June 2025
Media coverage:
Breakthrough in search for HIV cure leaves researchers ‘overwhelmed’ – Kat Lay, The Guardian, June 5, 2025
Major breakthrough in battle for HIV cure ‘previously thought impossible’ – Athena Stavrou, Independent, June 5, 2025
Used in Covid Shots, mRNA May Help Rid the Body of H.I.V. – Apoorva Mandavilli, New York Times, June 5, 2025
Original source(s):
Scientific journal article: Efficient mRNA delivery to resting T cells to reverse HIV latency – Nature Communications, May 29, 2025
Press Release: World-first discovery harnesses mRNA in the search for an HIV cure – Doherty Institute, June 6, 2025 (sent to journalists prior to publication online)
TAG’s commentary:
A paper published on May 29th in the journal Nature Communications became subject to a delayed barrage of mainstream media hype on June 5th. Multiple headlines parroted a press release issued by the Doherty Institute, describing the findings as a “breakthrough” or “major breakthrough” for HIV research.
While the work is encouraging and represents progress, these claims are misleading and exaggerated. Arguably the work represents a breakthrough for efficiently delivering mRNA into a particular type of CD4 T cell, but the implications for the search for an HIV cure are speculative and considerably less clear. The Doherty Institute release does try to provide this context by including cautious commentary by advocate Heather Ellis from Positive Women Victoria, regrettably though none of the media stories chose to quote Heather’s perspective.
An overarching caveat (emphasized appropriately by Apoorva Mandavilli’s accurate piece in the New York Times) is that the results are only from laboratory experiments, not studies in animals or people. Science journalists and editors should know better than to overstate the implications of this type of preclinical research (even if they receive a press release that does so).
The key finding from the research is that mRNA has the potential to be used as a platform to target the reservoir of HIV-infected cells that persists in people on antiretroviral therapy (ART). These cells represent a barrier to achieving a cure because HIV persists inside them partly in a state of dormancy (referred to as latency), hidden from the immune system, and the virus remerges if ART is interrupted — even after decades.
In the laboratory experiments described in the new paper, Dr. Paula Cevaal and colleagues show that mRNA can be designed to deliver a viral protein, Tat, into HIV-infected T cells and this can wake up latent HIV and potentially make the cell vulnerable to recognition and elimination by the immune system.
The uptake of low doses of the Tat-carrying mRNA into T cells was unusually efficient in a lab dish, reaching “up to 76%” of cells without causing immune activation or other untoward effects, leading to the hope that the technique might be able to affect a substantial portion of the HIV reservoir if it can eventually be tested in people.
The term for this strategy in HIV cure research is “latency reversal,” and it’s been pursued for many years with little evidence of success. This failure has largely been attributed to initial attempts in clinical trials (most commonly using a class of cancer drugs called HDAC inhibitors) not reaching a large enough proportion of the HIV reservoir. However, another important factor is the capacity of the immune system in people with HIV to effectively recognize and destroy virus-infected cells made visible by interventions — additional immune-based therapies are believed to be needed to promote clearance of virus-infected cells, even if latency reversal is achieved.
At the current time, the effects of successfully activating a majority — or even all — of the latent HIV in the body are unknown. According to the media reports, the next step for Dr. Cevaal and colleagues is testing in animal models.
There are several additional issues to bear in mind related to this work:
- Researchers originally assumed that essentially all HIV in the reservoir of infected cells that persists on ART was dormant. In recent years, it’s become evident that the virus can be intermittently or persistently activated in reservoir cells, leading to the generation of viral proteins and particles that are prevented from spreading by the presence of ART. In other words, natural HIV latency reversal occurs frequently in people on ART, without leading to substantial declines in the size of the viral reservoir (declines in the amount of intact HIV can become apparent over long periods of time in some cases). An implication of these findings is that promoting immune-mediated clearance of HIV-infected cells is as at least as important as reversing HIV latency.
- The delivery of Tat protein via mRNA has been tried before, which goes unmentioned in the current media coverage. A paper reporting evidence of HIV latency reversal by mRNA-transported Tat was published by Ellen Van Gulck and colleagues in October 2023 and the laboratory of David Margolis also published a report last year. Notably, the level of HIV latency reversal in these papers was far lower and less consistent, and it wasn’t possible to directly measure the efficiency with which the mRNA entered cells.
- In several of the media articles, Dr. Cevaal states that getting mRNA into T cells was “previously thought impossible” (in at least one case, this claim is included in a headline). The scientific literature appears to indicate otherwise: in addition to the studies mentioned above, a 2021 paper reports on a different and more cumbersome approach to facilitating mRNA entry into CD4 T cells, stating that uptake was observed in 80% of cells in the laboratory.
To be fair to the researchers involved and the Doherty Institute, it appears that part of the motivation for the coverage of these results is a desire to counter irrational fearmongering about mRNA and emphasize its value as a delivery platform. As Dr. Sharon Lewin states in the New York Times: “The fear right now is not rational…mRNA vaccines have been given to millions of people around the world, so we have a very good understanding of their risks.”
This is particularly important because the irrational fearmongering about mRNA currently extends to the US political party in charge of the executive branch and Congress, along with their appointed Secretary for Health and Human Services Robert F. Kennedy (a vaccine denialist and AIDS denialist). Amidst their broader ignorant and vicious assault on scientific research, grants to study mRNA have been specifically singled out for termination based on specious claims and conspiracy theories.
These misguided decisions must be opposed — mRNA has unique advantages as a delivery platform that deserve thorough evaluation. There’s nothing outlandish or frightening about messenger RNA, it’s ubiquitous in humans and all forms of life.
TAG will continue to follow this line of research in HIV, and if clinical trials are ultimately able to proceed they’ll be included in our online listing.