By Bridget Fisher and Dr Michael Moso
Latent HIV that remains ‘silent’ in CD4 T cells is a major barrier to an HIV cure. In this dormant form, HIV is invisible to the immune system but can reactivate if antiretroviral therapy is interrupted. Researchers are exploring a “shock and kill” approach to get rid of latent HIV. This involves reversing latent HIV to make it visible to the immune system so that it can be effectively cleared.
A promising new “shock and kill” strategy published by researchers at the University of Melbourne this month uses messenger RNA (mRNA) and lipid nanoparticles to deliver therapies that can safely and effectively reverse latent HIV in CD4 T cells.
Understanding mRNA and lipid nanoparticles
mRNA and lipid nanoparticles became better known through their role in COVID-19 vaccines. mRNA acts as a set of instructions for cells to make proteins. In therapeutic applications, mRNA can instruct cells to produce proteins with specific biological functions. However, mRNA is unstable and is rapidly degraded in the body. To protect it and enhance its delivery, scientists have used lipid nanoparticles: microscopic, fat-like particles that surround the mRNA, shielding it from degradation and helping its entry into cells.
In an HIV-focused application, researchers at the University of Melbourne have developed lipid nanoparticles that can enhance delivery of mRNA to CD4 T cells. This represents a significant advancement, as efficient delivery to CD4 T cells has been a major hurdle in advancing mRNA therapies for HIV cure.
Delivering tools to reverse latent virus
Using this delivery platform, scientists have introduced mRNA molecules that encode two key proteins designed to reverse latent HIV:
- Tat, a part of HIV that encourages HIV replication during infection. Delivering mRNA encoding Tat can reactivate the virus in latently infected cells.
- CRISPR activation, a system that targets HIV in the genome and switches it on, reactivating viral expression without altering the human genetic code.
When delivered into CD4 T cells using the novel lipid nanoparticles in the laboratory, these mRNA-encoded tools can reliably reverse latent HIV. Importantly, this method did not show toxic effects on the host cells, a crucial requirement for any potential cure strategy.
Implications for cure research
This approach represents the next generation of “shock and kill” HIV cure therapies using mRNA and lipid nanoparticle technology. Work in the laboratory is ongoing to make sure the strategy is safe and effective before proceeding to human clinical trials.
The work described above was conducted on CD4 T cells from blood donated by people living with HIV. The researchers extend their sincere gratitude to the generous donors.
Read the full paper
Efficient mRNA delivery to resting T cells to reverse HIV latency
