On World AIDS Day, December 1, 2025, a paper was published in the journal Nature presenting the most convincing signal to date that HIV can be kept under long-term control in a portion of patients even without lifelong antiretroviral medication. A team from the University of California, San Francisco (UCSF) conducted a combined immunotherapy trial which, alongside strict monitoring, enabled a planned treatment interruption and long-term low virus levels in 7 out of 10 participants. Although it is a small and single-arm clinical trial (without a control group), the result provides proof of concept that by smartly combining multiple immunological approaches, functional remission can be achieved – a state in which the virus is suppressed, and the person is clinically stable, without daily pills.

From chronic therapy towards drug-free remission

The introduction of combined antiretroviral therapy (ART) in the late 1990s radically changed the course of HIV infection – from almost certain mortality to a chronic, controlled disease. But ART is not a cure. The virus remains hidden in reservoirs – long-lived cells with an integrated viral genome – and typically returns quickly as soon as the person stops taking therapy. Because of this, functional cure (long-term control without drugs) has become one of the most important goals of modern HIV medicine. The latest findings show that a combination of targeted therapeutic vaccination, passive transfer of broadly neutralizing antibodies (bNAbs), and targeted immunostimulation can emphatically reverse the expected dynamics of viral rebound after treatment interruption.

Three pillars of one strategy

The protocol was designed as a coordinated "triple strike" on the virus. The first pillar was a therapeutic vaccine targeting conserved elements of HIV – parts of the viral proteome that change less and are harder to evade T-cell immunity. The vaccination schedule was DNA+IL-12 prime / MVA boost, meaning a DNA platform with interleukin-12 adjuvant was given first for a stronger response, followed by vector boosting with modified vaccinia virus (MVA) to expand and stabilize the repertoire of specific T-cells. The second pillar consisted of two broadly neutralizing antibodies – 10-1074 and VRC07-523LS – with an extended half-life and broad neutralization spectrum, which bind to key target structures on the HIV envelope and reduce the amount of circulating virus. The third pillar was immunostimulation with lefitolimod, a TLR9 agonist, designed to activate innate immunity and "expose" the latent virus to immune surveillance.

Who participated and how the monitoring proceeded

The study included 10 adults with HIV who were virologically suppressed on ART before entry. An important detail: most started treatment very early after infection, which is linked in literature to smaller reservoirs and more preserved T-cell responses. After completing the combined regimen and an additional cycle of bNAbs, participants entered the phase of analytical treatment interruption (ATI). During ATI, monitoring was intensive – with frequent viral load measurements, clinical examinations, and predefined thresholds for immediate reintroduction of ART in case of viremia growth or symptoms. Such supervision reduces risk and enables precise mapping of the temporal and immunological dynamics of viral rebound.

What happened after ART interruption

Without intervention, HIV typically returns in approximately two weeks after stopping medication and quickly reaches high values. Here, the opposite happened: only three participants experienced a rapid and sharp rebound. Six participants had a slow, suppressed rise while maintaining low viremia for months, and in one person rebound was not recorded at all during observation. Crucially, maintaining control could not be explained solely by residual concentrations of passively administered antibodies in the blood – suggesting that endogenous, cellular immunity mechanisms were also activated.

"Cat ready to pounce": what immunological analyses showed

The authors detailedly profiled immune responses and isolated correlates of successful control. Participants-"controllers" had an early and strong expansion of activated CD8+ T-cells as soon as the virus was detected again after ATI. The metaphor of a "cat ready to pounce" – cells "lurking" and waiting for a signal – quite faithfully describes the recorded dynamics. Precisely such a response correlated with lower median viremia after a transient peak, supporting the idea that the combined approach does not keep the virus low only "passively", but also teaches the immune system how to take control when a replication outbreak occurs.

Why combine: synergy of vaccines, bNAbs, and TLR agonists

Individual strategies have given limited results for years: therapeutic vaccines elicited specific T-cells, but often without strong impact on clinical dynamics; bNAbs temporarily reduced viral load, but the virus knew how to "escape"; drugs that "shake" reservoirs did not always lead to rapid clearing of infected cells. Combination solves each of these challenges from a different side: bNAbs reduce the amount of virus and limit spread, the vaccine creates T-cells that recognize conserved targets, and the TLR9 agonist lefitolimod enhances the innate signal and antigen presentation. The result is a coordinated immune response at the moment when it is most needed – immediately upon the appearance of replication after treatment interruption.

