Method by which HIV-1 harvests a product of our cells to infect us is uncovered by research led by MRC LMB in Cambridge

An extraordinary finding about the HIV-1 virus could lead to the design of new small molecules to prevent infection.

An international collaboration led by scientists at the MRC Laboratory of Molecular Biology (LMB) in Cambridge has uncovered precisely how the virus harvests a metabolite from our cells in order to infect us.

Disabling the mechanism, they have confirmed, renders HIV-1 non-infectious.

HIV-1 is the most common type of the pandemic virus, affecting about 95 per cent of people with HIV and infecting between one and two million people a year. It is genetically distinct from HIV-2, which is less transmissible.

HIV attacks the immune system and, if not treated, can lead to AIDS. If diagnosed in time, and with proper treatment, patients with HIV can now live long and healthy lives.

In 2021, there were 38.4 million people living with HIV, and about 650,000 died from AIDS-related illnesses, according to UNAIDS.

HIV-1 evades detection by our immune system by cloaking itself in a protective shell, known as a capsid.

Leo James’ group in the LMB’s PNAC Division led the collaboration that explored how HIV-1 builds its capsid using a metabolite – a substance produced during metabolism – called IP6 (inositol hexakisphosphate), which is captured by the virus using a net-like protein lattice.

Work in 2018 by the group, in collaboration with researchers at the University of New South Wales (UNSW) in Australia and the MRC Laboratory for Molecular Cell Biology (LMCB) in London, identified IP6 as being the potential key to the stability of HIV-1.

The virus replicates inside infected cells to produce thousands of new viruses, which assemble and bud from the cell surface.

A protein called ‘gag’ forms a hexameric lattice during this process, which coats the inside of each virus.

The latest work shows that this lattice creates hundreds of highly-charged pockets that HIV-1 uses to harvest the metabolite IP6 from the cell. Using a method developed with Adolfo Saiardi at the LMCB, the LMB’s Donna Mallery counted the IP6 molecules inside different HIV-1 viruses. She found that mutants without lattice pockets did not have the metabolite.

Then, using electron tomography to investigate the consequences of this, the LMB’s Nadine Renner discovered that IP6-deficient HIV-1 viruses fail to form a capsid properly.

Using TIRF (total internal reflection fluorescence) microscopy, the LMB’s Anna Albecka and Till Boecking’s lab at UNSW showed that even when IP6-deficient viruses manage to form a capsid, they are highly unstable and collapse within seconds.

The work shows that the inability to capture IP6 and form stable capsids has catastrophic consequences for HIV-1.

And infection experiments carried out at the LMB, and by Alex Kleinpeter in Eric Freed’s lab at the National Institutes of Health (NIH), showed that viruses unable to harvest IP6 or produced in cells missing key IP6 biosynthetic enzymes are almost entirely non-infectious.

It means the ability of HIV-1 to infect people is dependent upon a small metabolite produced inside our own cells.

Leo told the Cambridge Independent that the work continues.

“While we now know that HIV-1 needs the metabolite IP6 for its capsid, we don’t know why. This is what we are investigating next,” he said.

“HIV-1 may need IP6, which is highly negatively charged, because its capsid has positively-charged holes. We think these holes are used to bring into the capsid the material HIV-1 needs to make DNA.

“Whether other viruses need IP6 remains to be explored but it may be a particular feature of retroviruses, a family of viruses including HIV-1 that have to copy their genomes from RNA into DNA.”

Understanding the mechanism HIV-1 uses to obtain IP6 could lead to the design of small molecules that could prevent IP6 incorporation, preventing the virus infecting a person.

Leo explained: “It may be possible to develop drugs that prevent HIV-1 from stealing IP6. One way to do this could be by modifying existing small molecules called ‘maturation inhibitors’ so that they get in the way of the process. Without IP6, HIV-1 would be unable to build a capsid and infect cells. If they could be developed, it is conceivable that such antivirals could be used in PrEP (pre-exposure prophylaxis) or in ongoing therapy. But like other antivirals they could not by themselves cure HIV-1.”

The research, published in Nature Structural and Molecular Biology was funded by UKRI MRC, the Wellcome Trust, the NIH and the NHMRC.