Interleukin-2 (Proleukin) is a natural substance involved in the working of the immune system which stimulates the production and maturation of CD4 T-cells. Often called IL-2 for short, it is one of a group of immune system messengers that are collectively known as cytokines.

IL-2 is produced by T-cells to activate and recruit parts of the immune system to do their job. In particular, it is thought to stimulate production of the cytokine interferon gamma, and to activate natural killer cells and subsets of T-cells.

Levels of IL-2 tend to fall over time in HIV infection, and low levels are associated with an increased risk of disease progression. Therefore, researchers have studied whether it is beneficial to treat people with HIV with an artificial ‘recombinant’ form of IL-2 to boost immune functioning and delay disease progression. IL-2 may also reduce HIV’s ability to infect macrophages by reducing the number of receptors displayed by these cells. Recombinant IL-2 is also known as aldesleukin.

Availability and dosage

IL-2 is a licensed drug for treating a form of kidney cancer, but its use in people with HIV is unlicensed and experimental. If a doctor agrees to take full responsibility for its use, IL-2 can be prescribed to people with HIV outside of approved indications. Only a handful of people in the United Kingdom are accessing IL-2 in this way.

IL-2 has to be injected, either directly into a vein or under the skin. Cycles of injections are given over a period of a few days, every few weeks or months.

IL-2 is being studied at various doses. These are measured in millions of international units, abbreviated to MIU. A modified form of IL-2 has also been studied in the hope that it might lessen side-effects. This version is called pegylated (or PEG) IL-2 and is given intravenously.

Stimulating the immune system

In early 1995, American researchers reported substantial increases in the CD4 cell counts of people treated with intravenous infusions of IL-2 every eight weeks, plus antiretroviral therapy. Six out of ten people with baseline CD4 cell counts above 200 cells/mm³ experienced increases of at least 50% lasting two months after each infusion. Although participants’ CD4 cell counts then started to drop again, they never fell back to their starting values, and the next infusion increased them again. In some cases CD4 cell counts rose to 1000 cells/mm³ after two years of treatment^[1].

Subsequent trials have found that people on IL-2 and antiretroviral therapy have greater increases in CD4 cell counts compared with those who take antiretroviral therapy alone, regardless of baseline CD4 cell count^{[2][3][4][5][6]}. In addition, interim results from the large, randomised ESPRIT trial have suggested that patients experience larger rises in CD4 cell count if they have undetectable viral loads and higher ‘nadir’ (lowest-ever) CD4 cell counts^[7]. This trial is scheduled to continue until 2007.

IL-2 may be an attractive option for patients who fail to experience a rise in CD4 cell counts despite falls in viral load brought about by antiretroviral therapy. Benefits of IL-2 have been demonstrated in one randomized trial of 72 patients with CD4 cell counts below 200 cells/mm³, in which the patients randomised to add IL-2 to their anti-HIV treatment combination had higher CD4 cell counts after 24 weeks of treatment^[8]. French guidelines now recommend IL-2 for people with CD4 cell counts below 200 cells/mm³ after at least six months on an effective antiretroviral regimen.

IL-2 can also increase CD4 cell counts in HIV-positive patients who are not taking antiretroviral therapy, potentially delaying the start of antiretroviral therapy. One study of patients starting with CD4 cell counts above 350 cells/mm³ found that CD4 cell counts increased by 129 cells/mm³ after 64 weeks, compared with 13 cells/mm³ in patients not taking the drug^[9]. IL-2 is also effective in raising HIV-positive children’s CD4 cell counts, although they may experience more severe side-effects^[10].

Adding IL-2 to an antiretroviral treatment regimen begun during primary HIV infection can also be beneficial. In one study, IL-2 led to increases in CD4 cell counts, without affecting viral loads or CD8 T-cell numbers. However, the CD8 T-cell non-cytotoxic anti-HIV response was restored in the IL-2 group^[11].

