Information sheet for Planas et al., a study published in Journal of Clinical Investigation Insight, August 2017
Blood and biological samples, generously provided by anonymous volunteers, allowed us to think of ways to better treat and maybe cure HIV. These study results were published in the Journal of Clinical Investigation Insight, in August 2017.
CD4 T-cells are the main targets for HIV-1 and are rapidly lost after HIV infection, especially in the gut. But not all types of CD4 T-cells are infected with the same efficiency. In a previous study, we showed that a type of CD4 T-cell displaying a molecule called CCR6 is the preferred target for HIV. The CCR6 molecule helps HIV-infected cells migrate from the blood into the gut, where the virus can remain (a “reservoir”) despite antiretroviral therapy (ART). ART effectively controls HIV multiplication, but it does not clear the infected cells from the body. Nor does it restore the number and the function of CD4 T-cells to levels present before infection. In addition, ART is unable to control ongoing inflammation and the damage it causes to the gut. These effects contribute to illnesses such as cancer, diabetes and other “comorbidities” affecting people with HIV. ART must be taken every day for life to maintain a robust degree of viral control. If ART use stops, the virus multiplies. These drawbacks require research to find new ways to deal with HIV, particularly HIV which remains in tissue reservoirs.
1) What was the goal of our study?
Uninfected CD4 T-cells that display CCR6 are important for gut health. Based on our previous study showing how these cells help HIV migrate from the blood to the gut, cause damage and reside in a reservoir despite ART, we wanted to see if we could now identify ways to stop these deleterious consequences from happening.
HIV makes copies of itself in a process involving several steps. Any one (or more) of those steps can be interrupted to block HIV multiplication. Currently, ART only works to stop viral multiplication at some of these steps. The goal of this study was to identify new targeted therapies which would both limit HIV multiplication (as ART currently does, but not completely) and limit the inflammation attributed to these special CD4 T-cells which migrate to the gut (which ART cannot do).
2) How is this study related to a cure for HIV? or to treatment for HIV comorbidities?
In this study, we show that CD4 T-cells that display CCR6 and home into the gut carry high levels of an enzyme called “mTOR”. By inhibiting mTOR activity, we observed a decrease in the ability of HIV to multiply in these cells. We also observed a decrease in HIV’s ability to escape from viral reservoirs in participants who took ART. Thus, drugs that block mTOR may be an important step toward reducing inflammation-related comorbidities. Our findings may also lead to a novel cure strategy for HIV by keeping the virus silent. This may be an alternative to other tested yet unsuccessful cure strategies that tried to “shock” HIV out of reservoirs and kill it. Several mTOR inhibitors are already used for the treatment of cancer and diabetes.
3) Why are participant samples important to this research?
Matched blood samples and colon biopsies from participants living with HIV were essential for us to compare colon and blood CD4 T-cells and to understand why colon T-cells that display CCR6 are easily infected by HIV. By using these samples, we confirmed the role of the enzyme mTOR, as well as other molecules, and came up with the idea to test existing mTOR inhibitor drugs used in cancer and diabetes research to see if they can help people with HIV achieve remission and/or cure.
4) What was learned? What next?
This study provides an explanation as to why HIV is able to multiply and cause damage in the gut. Further research is needed to better understand the role of mTOR in HIV’s selection of CD4 T cells displaying the CCR6 molecule. Next, clinical trials using mTOR inhibitors will determine whether this strategy can be used for to cure HIV or to prevent HIV-related comorbidities.