Scientists from KU Leuven present a new therapeutic approach that may make it possible for HIV patients to (temporarily) stop their medication. The findings shed a completely new light on the search for a cure for HIV.
Existing antiviral inhibitors can suppress the replication of the HIV virus, but they cannot fully remove it from the human body. As a result, HIV patients have to take inhibitors for the rest of their lives. HIV researchers worldwide are currently developing new methods to eliminate the virus.
The HIV virus uses the cellular protein LEDGF as a kind of grappling-hook to attach itself to specific locations in our genetic material. Once its DNA is inside the cells of its human host, the virus can multiply and make the patient sick.
In 2010, the research team of KU Leuven Professor Zeger Debyser developed inhibitors – called LEDGINs – that block the ‘grappling-hook’. As a result, the virus cannot attach itself to its preferred locations in our DNA.
Doctoral student Lenard Vranckx has now discovered that, when treated with LEDGINs, the HIV virus settles elsewhere in our DNA, in locations where it cannot multiply. Lenard Vranckx explains: “We’ve shown that a treatment with LEDGINs not only inhibits the integration of the HIV virus, but also ensures that the virus doesn’t multiply once the treatment is stopped.”
“This discovery paves the way for new clinical studies with LEDGINs,” Professor Debyser continues. “We don’t know whether this approach will lead to a final cure for HIV, but even a scenario that allows patients to stop their medication for a while is an important step in the right direction.”
However, the researchers remain cautious: “We don’t want to give anyone false hope. Our discovery is based on cell cultures. The findings still need to be tested in mice and in clinical studies. That’s why a potential treatment based on the discovery is still years in the future,” says Professor Debyser. “But now, we already know the direction of our future research.”
Abstract of the study:
Persistence of latent, replication-competent Human Immunodeficiency Virus type 1 (HIV-1) provirus is the main impediment towards a cure for HIV/AIDS (Acquired Immune Deficiency Syndrome). Therefore, different therapeutic strategies to eliminate the viral reservoirs are currently being explored. We here propose a novel strategy to reduce the replicating HIV reservoir during primary HIV infection by means of drug-induced retargeting of HIV integration. A novel class of integration inhibitors, referred to as LEDGINs, inhibit the interaction between HIV integrase and the LEDGF/p75 host cofactor, the main determinant of lentiviral integration site selection. We show for the first time that LEDGF/p75 depletion hampers HIV-1 reactivation in cell culture. Next we demonstrate that LEDGINs relocate and retarget HIV integration resulting in a HIV reservoir that is refractory to reactivation by different latency-reversing agents. Taken together, these results support the potential of integrase inhibitors that modulate integration site targeting to reduce the likeliness of viral rebound.
Highlights of the study:
- LEDGF/p75 depletion hampers HIV reactivation in cell culture.
- LEDGINs relocate and retarget authentic HIV integration.
- LEDGIN treatment results in quiescent residual HIV provirus which is less susceptible to reactivation.
- LEDGIN treatment during primary HIV infection may lead to an HIV remission.
Different strategies to cure HIV infection are being explored. Although complete eradication of the HIV provirus is the ultimate goal, disease remission allowing treatment interruption without viral rebound would constitute a significant leap forward. HIV integration site selection is orchestrated by LEDGF/p75. The advent of LEDGINs, that block the interaction between integrase and LEDGF/p75, allowed us to examine the hypothesis that interference with HIV integration site selection would yield integration sites that are less optimal for productive infection. Here we provide evidence in cell culture that LEDGIN treatment during acute HIV infection yields an HIV reservoir refractory to reactivation.
Categories: Breaking News, Leadership in Medicine
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