The Canadian HIV Cure Enterprise (canCURE)
Dr. Eric Cohen is one of the principal investigators of CanCURE, the Canadian HIV Cure Enterprise. CanCURE began in 2013. It aims to understand the persistence of HIV during antiretroviral therapy (ARV) and to use this knowledge to develop cure interventions. It is a large collaborative group of 28 researchers from institutions across Canada as well as a community advisory board led by Robert Reinhard.
Dr. Cohen explained that we know that HIV hides in reservoirs in the body that are not affected by current therapies. This includes the brain, lymph nodes, gut, and genital tract. HIV DNA survives in a dormant state in memory CD4 T cells – long-lived cells indifferent to treatment. Much research attention has focused on these cells although there may also be other reservoirs in myeloid cells, particularly macrophages. Dr. Cohen went on to explore the role of these cells.
Macrophages are found in virtually every tissue in the body. Among other functions, they protect the body from infection by engulfing pathogens (phagocytosis). Research has shown that they are resistant to destruction by HIV and can harbour virus in a latent, or very low expression, state in cell cultures.
Cure strategies are aimed at clearing infected cells and enhancing immune control. CanCURE’s scientific objectives aim to support these strategies by:
- Identifying and characterizing the properties of marcrophages and other lymphoid cells that may act as viral reservoirs.
- Conducting detailed mechanistic studies of how viral reservoirs are established and maintained.
- Identifying drug candidates that enhance immune control or induce clearance of viral reservoirs.
- Testing whether or not immune-based therapies can reduce viral reservoirs in clinical trials.
Dr. Cohen highlighted a few recent findings by the CanCURE team including:
- The identification of a viral reservoir in CCR6+ T cells in the colon and blood of people receiving ART; HIV infected cells are preferentially retained (Gosselin A, Wiche-Salinas TR et al, 2017).
- A new assay which measures what proportion of seemingly latently infected cells might be capable of producing more virus (Baxter AE et al, 2016). It may help give more definitive answers about the role of macrophages as a viral reservoir.
- The potential for broadly neutralizing antibodies to enhance the immune system’s capacity to attack latently-infected cells (Pham et al, 2016).
Cytotoxic T-lymphocytes eliminate defective HIV proviruses without impacting infectious reservoirs
Brad Jones is a former OHTN-funded fellow now working as an independent scientist at George Washington University. He presented the two traditional approaches to cure – both focused on getting people off antiretroviral therapy (ARV):
- Sterilizing cure – the virus is completely eliminated from the body.
- Functional cure –the immune system is able to control the virus without antiretroviral therapy.
HIV-specific T cells (also known as CTLs or killer T cells) patrol the body and kill HIV-infected cells. Dr. Jones and his colleagues want to find ways to aim CTLs at the viral reservoir. The HIV viral reservoir refers to the DNA of HIV integrated into human cells (provirus) where it hides from the immune system. A small proportion is intact provirus, which means it can by “reawakened” and use the cell’s machinery to create infectious new virus. A much larger proportion of the provirus is defective, with large sections missing. This defective provirus cannot create more infectious virus, but CTLs do respond to it.
A landmark study (Shan et al, 2012) discussed the “shock and kill” paradigm. It suggested that even if you wake up latently infected cells and the virus inside them, the virus does not necessary kill the infected cell, and it may become latent again, perpetuating infection. In the shock and kill paradigm, a drug is used to shock the virus out of hiding but CTLs must also be present to kill off the infected cell.
Dr. Jones discussed some of his recent studies. In these studies, latently-infected cells from people living with HIV are collected, and a shock and kill strategy combining latency reducing drug and CTLs is tested.
In the first test, provirus in the cells was reduced by 50% (since both defective and intact HIV provirus is attacked). However, when the cells are allowed to grow, there was no decrease in the amount of infectious virus produced. (In a human being, this would mean that the virus would rebound and viral load would increase just as quickly in a treated person as an untreated one.) The team repeated the study with a stronger latency reducing agent (one too toxic for human use), but it still did not reduce production of infectious virus. The team has repeated these tests with different CTLs and latency reducing agents, and there is never a reduction in infectious virus produced – sometimes the trend is for an increase.
Although this approach will not lead to a functional cure, Dr. Jones and his colleagues speculate that since the immune system responds to defective provirus, it may contribute to inflammation and comorbidity. Reducing the proviral load in the body might reduce inflammation, improving health and quality of life for people with HIV. He will continue to study this phenomena, as well as pursuing a functional cure.
The BELIEVE Collaboratory
Douglas Nixon, of George Washington University, provided an overview of his newly funded initiative, BELIEVE – Bench to Bed Enhanced Lymphocyte Infusions to Engineer Viral Eradication. This is one of six Martin Delaney Collaboratories funded by the National Institutes of Health. Each collaboratory brings together resources from the public and private sectors to focus on developing a cure for HIV.
The Martin Delaney program is a unique funding mechanism that involves a more dynamic partnership with government. Resource allocations can change throughout the life of the project, and there is regular weekly communication with the funder. There is also a strong emphasis on community engagement.
In addition to the community advisory committee, at least one community member is part of the steering committee that guides the entire BELIEVE project. The community advisory committee will help link the study to those living with HIV in Washington, DC, which has one of the worse epidemics in the US, with 13,000 – 16,000 HIV-positive people. In disadvantaged parts of the city, HIV infection levels are similar to sub-Saharan Africa. The community engagement committee will be focused on three primary domains of concern:
- practical facets of recruiting participants
- education, outreach and engagement to build foundation for eventual testing and scale up
- study ethics.
Although the study is based in DC, research partners are engaged across the US, as well as in Toronto and Vancouver, with additional partners in Brazil and Mexico. Corporate partners include Altor BioScience and Torque, both biotech companies interested in enhanced immune control of HIV.
BELIEVE research goals:
- Expand the knowledge base on HIV latency and the persistence of HIV in people on ARV.
- Design and evaluate innovative cure strategies that enhance a person’s immune system to eradicate viral reservoirs.
- Translate findings to a clinical setting.
In the first phase, BELIEVE investigators will collect cells through leukophersis from donors and conduct viral sequencing and HLA typing. The researchers will then select HIV-specific T-cells and modify them with conserved epitope targeting to improve their anti-HIV function. After evaluating these enhanced cells in the laboratory, the eventual goal is to reinfuse the cells back to the original donors in the hope that the cells will work better and will help flush out the viral reservoir within the body.
Douglas Nixon also spoke briefly about his interest in the idea of precision cures (Nixon et al, 2016). This is a provocative idea that means selecting patients who might be more “curable” for therapy. Patients would be screened to identify those who might have lower viral reservoirs or other immune advantages that could lead to remission of HIV infection (control of HIV with antiretroviral drugs).