4Pre-clinical[108]
CiapavirSmall molecules mimetic of cIAP1LRAcIAP1Pre-clinical[67]
SBI-0637142; Debio-1143, AZD5582Small molecules mimetic of cIAP1LRAcIAP1Pre-clinical[76]
Nanoparticles containing
Tat mRNA (T66)		Tat agonistsLRATatPre-clinical[73,74]
Table 2. List of LPAs evaluated in pre-clinical or approved status.
Table 2. List of LPAs evaluated in pre-clinical or approved status.
CompoundFamily of CompoundsTypeTargetClinical StatusReferences
didehydro-Cortistatin A (dCA)Tat inhibitorsLPATatPre-clinical[11]
DasatinibTyrosine kinase inhibitors (TKIs)LPASAMHD1Pre-clinical[109]
Manidipine hydrochlorideNoise suppressor of gene expressionLPACalcium channel blockerPre-clinical[12]
TE-2, TE-10, TE-14, TE-20Thioredoxin reductase inhibitorsLPAThioredoxin reductase redox pathwayPre-clinical[110]
Senexin ACyclin-dependent protein kinases inhibitors (CDKi)LPACDK8/CDK19Pre-clinical[84]
FilgotinibJanus kinase (JAK) inhibitor
splicing modulator		LPAJAK
HIV mRNA		FDA-approved[88]
DigoxinSplicing modulatorLPAHIV mRNAFDA-approved[87]
Leptomycin BNuclear export inhibitorLPACRM1Pre-clinical[91,93]
BenfluoronNuclear export inhibitorLPARev-RREPre-clinical[92]
IvermectinNuclear export inhibitorLPAImportin BPre-clinical[89]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Izquierdo-Pujol, J.; Puertas, M.C.; Martinez-Picado, J.; Morón-López, S. Targeting Viral Transcription for HIV Cure Strategies. Microorganisms 2024, 12, 752. https://doi.org/10.3390/microorganisms12040752

AMA Style

Izquierdo-Pujol J, Puertas MC, Martinez-Picado J, Morón-López S. Targeting Viral Transcription for HIV Cure Strategies. Microorganisms. 2024; 12(4):752. https://doi.org/10.3390/microorganisms12040752

Chicago/Turabian Style

Izquierdo-Pujol, Jon, Maria C. Puertas, Javier Martinez-Picado, and Sara Morón-López. 2024. "Targeting Viral Transcription for HIV Cure Strategies" Microorganisms 12, no. 4: 752. https://doi.org/10.3390/microorganisms12040752

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop