Gut feeling for a functional cure
HIV infection takes a heavy toll on the gut. The virus enters the body and heads straight for the stomach and intestines. This is harmful, destroying most of the immune cells that live in the gut. This early damage sets the scene for some of the big problems of ongoing HIV infection. One of these issues is the chronic immune activation that gut damage triggers. The seeding of HIV reservoirs which develop early and stay even during treatment are another problem.
Why does HIV head to the gut?
Researchers are trying to find ways to slow and stop gut damage in HIV infection. A first step is to understand why the gut is a target for HIV. In 2008, US researchers showed that HIV directly binds to a protein called alpha4beta7. Some immune cells have alpha4beta7 on their surface. Alpha4beta7 acts as a key, guiding these cells to the gut. In the gut, it finds the ‘lock’ which is another protein found on gut cells. In some cells, the alpha4beta7 protein can be found close to CD4, which is the main receptor for HIV. Cells that have both alpha4beta7 and CD4 on their surface are easily infected with HIV.
A promising strategy to block HIV from the gut
In late 2016, a monkey study testing an alpha4beta7 blocking strategy showed potential for controlling virus. The study involved ART-treated monkeys with SIV (equivalent to HIV in humans). Researchers gave the monkeys a series of infusions of an antibody that blocks alpha4beta7. Four of the infusions were given during ART, and the final four infusions were given once ART was stopped. The study included a control group which received mock injections instead of the antibody.
In the control group, virus rebounded to high levels within 2 weeks of stopping ART. In contrast, some animals given the alpha4beta7 antibody didn’t show any virus rebound at all. The rest showed rebound followed by re-control. Animals who received the alpha4beta7 antibody restocked their supply of CD4 T cells and had less gut damage.
How does this strategy lead to less virus?
Exactly how the alpha4beta7 antibodies caused such a dramatic effect is not known. The animals given the blocking antibody were not cured of SIV. The virus remained in their body, but at a low level that was kept under control. Immune responses may have played a role, but were not notably strong. Virus levels dropped in the animals given the antibody, but remained high in some areas of the body. And while the antibody was directed towards CD4 cells in the gut, monkeys that were dosed with antibody had more gut CD4 T cells than those in the control group.
At CROI recently, Dr Christina Guzzo presented new research on why alpha4beta7 is such a good target. Dr Guzzo, from the National Institute of Allergy and Infectious Disease (NIAID) in the US, showed that the alpha4beta7 protein gets scooped up as new HIV particles form. Alpha4beta7 ends up embedded on the outside of the virus. HIV can then use alpha4beta7 to gain entry to gut cells that usually interact with alpha4beta7. This is in addition to preferentially infecting cells with alpha4beta7 on the surface. Blocking alpha4beta7 therefore has a direct effect on the virus as well as on immune cells that express alpha4beta7.
What now? Can this strategy be developed in people?
There are still many questions about this approach, and its use in humans with HIV. Why did antibody treated monkeys have higher levels of CD4 T cells with alpha4beta7 on the surface in their gut? What effect does the antibody have on the immune response? Would the approach work just as well in a larger group of monkeys? Can the results of the monkey study be replicated in humans?
The answer to the last question is under investigation. A small clinical study is underway at NIAID, aiming to recruit 20 people (NCT02788175). The study will use vedolizumab (Entyvio), an antibody against alpha4beta7 that is already licensed for use in humans with inflammatory bowel disease. The trial will involve adults with treated HIV infection. Participants will receive vedolizumab infusions over a period of 30 weeks. Part-way through the treatments, participants will stop antiretroviral treatment and undergo careful monitoring for virus rebound. Preliminary results of the trial are expected later in 2017.
Finding solutions to prevent, treat and cure infectious diseases and understanding the complexities of microbes and the immune system requires innovative approaches and concentrated effort. This is why The University of Melbourne – a world leader in education, teaching and research excellence – and The Royal Melbourne Hospital – an internationally renowned institution providing outstanding care, research and learning – have partnered to create the Peter Doherty Institute for Infection and Immunity (Doherty Institute); a centre of excellence where leading scientists and clinicians collaborate to improve human health globally.