An interview with Pr Carine VAN LINT
Director of Research F.R.S.-FNRS, Head of the Service of Molecular Virology at the Université libre de Bruxelles (ULB), Member of the International AIDS Society Scientific Working Group on HIV Cure
What expertise have you developed in the field of epigenetic mechanisms regulating gene expression of retroviruses, and what are your main discoveries in this area?
For more than 30 years I have been studying the transcriptional and epigenetic mechanisms regulating gene expression of the retroviruses HIV-1 (Human Immunodeficiency Virus type 1), HTLV-1 (Human T-lymphotropic Virus type 1) and BLV (Bovine Leukaemia Virus). In the context of HIV-1 and BLV, my laboratory has largely contributed to characterize and determine the role of chromatin structure in the molecular mechanisms regulating these viruses, in particular by studying nucleosome positioning, chromatin remodelling and epigenetic modifications (such as histone acetylation and methylation and DNA methylation).
We have highlighted the key role of certain cellular factors (such as CTIP2/Bcl11b, UHRF1 (R. Verdikt et al., 2022, eBiomedicine), AhR (D. Chatterjee et al., 2023, Cell Reports) and CTCF (M. Bellefroid et al., 2022, Nucleic Acids Research)) in the transcriptional regulation of HIV-1 and BLV, respectively.
What therapeutic avenues are you currently exploring in the field of HIV?
The major problem in eradicating HIV-1 is the persistence of latent “cellular reservoirs” which express little or no virus but which can be reactivated by various cellular stimuli. These reservoirs explain the rebound in viremia observed in most patients after interruption of the combination antiretroviral therapy (cART). This rebound is due to the reservoir cells in which the virus hides from the host immune system and escapes the cART treatment, waiting for a sign of immune weakness before re-emerging.
The virus is in a state of latency in these reservoir cells, where its transcription is repressed by various mechanisms, including epigenetic modifications. On this basis, several international consortia, of which my laboratory is a member, have proposed “shock and kill” strategies aimed at deliberately reactivating the viruses contained in these reservoirs using latency reversing agents (LRAs) (A. Rodari et al., 2021, Annual Review of Virology). The aim of this reactivation is to eliminate the latent HIV reservoirs, while maintaining cART to prevent the spreading of the virus. This kind of strategy would allow the “kill” phase during which latently-infected cells would then die from viral cytopathic effects or host immune clearance.
We obtained fundamental results demonstrating the reactivation of HIV-1 by a sequential combination of two LRAs: a DNA methylation inhibitor and a histone deacetylase inhibitor, thereby targeting two important mechanisms of HIV-1 epigenetic repression. This discovery led to the launch of an international clinical trial which is currently underway in collaboration with Prof. Stéphane De Wit at the CHU Saint-Pierre in Brussels (ULB).
Another important therapeutic strategy being studied by various international researchers and our laboratory is the “block and lock” approach, which consists not in reactivating but in reinforcing the latent state of the viruses to avoid a rebound in viremia after stopping the anti-HIV treatment. These are the strategies being discussed by the International AIDS Society Scientific Working Group on HIV Cure, a group of internationally recognized experts chaired by the 2008 Medicine Nobel Prize Laureate Francoise Barré-Sinoussi, of which I am the only Belgian representative.
What do you see as the main challenges in controlling HIV replication in the long term?
The main challenge is to gain a better understanding of the molecular mechanisms involved in the persistence of the HIV-1 virus, so as to be able to develop effective new strategies aimed either at eliminating latent reservoirs or at reinforcing the latent state of the virus so that it is no longer able to ‘wake up’.
However, the molecular mechanisms involved in HIV-1 latency are multiple and heterogeneous, and it is therefore very complicated to target all the mechanisms involved in the different cellular reservoirs with a single agent. The current aim is therefore to reactivate highly reactivatable viruses and block the expression of viruses that are more difficult to reactivate, in the majority of cellular reservoirs, with the goal of achieving control of HIV infection by the host immune system in the absence of antiretroviral therapy.
