Scientists have identified a new way to reactivate latent HIV, which could help overcome one of the biggest obstacles to finding a cure for the deadly virus. Researchers at the Gladstone Institutes found that increasing the random activity, or noise, associated with HIV gene expression – without increasing the average level of gene expression – can reactivate latent HIV.
When HIV infects an immune cell, it inserts its genetic material into the DNA of the infected cell. In most cases, the immune cell’s machinery makes copies of the viral genetic material, a process known as transcription. This eventually leads to the production – or expression – of all the components needed to make more viruses. The new viruses are released from the infected cell and spread the infection to other immune cells in the body. In some cases, however, HIV expression goes into a holding pattern and the virus enters a latent state within the infected immune cell. This means that a small percentage of HIV hides in infected cells, beyond the reach of even the most potent drugs.
So we cannot completely eliminate HIV from the body, and people with HIV infection have to take antiretroviral drugs (ARVs) for the rest of their lives, researchers said.
‘Understanding how to reactivate latent HIV is one of the major challenges we must overcome in order to find a cure for HIV,’ said Leor Weinberger, senior author of the study. One of the properties of latency that makes it so difficult to address is that it is random 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. 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.
First, they screened a library of 1,600 compounds using a specialised 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 per cent of them could synergise with activators