HIV: Lock it up and throw away the key

The research consortium, “Hope” for HIV Obstruction by Programd Epigenetics aims both to ‘muzzle’ and to eradicate latent HIV once and for all with “a fundamentally different approach from anything that has hitherto been attempted,” says lead author Dr Melanie Ott, director of the Gladstone Institute of Virology, and program director and principal investigator of the HOPE Collaboratory.

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Finding the best but definitive cure for people living with HIV

Targeting latent HIV in innovative ways: the virus is indeed known for its ability to hide in a latent state in immune cells. Although latent viruses do not cause overt symptoms or AIDS, they can cause long-term health complications for people living with HIV and cannot be targeted with standard antiretroviral therapy. Interruption of daily therapy may cause the infection to rebound rapidly.

Most treatment attempts have so far focused on deliberately reactivating the latent virus in order to eliminate it through antiretroviral therapy. But, with these strategies, there are always unreactivated copies that escape treatment, except to induce, with a very powerful ART (antiretroviral treatment), serious undesirable side effects. And even a small remaining reservoir of latent virus implies continued daily treatment.

block-lock-excise : the new approach targets latent HIV, without reactivating it. The researchers are inspired here by the strategy of “old” viruses that have integrated into the human genome over millions of years of evolution. HIV also integrates into the genome of a person living with HIV. However, unlike HIV, these ancient viruses either remain silent or are defective. The researchers therefore focused on this mechanism and discovered that these old inactive viruses were missing several genetic elements that are very present, on the contrary, in HIV:

1. a DNA sequence present at the beginning of the genetic code of HIV,
2. a protein called Tat, necessary for reactivation and replication, here latent HIV.

Blocking Tat, in particular, with small molecules – or future drugs – allows HIV to be locked in its dormant phase, and this blocking then persists for a certain time, even if ART is interrupted. This approach thus pushes HIV to become like one of these ancient viruses. In addition, scientists are working to modify the structure of the genetic material of HIV, in order to make it harder for other proteins to access and activate HIV genes.

a dual strategy, therefore, which locks HIV into a state of dormancy and then “throws the key” away

and thus keep it locked up forever. Then, it becomes possible to stop the antiretroviral treatment without reappearance of the virus.

Genome editing opens new doors because the technique could make it possible to modify the latent HIV inserted in the DNA of immune cells. “To the point that the virus would be destroyed.”

This collaborative approach, the HOPE Collaboratory, which brings together scientists from 12 institutes, is one of 10 to be supported by a 5-year grant under the Martin Delaney Collaboratories program, America’s flagship HIV research program.

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