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Host MicroRNAs-221 and -222 Inhibit Entry in Macrophages by Targeting the CD4 Viral Receptor

Information sheet for Lodge et al., published in Cell Reports, October 2017

Blood and biological samples, generously provided by anonymous HIV-negative healthy volunteers, allowed us to obtain macrophages and to investigate how these cells can resist viral infection. Macrophages are cells which can survive long after being infected by HIV, and if infected, will produce only low amounts of virus. Macrophages can also infiltrate many organs, were they are thought to establish HIV reservoirs. Reservoirs are cells and tissues where HIV is able to hide and persist in a dormant state, even when a person is taking effective antiretroviral therapy and has an undetectable viral load. However, we found that macrophages can resist HIV infection by using microRNAs. These small RNAs are generated by the cell and are increasingly found to regulate basic cellular processes in health and disease. Two microRNAs, 221 and 222, inhibit HIV infection of macrophages by reducing the level of CD4, the molecule which allows HIV to enter cells. These results were published in the prestigious journal Cell Reports in October 2017.

1) What was the goal of our study?

Macrophages in cell culture derived from blood monocytes are not efficiently "infectable" by HIV. The goal of this study was to find out more on how macrophages resist the infection. Using highly specialized techniques, we separated both HIV-resistant and HIV-susceptible macrophages from macrophage cultures infected with the virus in the laboratory. Then, using new technology, we compared the different amounts of microRNAs in each population. MicroRNAs are small molecules that control the expression of genes and proteins. Elevated levels of microRNAs-221 and -222 are found in the HIV-resistant population, and also in HIV resistant "activated" macrophages. These microRNAs reduce the amount of CD4, the important receptor by which HIV enters cells, which leads to less infection overall.

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

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 eliminate all HIV-infected cells. Indeed, a very small amount of virus remains dormant and hidden in HIV reservoirs, and is able to restart HIV replication if the person living with HIV goes off treatment. Thus, research for a cure must target cellular reservoirs such as HIV infected macrophages: much research is presently focusing on HIV infection in organs such as the colon and brain that seem to harbor HIV-infected macrophages. Understanding how some macrophages become resistant to HIV infection will inform and guide future strategies aimed at limiting the establishment of reservoirs in macrophages.

3) Why are patient samples important to this research?

This project would not have been possible without the participation of volunteers. Monocytes were isolated from donated blood samples, and from these cells were derived in the laboratory the macrophages necessary for our studies. We were also fortunate to have access to matched blood samples and colon biopsies from a number of healthy HIV-negative participants; these materials enabled us to link elevated microRNA-221 levels with greater HIV resistance in gut macrophages, as the latter represent a more authentic and relevant context.

4) What was learned? What next?

This study showed that microRNAs inhibit HIV-1 infection of macrophages. MicroRNAs are important gene regulators that are potentially involved in several aspects of HIV infection. Here, we focused on their role as antiviral factors that limit HIV infection of macrophages, which are cells that are part of the HIV reservoir. Much is still needed to learn of microRNAs and their potential use in targeting HIV reservoirs and to purge HIV-1 infected cells from the body. Strategies that would safely enhance the synthesis of microRNAs 221 and 222 in macrophages would render these cells resistant to HIV infection and limit the establishment of the HIV reservoir.

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