Researchers have identified a new way to make latent HIV reveal itself, which could help overcome one of the biggest obstacles to finding a cure for HIV infection.
Leor Weinberger, PhD, Associate Investigator in the Gladstone Institute of Virology and Immunology and senior author of the study, said understanding how to reactivate latent HIV is one of the major challenges we must overcome in order to find a cure for HIV.
One of the properties of latency that makes it so difficult to address is that it is random-or stochastic-in nature. Random fluctuations in transcription are unavoidable and a general aspect of life at the single-cell level and lead to "noise" around the average level of gene expression.
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.
The findings have been ere published in the journal Science.
