HIV-1, the most common strain of HIV, affects more than 35 million people worldwide. It can be effectively controlled with modern antiretroviral therapy (ART), but these drugs only suppress the virus by preventing it from replicating — they do not cure infection.
Finding a cure for HIV infection that would allow people to come off antiviral medication forever, known as a “functional cure,” represents a major objective of current research efforts worldwide.
Retroviruses such as HIV enter cells and place their genetic code into human chromosomes. This creates viral “reservoirs” in cells throughout the body that persist indefinitely.
Since these reservoirs are not impacted by ART, they normally serve as sanctuaries from which new viruses can emerge if a patient does not take medication to keep them in check. For people with HIV, stopping ART leads to rapid viral rebound, as viruses integrated in the human DNA can start making new copies of the virus and restart the infection.
Elite controllers, however, are a small subset of HIV+ individuals who are able to control the virus without medication, remaining healthy and keeping viral loads below detectable limits. These individuals, which make up less than 0.5% of people with HIV, serve as a model for a functional cure of HIV. Studying these patients may be the best way to unravel the mysteries that allow for natural control of HIV-1.
Ragon Institute of MGH, MIT and Harvard
Mass General Research Institute
Associate Professor of Medicine
Harvard Medical School
Co-author
Bruce Walker, MD
Director
Ragon Institute of MGH, MIT and Harvard[/ultimate_heading]
Xu Yu, MD, and her research group from the Ragon Institute of MGH, MIT and Harvard recently published a groundbreaking study in Nature in which they used cutting-edge sequencing technologies to precisely map the location of individual viruses in the chromosomes of cells from elite controllers.
The study shows a striking finding: In elite controllers, HIV is effectively contained within an inactive section of human chromosomal DNA that researchers call “gene deserts,” where the virus cannot replicate.
What Happens When HIV is Stranded in a Gene Desert
Human genomes are full of genes that are essentially instructions cells use to create essential products such as proteins. These proteins go on to drive numerous functions throughout the body.
Gene deserts, on the other hand, are areas of the genome that do not code for proteins.
In these inactive parts of the human genome, HIV-1 cannot be effectively expressed. This means that despite being integrated into the human genome, viral genomes remain locked in a silent state where they are incapable of causing disease.
This positioning of viral genomes in elite controllers, Dr. Yu says, is in marked contrast to what is seen in the vast majority of HIV infected persons who must control HIV with medication. In these patients, HIV is located in active human genes where new viruses can be readily produced.
What This Could Mean Moving Forward
When the authors collected hundreds of millions of cells from the elite controllers and infected them with HIV in the lab, they saw that the unlike what happens in the body, the viral genome embedded itself within an active section of the human genome, as opposed to a gene desert. This suggests the immune cells of elite controllers play a key role in keeping the viral genome in a dormant state.
The findings are groundbreaking because they suggest it may not necessary to completely eliminate all HIV in the human genome to cure HIV. This provides a much-needed path forward for inducing a functional cure in persons currently requiring ART.
“Ultimately, it may be sufficient to eliminate the viruses that sit in parts of the human chromosomes where they can be effectively expressed,” Yu explains. The remaining viruses that are located in non-active parts of the human genome could simply persist forever, as they don’t seem to cause any disease.”
Dr. Yu’s group also identified one elite controller in whom no intact HIV was found at all — after analyzing more than 1.5 billion cells. This raises the possibility that eliminating all HIV from the body — something that’s referred to as a “sterilizing cure” may also be possible.
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