Interleukin-2 is a cytokine or immune system messenger which encourages the proliferation and survival of CD4 T-cells. It is usually abbreviated to IL-2.

Genetically engineered or 'recombinant' IL-2 is being tested as an immune-boosting therapy for people with HIV. To date, IL-2 is known to increase CD4 cell counts but its long-term clinical effects are unknown.

Benefits

Several studies of IL-2 have found that people treated with antiretroviral therapy and IL-2 experienced significant, sustained improvement in their CD4 cell counts compared to people who received antiretroviral therapy alone. Early research indicated that people with low CD4 cell counts were unlikely to benefit from IL-2 but subsequently findings have found that IL-2 boosts CD4 cell counts irrespective of baseline level.

Results of the randomised ILSTIM study showed that the addition of IL-2 can boost CD4 cell counts significantly. Seventy-two people with low CD4 cell counts despite low viral load due to antiretroviral therapy were randomised to continue antiretroviral therapy alone or to add IL-2. The latter strategy resulted in significantly higher CD4 cell counts after 24 weeks of treatment. All participants subsequently received open-label IL-2, producing further CD4 cell count rises (Katlama 2002).

A German study compared T-cell responses in eleven people treated with IL-2 plus antiretroviral therapy to ten people treated with antiretroviral therapy alone. Both groups experienced a decrease in infected cells in the lymph nodes and blood plasma, normalisation of CD4 and CD8 T-cell activity and restoration of the lymph nodes. However, people on IL-2 had the additional benefit of a greater CD4 cell count increase and normalisation of particular T-cell subsets (van Lunzen 1999).

An analysis of three major randomised studies found that individuals who added IL-2 to antiretroviral therapy had significantly larger CD4 cell count increases from baseline compared to those who received IL-2 alone, significantly lower viral load and a trend towards fewer AIDS-defining illnesses (Emery 2000).

IL-2 without antiretroviral therapy may have benefit for people whose CD4 cell counts remain above 350 cells/mm³. One study has found that people on IL-2 for a year had improved CD4 cell counts but stable viral load. This preliminary finding contradicts accepted wisdom that IL-2 without antiretroviral therapy increases viral load in the long term (Youle 2000). It has also been supported by the results of a randomised study which found that IL-2 has no impact on viral load (Abrams 2000). Another study went even further, suggesting that IL-2 may actually reduce viral load among individuals taking antiretroviral therapy (Davey 2000).

There is some test-tube evidence that IL-2 may reduce HIV replication in macrophages, by reducing macrophage expression of CD4 receptors and CCR5 co-receptors. IL-2 plays a crucial role in the movement of immune system cells in the blood and tissue.

Does IL-2 delay disease?

The 'bottom line' test of the effectiveness of any treatment is its ability to delay opportunistic infections or prolong life, not just to produce changes in blood tests. For IL-2, the only clinical endpoint data consist of a pooled analysis of the occurrence of opportunistic infections among 157 participants in three placebo-controlled studies. Six opportunistic infections occurred among IL-2 recipients and 14 among placebo recipients, although this difference was not statistically significant and could simply be due to chance.

Large international studies called SILCAT and ESPRIT are now underway, looking at the effects of IL-2 on survival and symptoms.

Improving immune response to HIV

Currently, many researchers are searching for a treatment which triggers or improves the body's own HIV-specific immune response. IL-2 is one treatment that researchers hope will assist the body's immune response to HIV. To date there are very limited data to suggest that IL-2 plus antiretroviral therapy may act in this way.

One study found that two of 15 people on antiretroviral therapy plus IL-2 who discontinued treatment had only a transient viral rebound and CD8 cell count increases when they stopped treatment. These markers returned to levels seen on treatment within a month, and were maintained for several months, suggesting that antiretroviral therapy plus IL-2 may improve immune response in some individuals at least (Jacobson 1999). The Seventh Retroviruses Conference in 2000 heard of nine people treated with antiretroviral therapy plus IL-2 who stopped antiretroviral therapy and continued IL-2. Viral load rebounded to about 348,000 copies/ml but then declined to about 26,000 copies/ml, slightly lower than the baseline average of 70,000 copies/ml (Smith 2000).

While neither study confirms that IL-2 boosts the immune system's HIV-specific response, there is some evidence of improvement.

Most recently, a study of nine people randomised to antiretroviral therapy with or without IL-2 found no sign of improved HIV-specific immune responses among people treated with IL-2 (Dybul 2002).

Flushing out HIV?

The theory that IL-2 may 'flush out' HIV from long-lived, infected cells has been discredited by research from several centres. The theory emerged following the demise of David Ho's theory that antiretroviral therapy could eradicate HIV from the body. It was based on research by Dr Tae-Wook Chun and others from the National Institutes of Health (NIH) in the United States who found that HIV could not be cultured from T-cells of six of 14 people who received antiretroviral therapy plus IL-2. Of three individuals who underwent lymph node biopsy, HIV could not be detected in the lymph nodes of two individuals.

