In 1981, physicians in Los Angeles reported five young patients with Pneumocystis pneumonia, a rare lung infection later recognized as the first sign of HIV infection and a defining illness of AIDS.

At that time, the clinicians were puzzled. Opportunistic infections typically occur only in individuals with severe immune suppression; however, the cause, HIV, remains unknown.

The disease soon spread globally and became a pandemic until the introduction of zidovudine (azidothymidine), the first effective antiretroviral drug, in 1987.

After more than 40 years of research, HIV infection is viewed as a manageable rather than fatal chronic condition. With combination antiretroviral therapy (ART), individuals with HIV can live normal lives and do not transmit the virus sexually when their viral load is undetectable.

Despite these advances and decades of intensive research, the disease remains untreatable. With a few exceptions, all efforts to permanently eliminate the virus from the body have been unsuccessful.

This is largely because HIV-1 and the much rarer HIV-2 are highly genetically variable and largely evade the human immune system. Therefore, achieving sustained remission or a cure through viral elimination requires diverse strategies, persistence, and a substantial trial-and-error approach.

Researchers from France reminded the medical community that a cure for HIV is possible in an article published in The Lancet HIV. The article called for building on past successes and prioritizing curative therapies amid global cuts in HIV treatment.

Despite effective therapies and preventive strategies, 630,000 individuals died worldwide from AIDS-related illnesses, 40.8 million live with HIV, and 1.3 million were newly infected. According to the authors, these figures underscore the urgent need for curative therapies. Without sufficient funding, previous progress could be lost by 2030, and the pandemic cannot end without a cure.

The French Nobel laureate Françoise Barré-Sinoussi, a co-author of the article, began researching retroviruses in the early 1970s at the Pasteur Institute in Paris and later led its “Regulation of Retroviral Infections” department.

She led the 1983 paper that first identified HIV as the cause of AIDS, which is now freely accessible, thanks to co-author Willy Rozenbaum. Barré-Sinoussi and Luc Montagnier received the 2008 Nobel Prize in Physiology and Medicine for discovering the virus.

HIV therapy has several turning points that have significantly improved the quality of patient care. Key milestones include the development of ART, the introduction of HIV pre-exposure prophylaxis (PrEP), and the availability of multidrug therapies as single-tablet regimens. In recent years, injectable and long-acting therapies have expanded treatment and prevention options.

PrEP Breakthrough

Despite all this progress, HIV infection remains a global health concern. Low-threshold access to ART and PrEP is far from universal, yet it is essential to significantly reduce new infections, the incidence of AIDS-related illnesses, and AIDS-related deaths in the coming years.

Stigma and discrimination continue to cause social withdrawal and treatment avoidance, especially in the most affected countries.

Poor adherence also increases the risk for resistance to common HIV medications, such as dolutegravir, particularly where resistance testing is limited because of cost.

Long-acting HIV therapies have been developed to overcome these challenges. Since 2020, cabotegravir, the first injectable HIV integrase inhibitor, has been an alternative to daily oral ART.

After a 28-day oral induction phase to identify intolerances, patients received a single initiation dose of 600 mg cabotegravir and 900 mg rilpivirine intramuscularly, followed by monthly maintenance therapy.

A bimonthly regimen at the same dose is also available. Real-world data have confirmed that cabotegravir and rilpivirine are not inferior to oral ART in terms of efficacy.

This treatment benefits patients who do not want to disclose their HIV infection status or have limited storage and administration options. 

Cabotegravir and rilpivirine can also be used as PrEP, although lenacapavir has emerged as a better alternative to these agents.

The introduction of HIV PrEP has marked a significant advance in the prevention of new HIV infections. For several years, there has been a broad consensus that HIV PrEP should be offered to individuals at substantial risk for infection.

Lenacapavir, a long-acting injectable drug, has been available since 2024 and was initially approved in the US and EU in July 2025. As the first approved capsid inhibitor, it requires subcutaneous administration only every 6 months and has demonstrated nearly 100% efficacy in the phase 3 PURPOSE 1 and PURPOSE 2 trials.

Already approved for treating HIV infections, lenacapavir has shown compelling results in PrEP trials, and Science named it the 2024 Scientific Breakthrough of the Year.

Other long-acting PrEP options are in development, including the oral nucleoside reverse transcriptase translocation inhibitor (NRTTI) MK-8527, intended for monthly dosing or, in later phases, every 6 months, making it suitable for patients who prefer to avoid injection.

MK-8527 is similar to the first NRTTI, islatravir, which was stopped in phase 3 after several participants experienced CD4 cell count reductions. MK-8527 did not show these effects in phase 2 trials and is expected to benefit patients with low adherence.

Curative Strategies

Without consistent adherence, the HIV viral load can rebound within days, putting patients and their partners at risk for HIV transmission. Curative therapy is the most effective method for preventing AIDS-defining illnesses and new infections.

Recent advances have made a cure possible for the first time in the history of HIV research. 

Broadly neutralizing HIV antibodies (bNAbs) target highly stable regions of the HIV envelope and show promise as therapeutic and curative strategies.

Their use is still limited to clinical trials, and bNAbs have shown promising results in these trials. In these studies, participants stopped ART and received bNAbs with injectable antivirals to achieve long-term or permanent viral suppression. 

However, challenges remain: bNAbs must generate a sustained immune response, which has not yet been achieved.

In some participants, bNAbs reshaped viral reservoirs and strengthened the body’s immune response, supporting long-term infection control. Further research is needed to determine the individual factors that influence the efficacy of bNAbs and their potential therapeutic use.

HIV research has long focused on developing preventive and therapeutic vaccines, with the main goal of inducing bNAbs that can neutralize diverse HIV strains by targeting the conserved regions of the viral envelope.

Several vaccine approaches have been tested, including viral vectors that use harmless viruses to deliver HIV antigens and stimulate an immune response, protein-based vaccines that use purified HIV proteins to trigger immunity, and messenger RNA (mRNA) vaccines that instruct cells to produce HIV antigens and generate an immune response.

The development of HIV mRNA vaccines has accelerated due to COVID vaccine research. Although mRNA technology was originally explored for HIV, it was widely used during the COVID pandemic.

Insights from this experience are now being used to improve HIV mRNA vaccines and produce stronger immune responses than those of earlier experimental candidates.

New strategies for HIV treatment and potential cures often combine multiple approaches. The “shock and kill” method uses latency-reversing agents with bNAbs to activate and eliminate latent HIV reservoirs, while the “block and lock” approach uses latency-promoting agents to maintain viral dormancy.

Genome editing techniques, such as CRISPR-Cas9, may also help remove HIV reservoirs from the body. Ongoing clinical trials will determine which combinations are the most effective for long-term viral suppression and potential cure.

Funding Matters

Four decades of HIV research have relied on strong political commitment and funding, which are now declining. The USA, once the main funder, has withdrawn its support, and Germany, France, the Netherlands, and the UK have scaled back. Without coordinated international funding, the unprecedented opportunity to develop curative therapies for HIV could be lost.

This story was translated from Univadis Germany.