HIV-1 mimics an "enhancer" to maintain activation potential but avoid detection
When Human Immunodeficiency Virus Type 1 (HIV-1) infects a cell, the virus often becomes invisible to both the immune system and drugs. Now research from Karolinska Institutet shows that the integrated virus mimics a specific chromatin structure that lets the virus sequence remain accessible while preventing production of new viruses.
HIV-1 is still affecting millions of people around the world and although proper medication reduces the virus levels to undetectable, a cure is not yet available. One of the reasons why a cure is still missing despite virtually eliminating the virus from the body is that when a cell is infected with HIV-1, the virus can copy itself from RNA to DNA and then integrate into the host cell's DNA to form an HIV-1 provirus. There, the viral sequence is interweaved into the chromatin structure and cannot be distinguished from a common gene. In this way, infected cells avoid the immune system. Although no viruses are produced in this state, the cell retains the information to make new viruses later.
The HIV-1 provirus can remain latent in infected cells for several years but at any time the provirus can be activated, and we still do not know where or how it occurs. This "stochastic" HIV-1 activation is the reason why people living with HIV-1 need to be under constant medication to prevent the virus from resurging.
In a new study from Karolinska Institutet, published in Plos Pathogens, the authors have described how the integrated HIV-1 provirus can maintain its open and activatable structure, but at the same time avoid producing viruses that would expose the cell to the immune system. The research group led by Peter Svensson, a researcher at the Department of Biosciences and Nutrition, Huddinge, has discovered that in latently infected cells, the chromatin of the provirus mimics a so-called "enhancer" - an positive regulator of gene expression. These enhancer structures are linked to genes but do not themselves encode proteins that the genes make.
- This is a breakthrough for research into a future cure for HIV, to understand where new viruses come from, says Peter Svensson. Previously, we believed that a large part of silenced HIV-1 was encapsulated in heterochromatin, which is a structure that requires major changes to enable virus production. Clinical studies have tested the effect of molecules that open up chromatin, as these can be very effective against certain types of cancer. But unfortunately, these drugs seem to have very little effect on HIV-1. Instead, we show that the provirus takes on an "enhancer" structure in a small proportion of the latently infected cells. There, the provirus can be expressed without producing protein, but retains its open structure. When the virus is activated, it transitions from enhancer to gene expression and the cell begins to produce new virus particles. This shift opens up a whole new way of thinking in the battle against HIV-1.
The study is funded by the Swedish Research Council, Cancerfonden, Åke Wiberg Foundation, Clas Grochinsky Minnesfond, Läkare mot AIDS Forskningsfond, CIMED and Karolinska Institutet.
"Chromatin maturation of the HIV-1 provirus in primary resting CD4+ T cells," B. Lindqvist, S. Svensson Akusjärvi, A. Sönnerborg, M. Dimitriou, J. P. Svensson, Plos Pathogens, online January 30, 2020.