The 7th International Workshop on HIV Persistence during Therapy Started on December 8, 2015
Held for the second time in Miami, Florada, the workshop attracted 276 participants from all over the world.
The workshop is organized with the support of the NIH, the NIAID, AmFar and the ANRS.
Regarding firms, this year workshop was backed by Gilead, ViiV Healthcare, Bristol-Myers-Squibb and Merck.
The first day was dedicated to the DAIDS Martin Delaney Collaboratories, followed by an opening lecture from Carl Dieffenback, Director of the NIAID.
The first part of this session was dedicated to presentations of the current results of the 3 collaboratories.
Keith Jerome (Seattle, USA) presented DefeatHIV, a collaboratory aimed at cell and genome engineering. Four things have been learned from it:
-Manipulating and editing of host and viral genomes
-advances in delivery of DNA-modified enzymes
-modeling as an adjuvant to data interpretation
-use of NHP models.
He focused on rare-cutting endonucleases like megaTAL that shows, like Cas9, the best combination of activity and specificity.
TALENs appear to be too toxic.
The S20 mega TAL efficiently mutates HIV
AAV6 is used as a vector.
The speaker concluded by saying that NPH is the model of choice and that we must search beyond CCR5 disruption.
David Margolis (Chapel Hill, USA) spoke about the CARE collaboratory. Its goal was to bring novel molecules into the clinic by the end of 2016.
Several types of molecules are tested as Latency reversing agents (LRA): bromodomain inhibitors (in animals), Triazol-10 analogs, Bryologs, Ingenols...
When Merck screened 2,900,000 molecules they found 4,500 having LRA activity:
-17.4% were farnesyl transferase inhibitors
-16.1% were known HDAC inhibitors
-others were of unknown mechanism of action.
The future of this collaboratory is to build a pipeline of tools and models to study HIV eradication.
The DARE collaboratory was described by Steven Deeks (San Francisco, USA).
They tried to answer 3 questions:
1-Where HIV resides during ART?
Elite controllers for SIV have shown that B cell follicles are a reservoir. T cells can control SIV outside them but not inside. Transient disruption of the B cell follicules allow CTL to decrease the size of the reservoir.
In HIV elite controllers virus in blood is archival, clonal and enriched in terms of cells while virus in tissue is actively replicative.
During ART, SIV DNA+ cells in T cell zones decreases but persists at a stable level in B cell follicles.
Treatment at acute infection limits the reservoir size and prevents generation of CTL escape.
2-How does the local immune response shapes the reservoir?
The inflammatory response is rapid during HIV infection but the anti-inflammatory response eventually dominates resulting in an immunosuppressive environment.
Upregulation of immunosuppressive pathways, in particular IL-10, is obvious.
Collagen disposition/lymphoid fibrosis persists at all stages of infection, with ART, even in Elite controllers.
Immune checkpoints ligands/receptors are upregulated. For exemple, latent HIV is enriched in T cells expressing PD-1 and other immune checkpoints.
A major factor in maintaining the reservoir is expansion of clonal populations.
3-Does interruption of the pathways that contribute to chronic immune suppression allow the immune system to work better?
In fact, inflammation and immune suppression go hand in hand.
In one case report (AIDS 2015), Iplimumab increased cell-associated RNA and decreased steady state viremia (reservoir reduction).
Pembrolizumab (anti-PD-1) improves HIV immunity ex vivo.
The future of this collaboratory is:
-to test CMV vector vaccine in NHPs and humans,
-to test follicular disruption with anti-CD20 antibodies in NHPs
-test immune checkpoints blockade in NHPs and humans with cancer
-test immune modulation (mTOR, ACTG).
The second part of this session was a panel discussion (cross-cutting challenges in cure research) addressing 3 issues:
1-Industry partnerships and overcoming barriers to translational research.
Gilead and Merk are fully engaged in HIV cure research.
One barrier could be the lack of efficient tools to measure the reservoir and therapeutic intervention results.
Another barrier is that companies do not always want to provide their drugs if they are licenced in another field (or will be) in order to protect them.
2-ARVs and optimizing animal models for evaluation of HIV cure strategies.
According to Janice Clements, the drug price can be an obstacle (Darunavir for exemple).
We have to take into account that different strains are used.
We have to look closely at the question we address to choose the appropriate strain (for exemple a macrophage tropic strain to study the brain).
We have to take into consideration when ART is initiated after infection in animal models, what is the viral diversity at this time and ARVs duration.
There are some limitations of the humanized mouse model:
-mice are small
-it is an accelerated model of HIV infection in humans (but this can be an advantage)
-some of them have some degree of graft vs host disease
Finally, NHPs models and humanized mouse model appears to be both interesting.
3-Clinical trials design: appropriate populations and end points for control vs eradication studies
Contrary to what people think, gene therapy could be scalable in the future with the advances in technology.
An important question was raised: do whe have to test interventions for "cure" in acutely infected patients (where the reservoir is so low that we will not be able to measure its effect) or in chronically infected patients (where the immune system is compromized). Both populations can, however, be studied, with stratification of results.
The opening lecture was given by Carl Dieffenbach, Director of the NIAID.
Carl Dieffenbach is at the Division of AIDS for 25 years.
His talk was about the HIV cure agenda at NIAID.
First, he pointed out that a cure must be simple, safe and scalable.
His lecture was divided into 3 sections:
1-The establishment of the HIV reservoir.
He described the evolution of the Mississippi child and asked what are the critical steps and timing of the 24-48 hours after birth regarding the establishment of the reservoir and the immune response to HIV.
He presented 2 studies:
The IMPAACT study P1115 that tries very early intensive antiretroviral therapy in HIV-infected infants
The TIES study: treating infants early within 24-48 hours of birth
2-The characterization of the reservoir. Pointed out that there are anatomical reservoirs like B cell follicles from which CTL are excludes.
"The tissue is the issue, Carl Dieffenbach said, we sample blood only for convenience".
3-The novel interventions and research opportunities.Carl Dieffenbach said that we nedd to have agents that both suppress virus replication and promote killing of the infected cells at all the sites of new and ongoing replication.
He listed a wide variety of possible ways:
-Genetic strategies, including Zinc Finger Nucleases and CRISPR/Cas 9
-Strategies targetting the state of cell activation: but do these methods of activation simply propagate the reservoir?
-Methods of putting the provirus permanently to sleep: antisense transcripts, polycomb complex.
-DARTs that direct T cell mediated cytolysis of HIV latently infected cells
-Chimeric Antigen Receptor Technology (CARs)
-Therapeutic vaccines: but they have not really shown activity by now, except the CMV vector
-Combining immunotherapy with ART.
Key words: HIV cure, HIV eradication, HIV persistence, HIV reservoirs