Immune-modulating medication may help clear HIV reservoir

Ruxolitinib (Jakavi), an immunomodulating drug used to treat graft-versus-host disease, may reduce the size of the HIV reservoir and reverse immune dysfunction, according to study findings presented at the 12th International AIDS Society Conference on HIV Science (IAS 2023) and at the preceding HIV Cure & Immunotherapy Forum. What’s more, the drug may be helping to maintain long-term remission in a man who appears to have been cured after a stem cell transplant.

While antiretroviral therapy (ART) keeps HIV replication under control as long as treatment continues, the virus inserts its genetic blueprint – known as a provirus – into the chromosomes of human cells, establishing a long-lasting viral reservoir that is unreachable by antiretrovirals and invisible to the immune system. Even when viral replication is suppressed, people with HIV can experience ongoing immune dysregulation and inflammation that contributes to a wide range of health problems including cardiovascular disease and neurocognitive impairment.

“The barrier to an HIV cure is that the virus hides inside the DNA of cells,” said senior investigator Dr Christina Gavegnano of Emory University in Atlanta. “The brass ring [goal] is an agent that can eliminate these reservoir cells, which would ultimately eliminate HIV from a person’s body.”

Latent proviruses can lie dormant indefinitely in resting CD4 T-cells in the presence of antiretrovirals, but they usually start producing new virus soon after the drugs are discontinued, posing a major barrier to a cure. HIV cure researchers have tried numerous approaches to activate latent virus and make it susceptible to antiretrovirals (‘kick and kill’), permanently silence dormant virus to prevent it from ever reactivating (‘block and lock’), or even excise viral genes from host cells.

The phase IIa A5336 trial, sponsored by the AIDS Clinical Trials group, enrolled 60 adults with HIV who were on ART (NNRTIs or unboosted integrase inhibitors) with stable viral suppression for at least two years and had a CD4 cell count above 350. Forty participants were randomly assigned to add ruxolitinib (10mg twice daily) to their ART regimen for five weeks while 20 continued on ART alone.

Ruxolitinib is an oral Janus kinase 1/2 inhibitor that interferes with key steps in the JAK-STAT signalling pathway, which is involved in cell proliferation, immune regulation and inflammation. It is used to treat conditions such as myelofibrosis, atopic dermatitis and graft-versus-host disease that doesn’t respond to steroids.

Gavegnano and colleagues have been studying ruxolitinib for more than a decade. Back in 2016, they reported that ruxolitinib reduced HIV replication in human macrophages in the laboratory and improved HIV-related brain inflammation in mice. She later reported that baracitinib (Olumiant), a second-generation JAK 1/2 inhibitor, reduced the number of CD4 cells harboring latent virus in recently infected monkeys.

As previously reported, the main A5336 trial showed that ruxolitinib significantly decreased markers of immune activation and cell survival, leading the study authors to conclude that “future studies of JAK inhibitors should target people with HIV with residual inflammation despite suppressive ART.”

Gavegnano, PhD student Monica Reece and colleagues looked more closely at the effects of ruxolitinib on the peripheral HIV reservoir and immune biomarkers associated with HIV persistence. Study participants who received ruxolitinib were classified as having a high viral reservoir (top one-third) or low reservoir (bottom two-thirds). They were followed for seven additional weeks after five weeks on ruxolitinib.

The researchers measured integrated proviral HIV DNA in peripheral blood cells, noting changes over time. They saw a significant decline in proviral DNA from week 5 to week 12 in participants with a high viral reservoir who received ruxolitinib. The reservoir size did not change in ruxolitinib recipients with a low reservoir, while those who did not receive the drug had a slight increase. Based on the viral decay rate, the study team calculated that 99.99% viral clearance could potentially be achieved in just under three years.

Participants who received ruxolitinib also showed greater changes in numerous biomarkers related to immune activation and dysregulation, cell survival and reservoir establishment and expansion. Based on these findings, the researchers identified ‘niche’ biomarkers that predicted which individuals are likely to experience substantial reservoir decay when treated with ruxolitinib (BCL/KI67, pSTAT5, CD127 and IL-10).

A limitation of this analysis is that the researchers only looked at hidden virus in peripheral blood cells, not in lymph nodes or so-called sanctuary sites such as the central nervous system or gut that are shielded from the immune system.

This study offers evidence that JAK 1/2 inhibitors can reverse immune dysfunction and decrease the size of the reservoir in a subset of people with HIV, the researchers concluded. Studies looking at a longer duration of treatment are underway. If these findings are confirmed, ruxolitinib or baricitinib [another JAK 1/2 inhibitor] could potentially be used as “a backbone for cure-based eradication strategies,” they suggested.

“Our phase II human study with ruxolitinib provides a proof of principle that JAK 1/2 inhibitors, originally developed for inflammatory diseases, can reduce the HIV reservoir,” Reece told aidsmap. “We have demonstrated that ruxolitinib can reduce the reservoir by reducing the lifespan of cells harboring latent virus and by blocking inflammation that allows the reservoir to persist.”

According to Professor Vincent Marconi, lead author of the main A5336 trial: “These data are valuable because they show that JAK inhibitors can contribute to a long-term cure strategy for HIV, but they can also be used to slow the inflammatory process caused by other infectious diseases,” potentially including acute COVID-19 and long COVID.

The Geneva patient

Ruxolitinib is just one of the many agents that have shown promise as a cure strategy in early studies, but another presentation at the conference gives it added weight.

As previously reported, Dr Asier Sáez‐Cirión of Institut Pasteur in Paris reported that a man dubbed the 'Geneva patient' appears to be the latest person cured of HIV after a stem cell transplant for cancer treatment. But unlike the other five known cases, he received stem cells from a donor who does not have a rare mutation (CCR5-delta-32) that prevents HIV from entering cells.

The man was diagnosed with an aggressive type of sarcoma and underwent chemotherapy and whole-body radiation before receiving the stem cell transplant in July 2018. He developed acute and chronic graft-versus-host disease and was treated with various immunosuppressive drugs including ruxolitinib. He stopped ART in November 2021 and continues to have undetectable HIV 20 months later.

Researchers are still working to learn why this man was apparently cured after a transplant of stem cells without the CCR5-delta-32 mutation while other attempts have failed.

For example, in 2013, Dr Timothy Henrich, now at the University of California San Francisco, and colleagues described two HIV-positive men in Boston who received transplants to treat lymphoma using so-called wild-type stem cells. These cases generated considerable excitement, as the men appeared to be controlling HIV after stopping antiretrovirals. But hopes were soon dashed when they experienced viral rebound three months and eight months after ART discontinuation.

One factor might be the Geneva patient’s use of ruxolitinib, which he received for several years to manage ongoing graft-versus-host disease. The drug “may have had an impact of reducing the reservoir and the absence of viral rebound,” said Dr Alexandra Calmy of Geneva University Hospitals in Switzerland. Henrich, too, suggested that ruxolitinib may have contributed to the man’s long-term remission. However, other experts suspect the graft-versus-host reaction itself may have triggered HIV remission.

Stem cell transplants are far too risky for people who do not need them to treat life-threatening cancer, and the intensive and costly procedure is not feasible for most people living with HIV worldwide. But cases like this offer clues that could help scientists develop strategies that lead to a more widely applicable functional cure.