BET Inhibitors in AIDS Therapy: History
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Subjects: Virology | Immunology
Contributor:
Rungroch Sungthong
,
Thanarat Salahong
,
christian schwartz

AIDS first emerged decades ago; however, its cure, i.e., eliminating all virus sources, is still unachievable.

  • HIV-1
  • latently HIV-1-infected cell
  • latency-reversing agent
  • BET protein
  • BRD2
  • BRD4
  • LRA
  • BETi
  • epigenetics
  • immune response

1. Overview

AIDS first emerged decades ago; however, its cure, i.e., eliminating all virus sources, is still unachievable. A critical burden of AIDS therapy is the evasive nature of HIV-1 in face of host immune responses, the so-called “latency.” Recently, a promising approach, the “Shock and Kill” strategy, was proposed to eliminate latently HIV-1-infected cell reservoirs. The “Shock and Kill” concept involves two crucial steps: HIV-1 reactivation from its latency stage using a latency-reversing agent (LRA) followed by host immune responses to destroy HIV-1-infected cells in combination with reinforced antiretroviral therapy to kill the progeny virus. Hence, a key challenge is to search for optimal LRAs. Looking at epigenetics of HIV-1 infection, researchers proved that some bromodomains and extra-terminal motif protein inhibitors (BETis) are able to reactivate HIV-1 from latency. However, to date, only a few BETis have shown HIV-1-reactivating functions, and none of them have yet been approved for clinical trial. In this review, we aim to demonstrate the epigenetic roles of BETis in HIV-1 infection and HIV-1-related immune responses. Possible future applications of BETis and their HIV-1-reactivating properties are summarized and discussed. 

2. Background

Although antiretroviral therapy in AIDS patients reduces viremia, continuous administration of drugs is required, since HIV-1 gene transcription still occurs at a residual level in latently HIV-1-infected cell reservoirs, mainly in resting CD4+ T cells, in patients under combination antiretroviral therapy (cART) [1]. This residual transcription is associated with chronic immune activation and low-level inflammation, which support non-AIDS co-morbidities [2]. However, there is now compelling evidence that the composition of HIV-1 reservoir is heterogeneous [3]. Indeed, HIV-1 is latently established in various cell types such as hematopoietic stem cells, dendritic cells, microglial cells or in cells from the monocyte-macrophage lineage reviewed in [4][5][6]. Moreover, these cells localize in a variety of anatomical sites including tissues such as the blood, the brain, the gut-associated lymphoid tissue, the adipose tissue, the bone marrow, and the genital tract [7], making it difficult to clear all virus reservoirs.
A prerequisite to successfully eliminate reservoirs is to understand the molecular mechanisms implicated in the establishment and maintenance of HIV-1 latency. Understanding these mechanisms could help us to discover new target proteins in the viral cycle, which are not affected by cART [8]. Some of these molecular mechanisms have been identified. An important role for the cellular cofactor CTIP2 (Bcl11b) was shown in the establishment and the maintenance of HIV-1 post-integration latency in microglial cells [9][10][11]. CTIP2 works as a scaffold protein recruiting at least two different complexes in microglial cells. As part of a chromatin remodeling complex, CTIP2 is associated with the lysine demethylase LSD1, the histone deacetylases HDAC1 and HDAC2, and the histone methyltransferase SUV39H1 [9][12][13][14]. Moreover, CTIP2 is also involved in the control of the elongation process of gene transcription by inhibiting P-TEFb functions [15][16].
To date, two strategies are considered to achieve a functional and/or a sterilizing cure: the “Shock and Kill” and the “Block and Lock” strategies (Figure 1). The “Block and Lock” strategy aims to reach long-term control of HIV-1 in the absence of cART by inducing long lasting inhibition of HIV-1 gene expression [17]. Latency-promoting agents (LPAs) are molecules inhibiting HIV-1 expression, thus inducing deep latency (the “Block”) and preventing HIV-1 gene transcription (the “Lock”) [18]. The LPA, didehydro-cortistatin A (dCA), an inhibitor of the transactivator Tat, showed promising effect in preliminary results. However, a recent in vitro study described virus resistance to this factor [19]. Another recent pilot study, which assessed the effects of metformin on mTOR activation, showed reduced residual HIV-1 gene transcription in the gut-reservoir [20], suggesting that it could be a pertinent candidate among LPAs used in the “Block and Lock” strategy [21].
Viruses 13 01026 g001 550
Figure 1. Concepts of “Shock and Kill” and “Block and Lock” strategies in AIDS therapy. Latency-reversing agents induce HIV-1 transcription via epigenetic activations in the “Shock” step. Then, these viral particles will be processed and released, leading to the elimination of the infected cells by immune clearance and to the elimination of the virus by combination antiretroviral therapy in the “Kill” step. Immune clearance involves CD8+ cytotoxic T cells (CLTs) that recognize the MHC I: HIV-1 peptide complex on the surface of HIV-1-infected cells and induce apoptosis by secreting granzyme B and perforin. An optimization of immunotherapy by using therapeutic vaccines to enhance CTL responses, broadly neutralizing antibodies and/or immune modulators are needed since viral reservoirs do not die from viral cytopathic effects or via the cytotoxic CTL responses. In the “Block and Lock” strategy, latency-promoting agents are applied for blocking the HIV-1 transcription in the “Block” step, and epigenetic silencing occurs in the “Lock” step. The figure was created with BioRender.com.
The “Shock and Kill” strategy proceeds by first reactivating the latent virus and subsequently eliminating it by a reinforced cART. Clearance of the reservoirs is achieved either by the cytopathic effect of the treatment on the reactivated virus and/or by inducing the immune system via the actions of cytotoxic T cells (CTLs) [22]. For the time being, the “Shock and Kill” strategy is only conceivable with circulating reservoirs such as the resting T CD4+ cells. Indeed, the “Shock and Kill” strategy cannot be applied when targeting brain reservoirs due to several unique characteristics of the central nervous system discussed in [10].

3. Conclusions

The “Shock and Kill” strategy, which aims to reduce the pool reservoir, is based on the efficient reactivation of latent reservoirs, followed by the elimination of these reservoirs. Today, this strategy has shown its limits since both the “Shock” and the “Kill” steps do not optimally reduce the pool of reservoirs in vivo [23]. HDAC inhibitors used in the “Shock” step are the only LRAs currently tested in clinical trials but have shown multiple adverse effects in patients. The BETis, as transcriptional activators are promising LRAs that are worthwhile to test in AIDS therapy. Moreover, preliminary studies suggest that they have a positive impact on the immune system especially preventing inflammation and the cytokine storm. In vivo assessment and integrative application of BETis with other LRAs and antiretroviral drugs are the next steps required to evaluate their functions as HIV-1 LRAs.

This entry is adapted from the peer-reviewed paper 10.3390/v13061026

References

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