Strengths and limitations

The strength of the study is evident in the unexpectedly high proportion of participants with significant, clinically relevant control after ATI, as well as in the depth of laboratory analyses linking cause and effect between the quality of T-cell response and the shape of the viremia rebound curve. However, authors and independent experts clearly emphasize limitations: small sample, lack of a control group, and the fact that participants were mostly treated early (which is not a universal case). The regimen is also logistically complex (multi-component and time-demanding), so simplification without loss of efficacy will be necessary for wider application.

Safety and ethics of analytical treatment interruption

ATI remains the gold standard in cure research, because a validated biomarker that predicts long-term remission without drugs with high reliability does not yet exist. Conducting ATI requires strict protocols, frequent laboratory control, and clearly defined rules for immediate return to ART. Available reviews and guidelines emphasize that ATI under adequate supervision is of acceptable risk and is the only way to indisputably measure the effect of intervention on the time to and shape of viral rebound.

bNAbs: what makes them powerful

Broadly neutralizing antibodies like 10-1074 and VRC07-523LS were created by isolation from rare individuals whose immunity recognizes many HIV variants. Engineering modifications allow a longer stay in circulation, and smart combining of targets on the viral envelope reduces the probability of "escape" emergence. In this regimen, bNAbs were given during virologic suppression, and then again at the moment of treatment interruption, to bridge the early phase after stopping medication and "buy time" for vaccine-boosted T-cells to take control.

Why target "conserved elements" and what is the role of lefitolimod

HIV is an extremely changeable virus; mutation rate and diversity make long-term effective responses difficult. Vaccines focused on conserved sequences target parts of the virus that are key for replication and therefore change less, increasing the chances that T-cells remain useful even against new variants. Lefitolimod (TLR9 agonist) simultaneously activates innate pathways and can "wake up" part of the latent reservoir, making infected cells more visible to adaptive immunity.

Voices from the study: cautious but noticeable shifts

Co-senior author Steven G. Deeks points out that "we are finally seeing real progress towards a therapy that could enable people a healthy life without lifelong medication", while first author Michael J. Peluso emphasizes that this "is not the end game", but shows that a shift can be achieved on a problem often perceived as unsolvable. Statements are consistently accompanied by "hard" laboratory data on early CD8+ T-cell expansion and slowed viral rebound, which further solidifies the conclusion that this is a proof of concept with real potential for simplification and scaling.

Partnerships and funding

The study originated within a multi-year partnership of UCSF and amfAR (The Foundation for AIDS Research) launched in 2015, with support from the National Institutes of Health (NIH) and industry partners. Such a model of a "cure coalition" – where academia, the non-profit sector, and pharmaceutical companies pool resources – enables the construction of complex protocols, supply of high-quality bNAbs, advanced pharmacokinetic and immunological profiling, and ethical and logistical infrastructure for safe ATI implementation.

What December 2, 2025 means: messages for patients, clinicians, and decision makers

For patients, these data bring realistic hope that protocols enabling longer drug-free periods with preserved quality of life will exist in the foreseeable future. To physicians, they signal that the stake of immunotherapy is increasing and that sophisticated interpretation of immunological "signatures" will become an important part of daily practice in centers conducting ATI. To decision makers, they message that investments in cure research are not abstract: measurable shifts with the potential to reduce costs and treatment burden in the long run are being recorded already today.

The bigger picture and global context

It is estimated that about 40 million people live with HIV worldwide. Lifelong dependence on medication requires stable supplies, health infrastructure, financial funds, and high adherence – conditions not equally available everywhere. Strategies achieving drug-free remission – even through cyclical, supervised periods without therapy – could have a huge public health impact, especially in resource-limited settings. This paper fits into a broader trend of intensifying combined immunotherapy research and paves the way towards larger, international studies.

What follows: larger and smarter trials

The authors announce randomized, larger trials that will distinguish the contribution of each component, define the minimal effective "set" of interventions, and identify predictors of response – immunophenotypic and virological markers by which one can pre-select who is most likely to achieve lasting remission. In parallel, the global pipeline includes new immunomodulators and generations of long-acting bNAbs, and part of industry programs is already planning the integration of ATI into design, which will enable more robust comparisons of approaches.

Notes for interpretation (without premature conclusions)

These results do not mean that standard treatment guidelines change on December 2, 2025, nor that a sterilizing cure has been achieved. They mean that, for the first time in a human protocol designed this way, combined immunotherapy stimulated endogenous immunity to keep HIV under control even after stopping medication – for months, and in individual cases even longer. In the next phase, the task is to simplify the regimen, confirm findings in larger samples, and turn this proof of concept into a sustainable, widely applicable strategy that will provide many people with HIV a longer period of life without daily therapy.