Why isn’t there a HIV-1 cure?
Since I am defending the thesis soon, I would like to share the popular science summary of my thesis. Explaining your research can be challenging but I hope that this makes it more understandable.
I am defending my thesis on September 12th at 10am. The thesis can be accessed here “Mechanisms Controlling the HIV-1 Provirus”
Popular science summary of the thesis
42 years after the discovery of HIV and the start of the HIV pandemic in 1982 there is currently no cure of the chronic condition AIDS, caused by HIV. This is due the persistence of replication competent HIV proviruses the disease is incurable. Antiretroviral therapy (ART) when taken continuously stops HIV progressing to AIDS and allows for an unaffected lifespan with few side effects. However, its high cost means it is not a long-term strategy to eradicate HIV. A HIV cure has only been achieved in rare and high-profile cases with stem cell transplants which require extensive medical expertise and are prohibitively expensive for a global cure.
The widespread coverage of ART means that HIV-1 cases (the most prevalent HIV type globally) are stable or declining in higher income countries. However, it remains endemic in many middle- and lower-income countries. As a result, there are approximately 40 million people with HIV today with Africa accounting for approximately 66% of cases. Moreover, there are persistent issues with stigma and access to healthcare systems in many countries.
Why isn’t there a there a HIV-1 cure?
HIV integrates into the genome of the host CD4 T cells, important cells for the immune system, becoming a provirus. Once integrated, the proviral genes are expressed by the host cell to create more viruses which spread to other cells. ART stops new viruses from infecting and integrating into other cells and allows the immune system to target the cells that make new viruses.
However, a minority of proviruses can hide from the immune system by not creating any viral proteins. When someone with HIV stops ART, these latent proviruses can immediately resume making new viruses and depleting the CD4 T cell count. Due to being part of the genome, the integrated HIV-1 is replicated during cell division, and so cells with these latent proviruses persist. There is no way to identify cells with latent proviruses. Therefore the only solution is lifelong ART.
Because proviruses are part of the human genome they are regulated by the same mechanisms as other human genes. The human genome has packaging proteins called histones which help DNA compact into the nucleus and control which genes are expressed. Histones have a complex system of chemical modifications which determine if a gene is open and expressed or closed and not expressed.
This thesis will explore how different histone modifications and the immune system affects HIV gene expression. It particularly focuses on the histone citrullination mark. We find that histone citrullination increases HIV transcription by interfering with host’s mechanisms that repress HIV proviruses.
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