Hidden, but not forgotten: Understanding HIV hiding in the brain

Antiretroviral treatment (ART) has significant benefits for the health and quality of life of people with HIV. Despite this, a scalable effective cure remains a difficult challenge.

We already know that HIV can hide in blood and tissue cells throughout the body. This virus can stay in a dormant state, capable of reactivation. This latent virus is a major barrier to cure since it can rebound if the pressure of ART is removed. In addition to being a barrier to cure, persistent HIV in the brain causes an increased risk of brain disorders. More than 40% of people with HIV experience HIV-associated neurocognitive disorders. HIV is known to hide in CD4+ T cells in the blood and tissue – it can be found in the lymph nodes, spleen and gastrointestinal tract. However, a range of studies have found HIV-infected cells in other tissue sites including the brain. Until recently, it was unclear whether HIV could persist in the brain. Additional questions include how much virus is found in the brain, and whether it is capable of replication.

Defective HIV genomes: not all HIV is the same

Scientists have long known that HIV is a virus prone to mutation. The resulting virus variation is the major reason for using multiple antiretroviral drugs in HIV therapy. Specifically, mutated viruses can contain large deletions and other mutations in their genetic material. These changes can render the virus unable to replicate. In fact, studies in the blood have shown that >90% of HIV viruses in the body cannot replicate. Studies on tissues including the brain have shown less clear results.

The brain contains both intact (functional) and deleted (defective) HIV genomes

A team of scientists from RMIT and the Peter Doherty Institute for Infection and Immunity have recently demonstrated in the Annals of Neurology that the brain of people with HIV and on ART contains intact HIV viral genomes, potentially capable of replication. They have also shown that, like the blood, the brain also contains a high number of non-functional genomes.

Using a clever assay developed to detect defective or functional HIV genomes in the blood, they found intact HIV genomes in most brain material from the National NeuroAIDS Tissue Consortium (USA). They also found that brain resident myeloid cells (a subset of immune cells) contained HIV DNA. A surprising finding was that HIV levels in the brain were similar regardless of whether people were on ART or not.

What is the impact of HIV in the brain?

Taken together, this data demonstrates the presence of intact, potentially replication competent HIV in the brains of people with HIV on treatment. These findings are important for two reasons. Firstly, the presence of an intact HIV reservoir capable of making HIV proteins may be relevant to the ongoing neurocognitive impairment seen in people with HIV on ART. Secondly, this intact pool of HIV viruses in the brain may be a potential source of replication competent virus that leads to viral rebound in the absence of ART. Thus, future HIV cure studies need to address the brain reservoir.

Publication link: https://doi.org/10.1002/ana.26456

Twitter: @Neuroinfections

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