A new class of drugs could sharpen the body’s immune response to HIV

A new class of drugs called CD4 mimetics could be used to sensitise the immune system to HIV, the 26th International AIDS Conference (AIDS 2026) in Rio de Janeiro heard last week.

It is becoming clear that broadly neutralising antibodies, whether infused as a drug or generated by a vaccine, may not be sufficient to cure HIV, or even to lead to long-term remission off antiretroviral therapy.

Studies of the immune response to HIV in people who have managed to stay off antiretroviral therapy (ART) for prolonged periods without developing significant viral loads have found that their CD8 cells, which are the prime movers in the destruction of virally-infected cells, had preserved their ability to proliferate and respond afresh to new waves of HIV replication. The researchers called this capacity “stemness” because the cells preserved some characteristics of newly-produced stem cells – they were able to combat new waves in infection instead of becoming exhausted.

In other viral diseases like flu or COVID, this ‘autogenic’ (self-generated) immune response is sufficient in most cases to eventually clear infected cells from the system. Antibodies are generated that attach themselves to the viral proteins that infected cells display on their surfaces, as a ‘distress signal’.

Such antibodies can ‘neutralise’ infected cells by acting as a barrier. They can also stimulate the immune system’s natural killer (NK) cells to destroy infected cells with cell-dissolving enzymes, in a process called antibody-dependent cellular cytotoxicity (ADCC), or they may invite the large white blood cells called macrophages and monocytes to engulf them – this is called antibody-dependent cellular phagocytosis (ADCP).

However Étienne Bélanger of the University of Montréal told AIDS 2026 that HIV has a mechanism to hide the giveaway distress-signal proteins displayed by infected cells, which in its case consist of the Env protein, the spikes used by HIV to initiate infection of cells.

This lack of a signal is why autogenic antibodies generally fail to neutralise HIV-infected cells, and why cure and vaccine scientists have mainly concentrated on ‘allogeneic’ or ‘other-generated’ immune medications such as broadly-neutralising antibodies (bnAbs).

HIV’s genome contains two small genes called nef and vpu which ‘downregulate’ the CD4 receptor that HIV attaches itself to, and distinguishes the kind of cells it infects. This means that the CD4 molecules disappear from the cell surface.

This also renders the Env proteins that remain on the cell surface invisible to circulating antibodies. The Env protein is a trimer – it consists of three similar components that normally stay in a folded conformation (see illustration here), like a flower bud. It is only when the three ‘petals’ open, which in the case of infection only happens for seconds after the virus attaches to the CD4 receptor protein, that antibodies recognise, and can be generated against, the vital, ‘conserved’ components of the viral infection machinery.

Bélanger’s team, however, have developed a family of small-molecule compounds that mimic CD4. They attach themselves to the Env trimers and force them into the open conformation. They already knew this had helped to stimulate ADCC responses but wanted to know if they stimulated ADCP ones too.

Firstly, they developed genetically-engineered HIV viruses that lacked nef, vpu or both. They confirmed that about ten times as much antibody bound itself to cells infected with virus deficient in both genes, and which therefore displayed CD4 and opened up the Env proteins on their surfaces.

Then they stained monocyte cells so that they could detect HIV’s vital p24 capsid protein inside them, to see if they had swallowed HIV infected CD4 cells. They found that cells containing virus that lacked nef and vpu were 2.3 times more likely to be swallowed up by the monocytes.

Vpu deletion by itself had a stronger effect than nef deletion, as vpu deletion also increases the expression of another cell-surface molecule, BST-2 (also called tetherin). This prevents viruses from budding out from cells, and increases the amount of Env protein on cell surfaces.

They found similar results when, instead of using nef and vpu-deleted virus, they instead used a CD4 mimetic drug called CJF-III-288. This significantly increased both antibody binding and ADCP activity.

CJF-III-288 is one of a family of recently-discovered CD4 mimetics. It is a fairly small molecule, about the same size as lenacapavir, thoughat the moment is quite hard to synthesise.

Significant results were also obtained when instead of using stock cells, they used CD4 and monocytes taken from five people with HIV and individually cultivated ‘ex vivo’ in the lab dish, though the increase in ADCP responses was very variable, from a non-significant increase in one of the five to a more than 100% increase in others.

Using CJF-III-288 alone did not increase ADCP activity by as much as deleting the nef and vpu genes.

But Bélanger then added in interferon-beta. This is a cytokine (immune signalling chemical) that raises BST-2 levels, the opposite of what vpu does. This means more Env builds up on the cell surface more than doubling antibody recognition of infected cells and increasing ADCP activity by a further 33%.

Bélanger’s results indicate that they may have found a useful accessory drug to improve the chances of an HIV cure that would also probably need to employ bnAbs and antibody- and CD8-generating vaccines, but they are a first step towards inducing an immune response to HIV that is as effective as it is to other viruses.

Bélanger and colleagues commented, in a paper released at the same time as his presentation: “These results support that inducing BST-2 expression with interferon-beta can lead to the accumulation of Env at the cell surface, thereby increasing the recognition and ADCP-mediated killing of infected cells in the presence of CJF-III-288.”