Work on an HIV latency reversing agent (vorinostat) published – click here to learn more

Our work on one of the first HIV latency reversing agents, vorinostat, is published by PLoS Pathogens. As stated in the title of this paper, by fitting mathematical models to clinical data, we show that vorinostat induces both transient and delayed HIV transcriptional activation in vivo, but minimal killing of latently infected cells (read here for more details).

If you are not working on this area and would like to know a little background why we care about latency reversing agents and/or current challenges to cure HIV infection, here below is a short writing. Hopefully it is useful in terms of putting our work into a broader picture.

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Efforts to cure HIV infection are hindered by the existence of latently infected cells, i.e. cells infected by HIV but that do not actively produce virus. These cells form the HIV latent reservoir. A majority of these cells are resting memory CD4+ T cells. What do these ‘resting’ ‘memory’ CD4+ T cells do? The short answer is that they provide immunity to us: they are generated during prior exposure to pathogens to fight an infection. Once the infection is resolved, they switch to a ‘resting’ state, and hardly do anything apart from moving around within our body. However, once they encounter a pathogen they have ‘seen’ before, they respond immediately and signal to other immune cells to fight the pathogen right away.

Resting memory CD4+ T cells live for a long period of time (up to many years). This is a great property in terms of immunity: the longer they live, the longer we are protected. However, when they are infected with HIV, this property becomes problematic. HIV can ‘hide’ in these cells without doing anything for an extremely long time. In this way, HIV is invisible to the immune surveillance: neither infected cells themselves nor other immune cells see anything wrong. From time to time, HIV can start to express gene products and viral particles when the condition is right (the exact conditions have not been figured out, although this is a very active research area). These newly produced HIV particles may reseed the infection in the absence of an effective anti-retroviral therapy (the so called ‘cocktail’ therapy). Because this population of infected cells is extremely stable, patients have to be treated with the ‘cocktail’ therapy life-long.

Thus, recent research has focused on developing/testing latency reserving agents, such as vorinostat we study here, to activate HIV production in latently infected cells, such that they could be recognized and purged by cellular protective mechanisms (i.e apoptosis/suicide) or extracellular immune mediated killing (antibodies or cytotoxic T cell response). The aim is to reduce the population size of the latently infected cells, eradicate this reservoir and ultimately cure HIV infection. To us, this is such an exciting research area to work on!

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