1.7 million are infected with the human immunodeficiency virus (HIV) each year worldwide. They are condemned to lifelong antiretroviral therapy (ART) or risk developing fatal aids. Only 22.3 million out of 37.9 million have access to ART, offering that group near normalcy. There are limitations with ART—from not reaching the cells where the virus sits dormant for years to potential long-term adverse effects which are still unknown. Enter Université de Montreal Eric Cohen and team, at the Montreal Clinical Research Institute. They have identified a way to thwart HIV infection at its very early stages. Could this turn into a superior vaccine?
The Montreal Clinical Research Institute (IRCM)
Scientists Eric A. Cohen and Tram NQ Pham recently identified a way to thwart HIV infection at its very early stages. Their study results were recently published in Cell Reports.
The Window of Vulnerability Occurs in First Few Crucial Days
Eric Cohen, director of the Human Retrovirology Research Unit at the IRCM and a virology professor in the Department of Microbiology, Infectious Disease and Immunology at Université de Montréal noted “We are studying the window of vulnerability of the virus, meaning the moments in the infection process when it could be weakened or attacked. We focused on the very early stages following viral invasion.”
They note that once HIV is transmitted it doesn’t immediately spread through the body but rather it has to multiply locally—typically in the genital tissues. It is after this initial, local expansion, that the virus spreads throughout the body. The localized expansion in those first few days represents a brief window of vulnerability prior to the virus actually moving into a systemic infection mode.
Plasmacytoid Dendritic Cells (PDC)
Part of the phagocyte group of defenders against enemy invaders in the body, these “PDCs” are round shaped cells that patrol the body, in a quest to both find pathogens and antiviral response orchestration. They can be thought of as whistleblowers—important ones through which the entire defense process is set into motion. When they detect a threat, they change shape and develop protuberances called dendrites. These PDCs start producing large amounts of interferon—”a protein that triggers a state of infection resistance in other cells,” reported Cohen.
Once HIV arrives it swiftly moves to push PDCs out of the way and prevent them from their whistleblowing function. The researcher Pham noted, “The virus doesn’t seem to kill them directly, but it makes them disappear in a way that is still not understood.” It would appear that it is the actual loss of PDCs that help HIV establish the infection.
PDC Boosting Therapy
So with this information the team sought out to boost PDCs levels and their function both prior to and during infection. So they by utilizing Flt3 receptor ligand, a specialized protein, to stimulate the production of PDCs from bone marrow of humanized mice—meaning rodents that are engineered to have a human immune system in place of their own mouse machinery. Hence, in an infected human mouse, HIV behaves as it otherwise would be a human host.
Well the preclinical researchers were pleasantly surprised. First, the initial number of infected mice was reduced; second the time it took for the virus to be detectable in the blood was lengthened and 3) the amount of virus in the blood (viremia) was significantly reduced. Pham commented “In other words, the initial infection is a suppressed by maintaining a high level of PDCs.”
A Vaccine Potential?
The injection of Flt3 receptor ligand not only increased PDC abundance, but also boosted their ability to detect the virus and produce interferon following its detection. Cohen notes “These new findings will be crucial in the design of an HIV vaccine, which is basically aimed at teaching the immune system to defend itself by introducing it to a weakened form of the virus.” He continued “We can focus on PDCs in order to control the seeding and expansion of the virus at the early stage of infection.”
The study was funded by the(CanCURE) of the Canadian Institutes of Health Research and the Université de Montréal-IRCM Chair of Excellence in HIV Research. The study also relied on the infrastructures of the AIDS and Infectious Disease Network, which is supported by the Fonds de recherche du Québec—Santé
Eric Cohen, director of the Human Retrovirology Research Unit at the IRCM and a virology professor in the Department of Microbiology, Infectious Disease and Immunology at Université de Montréal
Tram NQ Pham, Senior Scientist, Montreal Clinical Research Institute