HIV virulence varies with DNA integration site

Researchers from KU Leuven have discovered that the site in which HIV inserts itself in its human host determines how quickly the disease progresses. Their study has been published in the journal Cell Host & Microbe.

The HIV protein integrase, which catalyses the process by which viral DNA is inserted in host DNA, can insert this DNA in various locations - but virologists have so far been unable to determine how the virus selects these points. The researchers, from KU Leuven’s Laboratory for Molecular Virology and Gene Therapy, say the answer lies in two amino acids.

“HIV integrase is made up of a chain of more than 200 amino acids folded into a structure,” said doctoral researcher Jonas Demeulemeester, first author of the study. “By modelling this structure, we found two positions in the protein that make direct contact with the DNA of the host. These two amino acids determine the integration site. This is not only the case for HIV but also for related animal-borne viruses.”

The HIV protein integrase (blue) can insert viral DNA (red) at different locations in the DNA of its human host (orange).

In a second phase of the study, the researchers were able to manipulate the integration site choice of HIV. Co-senior author Rik Gijsbers said, “We changed the specific HIV integrase amino acids for those of animal-borne viruses and found that the viral DNA integrated in the host DNA at locations where the animal-borne virus normally would have done so.

“We also showed that HIV integrases can vary. Sometimes different amino acids appeared in the two positions we identified. These variant viruses also integrate into the host DNA at a different site than the normal virus does.”

Finally, the team studied the impact of these viral variants on the progression towards AIDS in a cohort of African HIV patients. Co-senior author Professor Zeger Debyser said the disease “progressed more quickly when the integration site was changed. In other words, the variant viruses broke down the immune system more rapidly.

“This insight both increases our knowledge of the disease and opens new perspectives,” said Professor Debyser. “By retargeting the integration site to a ‘safer’ part of the host DNA, we hope to eventually develop new therapies.”

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