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Blood and biological samples, generously provided by anonymous volunteers, were central in this study. We want the public to learn how this study turned out and how the role of the volunteers was important to the outcome. This information sheet discusses the discovery of a new technique to identify those cells where HIV hides in people on antiretroviral treatment with an undetectable viral load.

HIV reservoirs are the cells and tissues where HIV lies dormant (“asleep”), even when a person is taking effective antiretroviral therapy and has an undetectable viral load. For the most part, HIV lives and replicates in a type of white blood cell, commonly known as a CD4 T cell. While antiretroviral therapy is generally successful in controlling the viral load in people with HIV and preventing progression to AIDS, currently available antiretrovirals don't completely kill all HIV-infected cells. A very small amount of virus remains dormant in the HIV reservoirs, causing chronic inflammation and able to restart HIV replication if the person living with HIV go off go off treatment. Research to cure HIV must target all cell reservoirs, CD4 cells and others.

1) What does our study show?

A major challenge in the HIV research field has been the lack of technologies available to identify “sleeping” CD4 T cells very precisely. This study presents a new way to identify such cells accurately.

2) How is this study related to a cure for HIV?

HIV can remain dormant in reservoir cells and tissues for years and can be reactivated if people stop their treatment. In order to develop new therapies against the remaining HIV reservoir, researchers need to find exactly where the virus is hiding among an individual’s total population of CD4 cells. One of the strategies that holds a promise in the search for the cure for HIV is a “shock and kill” strategy. This strategy would eliminate the dormant HIV in two stages. Firstly, new experimental drugs called “latency-reversing agents” would “wake” HIV from its dormant state. Once awake and active, HIV becomes visible to the immune system and to antiretroviral drugs that can eliminate it. In order for the “shock and kill” approach to work, we need to know more about the types of CD4 T cells in which these latency-reversing agents will work. Our study could also help identify other cells in addition to CD4 T cells where the virus can hide.

3) Why are patient samples important to this research?

To obtain results which are relevant to “the real world”, our study needed to analyze the white blood cells of volunteers directly, not cells grown in a laboratory. We obtained samples from individuals before they started treatment or while they were taking antiretroviral therapy. We also examined samples from participants not infected with HIV for comparison and accuracy. To conduct our studies, we needed large numbers of blood cells, because it is difficult to find infected CD4 T cells in people with an undetectable viral load. We could not have discovered these results without the participation of volunteers.

4) What was learned? What next?

Our team developed a new technique for detecting these reservoirs – a way of taking a “photo” of each individual cell which was hiding the virus. This breakthrough approach is 1,000 times more accurate than current technologies. We are now capable of accurately detecting infected CD4 T cells, which represent 1 in a million CD4 T cells in someone with undetectable viral load. We were capable of finding the "needle in the haystack" in almost all of the blood samples we analyzed. Next, we described the unique features of these cells that set them apart. We then tested two drugs that are experimental to shock HIV: one called bryostatin and the other a derivative of a substance known as ingenol. We found that these two drugs wake up different populations of CD4 T cells, thus reactivating different cells we store in the laboratory (we don’t know if these drugs are safe enough and work in people yet and they do not work in other types of cells where HIV can hide). This level of accuracy in our ability to show how different drugs target different reservoirs opens the door to the concept of individualized monitoring for people with HIV. Ultimately our research findings may facilitate the development of personalized HIV therapies. Next, we plan to evaluate the effectiveness of these experimental latency-reversing drugs to identify and awaken viral reservoirs in monkeys. Then we may proceed to clinical trials in people with HIV.

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