Subsequent reports have dampened hopes that IL-2 may be the key to viral eradication. In October 1999, Dr Chun reported that two participants, with undetectable viral load for over 30 months and no replication-competent virus among 330 million cells checked by researchers, had speedy viral rebound after stopping treatment.

Another member of the NIH team, Dr Anthony Fauci found that virus which re-emerged was different to that found in the resting pool of infected lymphocytes. This suggests that this new virus had come from another, as yet undiscovered reservoir. The rebound in viral load also caused the resting T-cells to become repopulated with HIV, even in those people whose use of antiretroviral therapy and IL-2 appeared to have successfully 'flushed out' the virus. The NIH research indicates that viral reservoirs persist even after seemingly successful treatment with antiretroviral drugs and IL-2.

Several other studies have also confirmed that HAART plus IL-2 does not eradicate HIV by flushing out HIV from resting cells (Davey 2000; Lafeuillade 2001). However, other more encouraging research has been reported. A British-Dutch team has attempted to put the use of IL-2 into perspective, arguing that it can be either beneficial or detrimental depending on antiretroviral potency and the degree of T-cell stimulation induced. They found that repeated, low-level immune stimulation may reduce the pool of infected, long-lived CD4 T-cells but that repeated, high-level immune stimulation produced negative results by failing to reduce viral reservoirs, depleting CD4 T-cells and disrupting the CD4:CD8 T-cell ratio (Fraser 2000).

For more information and references on interleukin-2, see Interleukin-2 (IL-2) - overview in Drugs used by people with HIV.

While IL-2 mostly increases T-cell numbers by raising proliferation of mature memory and naﶥ CD4 T-cells in the blood and lymph nodes, a different cytokine called IL-7 may not only have beneficial effects at this stage of a T-cells life but also two earlier stages:

• In the thymus by increasing T-cell survival during thymic development.

• In the bone marrow by increasing the production and release of T-cell precursors.

Interestingly a number of studies point to an important role for interleukin-7 in the regulation of T-cell numbers.

In a San Francisco cross sectional study of 168 HIV-infected patients and a longitudinal analysis of eleven patients, increased levels of IL-7 in the blood plasma were strongly associated with reductions in CD4 cell counts, suggesting that as the CD4 cell count falls, the immune system produces more and more IL-7 to try and push the numbers back up (Napolitano 2001).

Stored blood samples taken from 237 HIV positive women before and after starting antiretroviral therapy were assessed for their plasma levels of IL-7. This showed that increased levels of IL-7 at the time the patients started antiretroviral therapy predicted a greater degree of CD4 T-cell gain thereafter. In addition, the more the patients' CD4 cell counts increased, the more their IL-7 levels returned to normal.

While investigations of the effects of recombinant therapeutic IL-7 have been carried out in monkeys, there are little data yet in humans. Administration of IL-7 to rhesus macaques infected with simian immunodeficiency virus (SIV) caused marked increases in the numbers of memory and naive CD4 and CD8 T-cells, without increasing viral loads. Phase I clinical trials of IL-7 in people with HIV have begun.

References

Abrams DI et al. IL-2 therapy produces no change in HIV RNA after one year. Terry Beirn Community Programs for Clinical Research on AIDS. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, abstract L-11, 2000.

Davey R et al. Immunologic and virologic effects of subcutaneous interleukin 2 in combination with antiretroviral therapy. JAMA 284: 183-189, 2000.

Dybul M et al. Pilot study of the effects of intermittent interleukin-2 on human immunodeficiency virus (HIV)-specific immune responses in patients treated during recently acquired HIV infection. J Infect Dis 185: 61-68, 2002.

Emery S et al. Pooled analysis of three, randomised, controlled trials of interleukin-2 therapy in adult HIV disease. J Infect Dis 182: 428-434, 2000.

Fraser C et al. Reduction of the HIV-1-infected T-cell reservoir by immune activation treatment is dose-dependent and restricted by the potency of antiretroviral drugs. AIDS 14: 659-669, 2000.

Jacobson EL et al. Restoration of immunity after HIV infection. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, abstract 1828, 1999.

Katlama C et al. Interleukin-2 accelerates CD4 cell reconstitution in HIV-infected patients with severe immunosuppression despite highly active antiretroviral therapy: the ILSTIM study--ANRS 082. AIDS 16: 2027-2034, 2002.

Lafeuillade A et al. Impact of immune intervention on proviral HIV-1 DNA decay in patients receiving highly active antiretroviral therapy. HIV Med 2: 189-194, 2001.

Napolitano LA et al. Increased production of IL-7 accompanies HIV-1 mediated T cell depletion: implications for T-cell homeostasis. Nat Med 7: 73-79, 2001.

Smith KA et al. Cessation of HAART plus daily low-dose interleukin 2 to promote immunity to HIV. Seventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 355, 2000.

van Lunzen J et al. Development of T cell activation and proliferation in lymph nodes and peripheral blood during HAART with or without adjuvant interleukin-2. Antivir Ther 4: 107, 1999.

Youle M et al. Randomised study of intermittent subcutaneous interleukin-2 (IL-2) therapy without antiretrovirals versus no treatment. Thirteenth International AIDS Conference, Durban, abstract LBO27, 2000.