New Approach to Reactivate Latent HIV Shows Promise

Scientists at the Gladstone Institutes have discovered a new method of reactivating latent HIV, which could be one of the keys to finding an HIV cure, according to a study published in the journal Science. By increasing the random activity, or noise, associated with HIV gene expression -- without actually increasing the average level of gene expression -- the researchers found that they could reactivate latent HIV hidden within the HIV reservoirs.

"If we can make the virus show itself, we can then use ARVs [antiretrovirals] to eliminate it. This so-called 'shock and kill' approach holds great promise, but to date it has unfortunately shown only limited success," said lead author Roy Dar, Ph.D., in a press release from Gladstone Institutes.

One of the things that makes HIV so elusive is its ability to hijack and embed itself into the DNA of an infected cell, causing the cell to make copies of HIV's genetic material, a process known as transcription. This leads to the production of more virus, also known as expression, which leads to more hijacking of other immune cells in the body.

While today's ARVs are very good at inhibiting HIV from replicating, some virus remains hidden in reservoirs where ARVs can't reach. According to the researchers, one of the reasons this proves difficult is because of the random, or stochastic, nature of HIV latency. Random, unavoidable fluctuations in transcription lead to "noise" around the average level of gene expression; HIV happens to have very noisy gene expression. Because of this noise, previous approaches to reactivating latent HIV have not been so successful.

According to the press release:

In this study, the team tested the counter-intuitive notion that compounds that increase noise in gene expression could work together with transcriptional activators to increase overall levels of HIV reactivation. The concept borrows from other fields of science such as chemistry, where theoretical arguments long ago argued that increased fluctuations can increase the efficiency of reactions.

First, they screened a library of 1,600 compounds using a specialized cell line that produces a green fluorescent protein (GFP) when gene expression is activated. The team identified 85 small molecules that increased noise without changing average GFP gene expression levels. They then combined these newly identified noise enhancers with known transcription activators in a cell line that serves as a model for HIV latency.

They found that while the noise enhancers could not cause reactivation on their own, 75 percent of them could synergize with activators and increase viral reactivation relative to activator alone. In fact, some noise enhancers doubled reactivation levels when combined with activators. Furthermore, they found a direct correlation between noise enhancement and the degree of reactivation synergy; the greater the noise, the greater the effect on reactivation. For the first time, these results show that expression noise and reactivation of latent HIV are directly related, and identify new candidates for the "shock and kill" approach to treating latent HIV infection.

Further research is needed, but these early results are promising. "The implications for using noise also extend far beyond HIV reactivation, since random cellular activity contributes to a wide range of processes, from antibiotic persistence to cancer metastasis. Thus, this approach could represent a new tool for drug discovery across multiple fields," concluded Leor Weinberger, Ph.D., senior author of the study.