Despite the observed increases in CD4 cell counts, there is little information about whether IL-2 can prevent disease progression or opportunistic illnesses. A meta-analysis of three studies comparing IL-2 to placebo found greater improvements in CD4 cell counts and greater decreases in viral load and a trend towards fewer clinical events among the people treated with IL-2^[12]. In addition, although it can cause a short-term reduction in quality of life, adding IL-2 to antiretroviral therapy may have a positive impact on quality of life after a year’s treatment, particularly if they use IL-2 injected under the skin^[13]. However, long-term clinical endpoint studies, which will determine whether IL-2 reduces opportunistic infections and death, are now underway.

IL-2 may also play a role in stimulating HIV-specific immune responses, although this is not currently proven^[14][15].

Interleukin-2 to flush out infected, resting CD4 T-cells?

During 1999 a popular theory hypothesised that IL-2 could be used to ‘awaken’ the reservoir of ‘resting’ HIV-infected CD4 T-cells among people receiving anti-HIV therapy^[16]. This was tested in one study: the researchers could not to culture HIV from the T-cells of six of 14 people who received antiretroviral therapy plus IL-2, and they could not detect any HIV in the lymph nodes of three of these patients. However, when treatment was stopped, viral rebound occurred within weeks, indicating that some viral reservoirs persisted despite seemingly effective treatment^[17].

Spanish and French studies have also reported disappointing findings, albeit in patients who had achieved viral suppression that might be considered incomplete by today’s standards. For example, ten people taking antiretroviral therapy plus IL-2 and interferon gamma produced excellent viral suppression and strong immune responses, but HIV could still be cultured from all individuals after twelve to 18 months of treatment. Furthermore, HIV’s DNA was not eliminated from blood cells and viral rebound was reported in individuals who stopped treatment^[18].

A treatment interruption study called NoHRT found that IL-2 therapy did not affect the rate of viral rebound in 18 individuals who had ceased treatment after two years of viral suppression. Twelve of the 18 had been treated with IL-2. Despite the small size of the study, it discredits the notion that IL-2 plus antiretroviral in the short-term can eradicate HIV^[19]. Two other studies have further discredited the theory that IL-2 may lead to viral eradication^[20][21].

Side-effects

Side-effects from intravenous IL-2 are substantial and include blood disorders (neutropenia and anaemia), chills, fevers, muscle pains, nausea, diarrhoea and abnormal liver and kidney function. In one trial, participants suffered a severe influenza-like illness during the infusion period. If it is being taken alongside the nucleotide analogue reverse transcriptase inhibitor tenofovir (Viread), kidney function should be closely monitored, because of the elevated risk of kidney damage.

One study showed that 10% of 289 people on IL-2 had some evidence of under-activity of the thyroid gland. This was characterised by a slowing of the body’s metabolic rate, although symptoms were rare.

Side-effects are less common when the IL-2 is given as a subcutaneous injection^[22][23]. Studies into agents that can reduce the severity of IL-2’s side effects are being conducted.

Other forms of interleukin-2

PEG IL-2, which remains in the body for longer than conventional IL-2, has been compared to standard IL-2 in a study, with both drugs combined with AZT (zidovudine, Retrovir). While PEG IL-2 led to significant CD4 cell count increases, these were not as substantial as those seen with standard IL-2^[24]. The rates of withdrawal from the trial were similar for both forms of IL-2.

Researchers have also studied a genetically engineered molecule called IL-2 fusion toxin. This is also known by the code-name DAB₃₈₉IL-2 and is manufactured by Seragen Inc. Studies have suggested that HIV is more likely to become re-activated in infected cells that carry a receptor for IL-2. The theory behind IL-2 fusion toxin is that it will bind to cells that carry the IL-2 receptor and then kill them with a diphtheria toxin, which is incorporated into the molecule. In test tube studies, IL-2 fusion toxin selectively killed HIV-infected cells without harming uninfected cells^[25]. However, no anti-HIV effects were seen in a trial of HIV-positive patients^[26].