An Interview with Nicolas Chomont
Nicolas Chomont is Associate Professor at the Department of Microbiology, Infectiology, and Immunology at University of Montreal and a researcher at the Centre de Recherche du CHUM.
His research program is aimed at localizing, quantifying and characterizing the cells in which HIV persists in individuals receiving antiretroviral therapy, with the ultimate goal of eliminating these cells and contribute to the development of a cure for HIV infection.
According to current knowledge, where the HIV-1 reservoir is located?
At the anatomic level, it is now clear that several tissues serve as a reservoir for HIV: Gut, lymph nodes and probably the brain. Other tissues may also harbor persistent HIV and have been largely neglected: the liver and testis for instance. Most of the data available on tissue reservoirs were generated using assays that do not necessarily measure replication competent HIV. In addition to the difficulty in accessing such tissues from virally suppressed individuals, it is technically challenging to outgrow HIV from these tissues. Many investigators agree that tissues are the place we should look at. For the reasons mentioned above, most of the work has been done on cells isolated from peripheral blood. We need to develop better assays to characterize and measure these tissue reservoirs.
Is there a reservoir outside CD4+ T cells and, if yes, in what kind of cells and what is its qualitative role in HIV-1 persistence?
At the cellular level, HIV mainly persists in CD4+ T cells, although other cell types may also harbour HIV, particularly tissue macrophages. The quantitative contribution of these alternative reservoirs may be small compared to CD4+ T cells, but their qualitative contribution is largely unknown. The example of the Boston patients indicate that viral rebound can occur after months of control and suggests that it may not take much infected cells to reignite infection.
The qualitative contribution of the different cellular reservoirs is difficult to evaluate in vivo, but more and more groups are investigating these questions.
The qualitative contribution of the different cellular reservoirs is difficult to evaluate
What are the immunologic mechanisms at play to maintain HIV-1 persistence?
The immune system plays en essential role in HIV persistence. The major cellular reservoirs for HIV are memory CD4+ T cells, a pool of cells that ensure the maintenance of a long-lived cellular immunity. Therefore, the immunological mechanisms that contribute to the maintenance of these cells are also responsible for HIV persistence. Some of these cells (like central memory) have an intrinsic ability to survive for decades, as a result of a pro-survival signaling program that is continuously turned on. Other cells, like effector memory cells, persist through continuous slow division, a mechanism known as homeostatic proliferation. In addition to the persistence of a pool of latently infected T cells, HIV may also replicate at low levels, particularly in tissues. In that case, residual inflammation, which is an unresolved dysregulation of the immune system, will also contribute to HIV persistence.
In there a difference between patients treated early with antiretroviral therapy and those treated at a later stage, and if yes, what are the implications in the search for a cure?
Yes, it is absolutely clear that people who received ART within the first few weeks after infection harbor a smaller reservoir than those who started during the chronic phase. We are currently working with the US Miltary HIV Research Program (Dr. Jintanat Ananworanich) to better understand not only quantitatively but also qualitatively the effects of early ART on HIV persistence. The earlier ART is initiated, the smaller the reservoir will be after 1 or 2 years of therapy. This raises hope that initiation of ART very early after infection could prevent the establishment of a clinically significant pool of latently infected cells, although this will require much more work to be demonstrated.
As the reservoir is smaller in those who started ART during acute infection, it may be easier to eradicate HIV in this population. However, the qualitative nature of this small reservoir should also be considered and we currently do not know if this small reservoir will be targeted by our current eradication strategies.
Trials with HDAc inhibitors in HIV-infected patients have been disappointing. In the light of your research, what should be now the approaches to test in priority to induce a functional HIV-1 remission ?
The HDACi used so far did not eradicate HIV, but perturbed the reservoir in some ways, which in my opinion, is already a success. Of course, these molecules are not potent enough to reactivate HIV in all reservoirs and ensure their clearance. Not mentioning the fact that they have no effect on residual levels of viral replication. Nevertheless, the new HDACi currently tested (Panobinostat and Romidepsin) have shown promising results. The field progressed pretty fast to “shock” the reservoir. The “killing” part is just beginning and recent data from the group of Bob Siliciano suggest that it may be more difficult than we thought. The “shock and kill” approach certainly needs more development, but alternative strategies should be explored in parallel. Resetting the immune system through infusion of protected cells (Sangamo study) is a fascinating approach that has shown promising results. I think we should think more often “outside of the box”. As I mentioned above, HIV persistence is ensured by the immune system. Manipulating these mechanisms without depleting all cells, by targeting specifically the persistence of the cells in which HIV persist would be ideal. We are at the beginning of the identification of cellular markers that could be used to identify these cells and interfere with their survival. For instance, blocking immune checkpoints (like PD-1) is currently investigated by several groups.
What are currently your main fields of research ?
My group is exploring the immunological mechanisms that are responsible for the persistence of persistently infected cells. In addition to PD-1, we have recently identified other cellular markers that can be used to enrich in latently infected cells and that could be manipulated to clear persistently infected cells.
In addition to PD-1, we have recently identified other cellular markers that can be used to enrich in latently infected cells and that could be manipulated to clear persistently infected cells.
We are also investigating the mechanisms of latency in different cellular reservoirs that contribute to HIV reservoir (central and effector memory cells). Our data suggest that these distinct reservoirs ensure viral persistence through distinct mechanism and that eradication strategies may have differential effects on these cells. Finally, we are also developing novel assays to characterize and measure the frequency of latently infected cells, which will be essential to assess the efficacy of eradication strategies.
Key words: HIV cure, HIV persistence, HIV reservoirs, Nicolas Chomont, interview