April 20, 2024

Understanding the Mechanisms of HIV in Preclinical Research

A groundbreaking study conducted by researchers at Mayo Clinic has shed light on the molecular mechanisms that determine which cells infected with human immunodeficiency virus (HIV) survive and which ones die. This discovery is a significant step forward in the quest to eliminate all HIV-infected cells from the body.

The current approaches to treating HIV infections involve either blocking HIV proteins to prevent cell replication or preventing HIV from reaching cells. However, these treatments do not reduce the number of cells in the body that harbor the virus. Known as the HIV reservoir, these cells are resistant to current therapies.

The Mayo Clinic research takes a different approach to eliminate HIV-infected cells. The researchers aimed to understand why some of these cells die after acute HIV infection, which would allow them to design medical interventions that induce cell death in the majority of infected cells, explained Dr. Andrew Badley, senior author of the study.

The findings of this extensive research that spanned over a decade have been published in the Journal of Virology. The key to unraveling the mystery of why HIV-infected cells perish or survive lies in understanding how HIV proteins interact with other proteins within the cell. When a cell becomes infected with HIV, it produces a protein called Casp8p41.

In a previous study, the Mayo Clinic research team discovered that Casp8p41 triggers cell death in HIV-infected cells. However, not all infected cells die because Casp8p41 can bind to a human protein called Bcl2, which neutralizes its effect. The team found that if Casp8p41 binds to Bcl2, the infected cells survive. On the other hand, if Casp8p41 does not bind to Bcl2, the infected cell dies, ultimately reducing the number of HIV-infected cells.

According to Dr. Badley, the determining factor for whether a cell lives or dies is the levels of these two proteins within the cell. Building on this discovery, the researchers explored whether inhibiting Bcl2 could eliminate HIV-infected cells in mouse models by preventing its binding to Casp8p41. Bcl2 inhibitors have shown promise in treating blood cancers with similar properties.

The study demonstrated that the Bcl2 inhibitor has the potential to kill infected cells, including dormant cells that harbor the virus, thereby reducing the HIV reservoir. What sets this research apart is that the Mayo Clinic team was one of the first, if not the first, to translate this study into mouse models implanted with human immune systems and infected with HIV. The researchers compared the effects of the Bcl2 inhibitor in these mice to a control group without the inhibitor.

HIV causes acquired immunodeficiency syndrome (AIDS), a chronic and potentially life-threatening condition that weakens the immune system by destroying immune system cells. While antiretroviral therapy is effective in suppressing HIV replication, it does not eliminate infected cells or reduce the size of the HIV reservoir, which can become active at any time, leading to HIV resurgence.

The data from this study confirm the significant anti-HIV effects of the Bcl2 inhibitor during HIV infection in humanized mice models. Dr. Badley expressed hope that this research will contribute to the development of a cure for HIV.

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