Bad news for HIV

da molecularpost | Mag 30, 2018 | Biologia Molecolare

Compared to a few years ago we no longer hear much about HIV, AIDS or drugs against the virus. The questions we have asked ourselves are: HIV continues to be a problem? Are there any effective treatments against the virus? In short, is it still a problem that should not be underestimated? What we found is very interesting. Let’s start from beginning, what is HIV? [1]. HIV is a virus belonging to lentivirus, a particular genus of retroviriadae family. First isolated from a lymph node of a patient at Pasteur institute in Paris, the virus is associated with AIDS, a disease that affects the immune system and causes a condition of immune deficiency. As all retroviruses, HIV has a single strand RNA genome which means that it needs a particular enzyme, called retrotrascriptase to convert its RNA genome into a molecule of DNA. This DNA molecule can be integrated in genome of human host cell and by transcription generate new copies of the virus in human cells. HIV, indeed, exploits the cellular synthesis structures and the raw materials available to the same cells to produce the structural proteins necessary for the formation of viral progeny and of the various associated regulatory enzymes. Until now the drugs used for the treatment of HIV infections have been based precisely on the molecular targets of the virions such as constitutive proteins or enzymes, inhibiting viral replication; these drugs are called anti-retroviral therapies (ARTs). But there is a related problem: since HIV can integrate in the host genome, it is able to establish a viral latency. Some particular T lymphocytes, T cells CD4, are considered to be true HIV reservoirs, in which the virus is latent. Indeed, HIV infection causes a chronic illness and it is easy to understand the ARTs aren’t enough as a HIV cure. There are several issues correlated to ARTs:

ARTs are not able to eradicate the HIV from reservoir
ARTs may have toxic effects on the organism
Treatment with ARTs continue lifelong

Therefore, ARTs are able to stop just HIV replication. Instead, the aim of the new studies is to destroy hidden reservoirs of HIV, that is fundamental to cure the disease. There are new drugs, called LRAs, tested to wake up the reservoirs. These drugs are used in combination with ARTs in a strategy called “shock and kill” [2], where LRAs (for example Vorinostat) induce the disrupting of latency and ARTs lead to death of HIV-producing cells [2]. LRAs strike some signaling pathways involved in maintenance of latency. The main pathway is the protein kinase C (PKC)-NF-κB pathway.

In the article “HIV latency is reserved by ACSS2-driven histone crotonylation” Jiang et al. [3] have found a particular epigenetic modification on the histone tails which reverses virus latency, without intervening on the signaling pathways illustrated above. This modification is called crotonylation (Figure 1) of the HIV long terminal repeat, a critical site for the establishment of the latent reservoir. A particular enzyme, acyl-CoA synthetase short-chain family member 2 (ACSS2) mainly present in gut tract, can add the crotonyl group to side chain of a lysine, component of the histone tails, inducing reactivation of HIV transcription.

Figure 1. Molecular structure of the crotonate (performed with www.molcalc.org). The oxygen atom linked with a single bond has a negative charge.

In the first part of the study the authors sought to demonstrate that ACSS2 is responsible of the crotonylation of histone tails and this modification effectively leads to reactivation of HIV transcription. These experiments were made in vitro and ex vivo (in primary and resting CD4+ T cells). The results are in agreement with the hypothesis. It is now necessary verify the molecular mechanism of ACSS2-induced disrupting HIV latency. From the data it is clear that ACSS2 involves a global reprogramming of local chromatin at HIV LTR. Despite that LRAs and ACSS2 use two different targets to reactivate latent HIV, the authors proved to determine whether they have a synergistically effect. PEP005 (a LRA activating the PKC/NF-kB pathway) showed the most efficient synergy with ACSS2, also in primary CD4+ T cells. In order to have ACSS2-induced crotonylation really effective, it is important that the reactivation of latent HIV do not impact the level of immune activation. It was demonstrated that ACSS2 does not cause activation or suppression of T cells. Finally, the authors found that ACSS2 expression in vivo was increased by HIV infection during acute stage whereas it was decreased during chronic stage. These results derivate by studies on SIV-infected rhesus macaques. Furthermore, since ACSS2 is involved in lipid and fatty acid metabolism, it was sought if the modulation of this metabolism may regulate HIV replication. Effectively, during SIV infection lipid and fatty acid metabolism result altered but involvement in gut mucosal damage needs to be investigated.

In conclusion there are bad news for HIV but good news for patients infected by the virus because this research opens new possibilities for HIV cure. It is clear that common anti-retroviral therapies are essentials for the removal of the virus and they will still be used. Findings about intervention of chromatin reprogramming on maintenance of HIV latency and in particular the possibility to use jointly inducing crotonylation factors and LRAs allow to eradicate also HIV reservoirs. Future perspectives for therapeutic applications include the use of a method that can increase the activity of ACSS2 in order to increase histone crotonylation and to break the latency of the virus.

References

Flint, V. Racaniello, G. Rall, A.M. Skalka, Principles of virology, volume II: Pathogenesis and Control, 4^th edition, Washington, American Society of Microbiology, 2015.
G. Deeks, HIV: Shock and kill, News and Views, Nature, vol. 487, 26 July 2012, p. 439-440
Jiang, D. Nguyen et al. HIV latency is reversed by ACSS2-driven histone crotonylation. The Journal of clinical investigation.2018;128(3):1190:1198

Mattia Russo

Master Industrial Biotechnology student

[email protected]

Pietro Uscello

Master Industrial Biotechnology student

[email protected]