Abstract

According to WHO, over 40 million people live with HIV globally. While antiretroviral therapy (ART) can suppress the virus in the blood, it cannot eliminate the hidden HIV reservoir—cells that carry silent, yet infectious, HIV. These latent cells survive deep in tissues and when patients stop taking ART (either in a clinical trial or due to non-compliance), hidden HIV in them quickly returns, forcing patients to take ART for life. That is why the hidden HIV reservoir is the main barrier to an HIV cure.

This project focused on facilitating the clearance of these hidden cells. Studies found that latently infected cells often resist normal cell death signals, making them hard to eliminate. To overcome this, special compounds called SMAC mimetics and BH3 mimetics were used to re-sensitize infected cells to cell death. This was tested in a pre-clinical model with a human-like immune system. One of the compounds tested, Xevinapant, can induce cell death by removing a protein called cIAP1 that promotes survival.

Because stopping ART is known to cause HIV to return quickly, Xevinapant was tested for its ability to delay HIV return. Indeed, Xevinapant delayed the return of HIV after ART was stopped. This result suggests this drug may help shrink the HIV reservoir by inducing cell death in infected cells in a controlled way.

This research offers a new direction for HIV cure research: by helping hidden infected cells die in a controlled manner. Combining these drugs with other therapies could make a real impact on HIV infection.