Locking in HIV – can silencing lead to cure?
During primary infection, HIV naturally establishes latency in specialised immune cells, mainly CD4 T cells. A research group led by Professor Anthony Kelleher and Dr Chantelle Ahlenstiel from the Kirby Institute in Sydney is developing a gene therapy approach to stop HIV replication. The group has identified several new RNA molecules that block HIV replication. The blocking happens through a process called transcriptional gene silencing. The silencing process causes DNA compaction, creating a DNA structure that is very similar to the natural latent HIV state. This process squeezes the HIV DNA into a tightly condensed form. In this form, proteins which the virus needs for activation are locked out and unable to access the HIV DNA. The virus is then pushed into a permanent state of latency. This could lead to remission where an HIV positive person can stop ART without the virus rebounding.
What are the researchers going to do?
The group has already published several studies in laboratory models (see here and here). The early studies showed that the RNA molecules can strongly suppress HIV in different human cell models. The researchers are now starting studies in humanised mouse models of chronic HIV. The researchers will inject human immune cells carrying the RNA molecules into mice and then infect the mice with HIV. They are also planning experiments that will mimic the gene therapy strategy in HIV patients on ART. These experiments will involve injecting human immune cells with the synthetic RNA molecules into mice, infecting the mice with HIV and also treating the mice with ART to control the virus. The important test will be to stop ART and see whether the RNA sequences can keep the HIV DNA in a permanent latent state. The researchers expect results from these studies later this year which could lead to human clinical trials to test a permanent, functional cure.
Professor Kelleher states
‘We are really excited to be investigating this new strategy that could provide an alternative way of controlling HIV infection. Rather than trying to get rid of the virus, we are looking at a method for locking in and disabling the virus. This would ultimately have a similar effect for people living with HIV, meaning that they could stop ART without virus rebound’.
Watch this space. We will report progress on this work later in the year.
Below is a T cell line infected with fluorescent HIV-1 (yellow), where the virus DNA has integrated into the host DNA, shown in the nucleus (blue). The short interfering (si)RNA sequence (red fluorescence and arrowhead) is shown entering the nucleus, where it will induce virus silencing through DNA compaction and prevent proteins from activating the virus. The silencing process maintains HIV DNA in a permanent state of latency, effectively achieving sustained virus remission.