Meet Our Researchers

Alex Shalek

Associate Member at the Broad Institute
Assistant Professor at MIT
Assistant in Immunology at Massachusetts General Hospital (MGH)
The Question

HIV spreads throughout the body by constantly shifting shape to avoid the immune system. This allows the virus to replicate without being held in check. But some HIV-positive individuals, known as elite controllers, manage to mount an immune response that keeps HIV at low, undetectable levels—even in the absence of treatment.

In our BroadIgnite-funded work, we seek to investigate how the immune systems of elite controllers keep HIV at bay. Perhaps some of these individuals’ immune cells exist in unique states that are effective at combatting the virus. Alternatively, they may have an unusual combination of immune cells that work together to maintain low HIV levels. Figuring out how elite controllers’ immune systems regulate the virus could transform our ability to develop immunotherapies and vaccines for HIV and other infectious diseases.

The Approach

Our research group is interested in which cells are involved in the immune system response to HIV, what molecular changes occur within them, and how this influences their ability to work together. To identify these changes, we used single-cell RNA sequencing (scRNA-Seq) to analyze the expressed genes of individual cells and to probe immune cells from elite controllers. Specifically, we studied dendritic cells—the first line of defenders against viral infection—during exposure to HIV-1. These cells recognize and present parts of an invading pathogen to other immune cells to help initiate a global immune response.

The Results

In our initial work, we found multiple different dendritic cell responses to HIV-1. One activated cellular state—marked by expression of the proteins PD-L1 and CD64—turned out to be particularly good at displaying HIV and triggering global responses. Encouragingly, the activated state is not unique to elite controllers, although these people have more dendritic cells in this state. This suggested that shifting the fraction of responding cells to favor these important ones might provide a new avenue for therapy. To test this, we first developed computational tools to identify pathways involved in the development of this responsive state. We then used adjuvants and drugs targeting these pathways on cells from healthy uninfected donors to increase the fraction of responding cells, boosting immune responses in vitro.

Our initial findings were promising, but to extend and validate them, we needed a much larger cohort. To achieve this, we established collaborations with researchers at the Kwazulu-Natal Research Institute for Tuberculosis and HIV in Durban, South Africa. BroadIgnite funds provided support for our travel costs to work with these collaborators, whom we’ve trained in single-cell technologies. Due to the high incidence of HIV in this region, we were able to access samples (e.g., blood samples from early HIV infection) that were unavailable in Boston. In these samples, we found substantial changes in the immune system’s composition, including missing cells and dysfunctional circuitry, findings that suggest there are potential therapeutic paths we can follow. All of this exciting progress helped our lab earn a grant from the Gates Foundation to advance this important work, which we hope will help us make critical new inroads in the fight against HIV.