Some cells attacked by HIV can resist infection by closing the door to the virus.

Now that medication can keep HIV under control and prevent progression to AIDS, researchers around the world are moving to the next step: eradicating the virus or, at least, controlling it without having people living with HIV to take anti-retroviral drugs for the rest of their lives. Indeed, HIV is cunning as it lies dormant in certain immune cells, in particular, lymphocytes and macrophages. These viral niches or reservoirs allow HIV to escape medication and reactivate the infection when therapy is stopped. But how does HIV create these reservoirs? And how can we eliminate or control them?

This is what scientists are trying to find out so that HIV/AIDS can be cured. Éric A. Cohen, Director of the Human Retrovirology Research Unit at the Montreal Clinical Research Institute (IRCM), and members of two pan-Canadian research teams—the Canadian NeuroAIDS Research Team (CNART) and the Canadian HIV Cure Enterprise (CanCURE)—have found part of the answer. They have identified a defense mechanism that allows macrophages to protect themselves from infection. This breakthrough raises the possibility of preventing the establishment of reservoirs in macrophages, especially in the central nervous system where such cells play a major role in HIV persistence.

The researchers suspected that macrophages were reservoirs because the virus infects them without destroying them, and they exhibit inflammatory responses even when the infection is controlled by medication. In addition, “as macrophages show varying degrees of susceptibility to infection, we thought that their defense mechanisms must vary depending on their tissues of origin,” explained Dr. Cohen, who leads CanCURE. By analyzing macrophages in more detail, the research group noticed that some cells, such as those in the intestines, resist viral infection. How do they do it? Éric A. Cohen and Robert Lodge, lead author of the study and an IRCM research associate, suggest that susceptibility to infection is partly controlled by microRNAs: very small non-coding molecules that “filter” instructions carried by messenger RNAs. In this way, microRNAs control protein expression in cells.

To check their hypothesis, the scientists analyzed the profile of microRNAs in blood samples donated by healthy volunteers. First, they isolated the monocytes, the precursors of macrophages. In the laboratory, they differentiated them into macrophages, which they exposed to HIV. The outcome: only 5 to 10% of the cells were infected by the virus, and the rest resisted infection. The researchers then identified over 400 different microRNAs that were modulated among the infected and non-infected cells. Two of the microRNAs, 221 and 222, specifically prevent macrophages from synthesizing the protein CD4, the receptor by which HIV enters and infects a cell. In other words, these two microRNAs close the door to the virus.

But why do only some macrophages have these protective microRNAs? “It seems that these microRNAs are part of the antiviral response of macrophages in some tissues,” said Dr. Cohen, who will be addressing this question in a subsequent study. Now that researchers understand how some macrophages fight HIV infection, they hope to be able to increase the production of microRNAs 221 and 222 to make all macrophages HIV-resistant. With one less place to hide, HIV will find it more difficult to outsmart medication and persist in the body.