Immunologic Control of HIV Reservoirs.
An interview of Professor Giuseppe Pantaleo, Chief of the Division of Immunology and Allergy, Head of the Laboratory of AIDS Immunopathogenesis, Department of Medicine, Centre Hospitalier Universitaire Vaudois (CHUV), University of Lausanne, Switzerland.
During the past 15 years, Giuseppe Pantaleo’s research has been focused on the delineation of the immuno-pathogenesis of HIV infection. His research activities includes human T cell cloning, human T cell phenotypic and functional analysis, T cell activation, differentiation and memory, immuno-pathogenesis of HIV infection, HIV distribution in different anatomic compartments, antiretroviral therapy, immune reconstitution after antiretroviral therapy and immune-based therapeutic strategies. Furthermore, since 1998, he has been one of the major contributors to the development of a HIV vaccine. Professor Pantaleo kindly agreed to share his views on the immune control of HIV reservoirs
Alain Lafeuillade: Since you were the first (1) to describe the role of lymphoid tissues in HIV pathogenesis, how have evolved your views on the immunologic mechanisms allowing HIV persistence?
Giuseppe Pantaleo: There are two main immunological mechanisms that may explain the failure of the immune system to control infection and the establishment of the HIV reservoir: 1. The very late (2-4 years in average) production of potent neutralizing antibodies which -if generated at the time of acute infection- will have the potential to block efficiently HIV infection of and spreading between the target cells; and 2. The limited efficiency of HIV-specific CD8 T cells to eliminate the pool of productive infected target cells. It is not clear how CD8 T cell can efficiently kill different types of HIV infected target cells.
AL: When we look at the report (2) of a patient with undetectable HIV DNA in blood and gut during ART, the lowest level of the reservoir ever measured (1 infected cell/1.7 billion CD4s) and see that viremia rebound occurred after ART cessation, does that mean that any strategy trying to reduce the reservoir will have to include an immunologic component?
GP: There is clear evidence that ART is not able to impact on the HIV reservoir. It is therefore critical to explore immunological interventions. Immunological intervention in the treatment of HIV infection has been explored in the past and it has shown limited efficacy. However, it is time to reconsider immunological interventions not as alternative to ART (as it was the case in the past) but rather as complementary. Currently, major advances have been made in the understanding on the regulation of the immune responses and we have promising strategies to apply to the field of HIV.
AL: What do you think of IL-15 as immune therapy in HIV?
GP: It may be an interesting approach to explore. However, the delivery of cytokines needs substantial improvement since the largest amount of what it is administered is metabolized very rapidly and it is very hard to selectively target the immune cells that may benefit of the cytokine effect. With regard to IL-15, it would target memory CD8 T cells and increase survival of these cells. It may be a strategy to combine with other immunological strategies.
AL: What do you think of anti-PD-1 antibodies to target the reservoir?
GP: It is an interesting approach that deserves to be seriously investigated. However, there are a number of issues that need to be addressed on the mechanisms involved in the recovery of ‘exhausted’ T-cells. Anti-PD-1 as other immunological interventions should be used in combination immunological therapy as opposed to single intervention.
AL: What are the immune mechanisms at play in Elite Controllers?
GP: The mechanisms are multifactorial, i.e. genetic, virological and immunological. Elite Controllers are an important model but I am not sure that will guide our understanding of control of HIV infection. The challenge in front of us is to understand what needs to be done and how to achieve control in patients that do not have any of the genetic, virological and immunological factors that may favor spontaneous control.
AL: What is, in your view, the decisive mechanism that cured the ‘Berlin patient’ (the delta 32 deletion, the preconditioning regimen, the GVH disease, a combination of these factors)?
GP: A combination of these factors.
AL: Do we have sufficient data to recommend treating all cases of acute HIV infection?
GP: I have been since ever a strong advocate of treating HIV infection and I am even more convinced than ever. Treating acute HIV infection is probably the chance we have to impact the course of the infection and hopefully to render the patients more responders to immunological interventions.
AL: Where your current research for an HIV vaccine is heading to?
GP: It is a very exciting period in HIV vaccine research. It has been shown that an HIV vaccine is able to prevent HIV infection. We have now a number of very promising vaccines and we have finally a better understanding of the immune correlates of protection and how to induce these relevant responses.
1-Pantaleo G, et al. Nature 1993; 362(6418): 355-8.
2-Chun TW, et al. AIDS 2010; 24(18):2803-8.
3- Porichis F, et al. Curr HIV/AIDS Rep 2012; 9(1): 81-90.
Key words: HIV cure, HIV reservoirs, HIV vaccine