Shedding light on HIV latency

There are almost 40 million people throughout the world living with HIV. 35 years after its discovery there is a good anti-HIV therapy; however, this treatment cannot fully eliminate the virus.

Anna Kula-Pacurar 

The major reason for this is that HIV hides away in cells by switching off its genome (its so-called latent state), becoming invisible to drugs and the immune system. When the antiretroviral therapy attacks HIV, it is not able to eliminate the hidden/dormant virus, which eludes the therapy. Whenever a patient stops the antiretroviral regimen, the latent virus reappears. Therefore, the HIV-infected patient has to take the antiviral medications for the rest of their life.

Consequently, latency persists, cannot be eliminated and represents a major hurdle in finding a cure. New strategies aimed at eliminating the latent virus are absolutely necessary in order to reach a cure. By unlocking the secrets of latency it may become possible to cure – not just control – HIV.

With no vaccine on the horizon, several strategies are currently proposed in order to fight latent HIV. One of them is ‘shock-and-kill’. This strategy involves waking up the sleeping virus (‘shock’) using so-called latency-reversing agents while keeping the anti-HIV therapy (‘kill’) so that the reactivated virus can be eliminated. This kind of strategy would allow the latently infected cells to die from viral cytopathic effect or host immune response. However, scientists are now aware that this strategy for some reason is not potent enough to reactivate the virus and to eliminate the latent reservoir. Therefore, development of additional tactics is necessary.

The goal of the research was to discover if MATR3 and PSF cellular proteins matter for HIV latency. Researchers found out that these two factors are poorly expressed in latent cells from patients and further demonstrated that lack of these factors blocked the latent virus from full reactivation using existing drugs. They therefore identified a novel block related to MATR3 and PSF that impedes the action of drugs.

This demonstration at least partially answers the question as to why the current shock-and-kill therapy is insufficient and highlights that further studies are urgently needed to understand the blocks.

How did you benefit from the POLONEZ fellowship?

The POLONEZ grant allowed me to come back to Poland after 12-years of doing research in Italian and Belgian laboratories to establish pioneering HIV research in my country from scratch. This project bridges the gap between ongoing HIV epidemiological and clinical studies as well as broadens the virology research in Poland to a new area of high impact.

Moreover, thanks to the grant I could carry on already established and initiate new multidisciplinary collaborations with clinicians, chemists and other virologists from Poland and abroad. Realization of this grant in collaboration with international laboratories allowed to demonstrate a novel block of latency that needs to be relieved to potently awake the virus from latency. This discovery directly impacts on the development of the HIV field with implications for therapy.

Importantly, I could say that without the POLONEZ grant I would not have been able to establish myself as an independent researcher in Poland with solid and recognized research program. Realization of this grant helped me to be successful in obtaining SONATA BIS grant from NCN that aims at continuing the research initiated during POLONEZ.

Dr Anna Kula-Pacurar is a molecular virologist focused on the HIV-host interactions. After she graduated from the University of Gdańsk, Poland (MSc in 2005), she moved to Italy, where she undertook research training at the International Centre for Genetic Engineering and Biotechnology, investigating novel pathways controlling HIV gene expression (PhD in 2009). In 2013 she began her post-doctoral training at the Institute of Molecular Biology and Medicine, Université Libre de Bruxelles, Belgium focusing on aspects of an HIV cure. With the help of the POLONEZ grant from the National Science Centre she moved back to Poland in 2017 to initiate an independent research focused on molecular mechanisms leading to HIV latency/reactivation and the implication for therapy at the Malopolska Centre of Biotechnology, Jagiellonian University in Kraków.