IL-7 may boost CD4 and CD8 T-cells, study shows

Injections of the cytokine interleukin-7 (IL-7) led to "brisk" increases in naive and central memory T-cells and appeared to stimulate multiplication of precursor cells in the thymus, investigators with the small INSPIRE study reported this week at the 49^th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in San Francisco.

Loss of CD4 T-cells leading to immune suppression is the key feature of HIV disease progression. Several recent studies have shown that spending more time at a lower CD4 count increases the risk of both AIDS-related and non-AIDS illnesses, even before reaching the 200 cells/mm³ threshold for advanced disease.

Despite effective antiretroviral treatment that fully suppresses viral load, some people with HIV do not experience adequate CD4 cell recovery, and the cells that do come back may not work as well as those that were lost. Researchers therefore have explored strategies to rebuild the immune system, including the use of various cytokines, or chemical messengers.

Yves Levy and colleagues with the international INSPIRE study looked at the effects of recombinant human IL-7 on T-cell recovery and thymic function in a small group of HIV patients who had viral load suppressed on antiretroviral therapy.

The thymus is a gland in the upper chest where T-cells mature; normally the organ shrinks and becomes less active as people age. Past research has shown that IL-7 stimulates T-cell maturation and release from the thymus, as well as inhibiting spontaneous death of CD4 and CD8 cells.

INSPIRE participants were randomly assigned to receive three weekly injections of 10, 20 or 30 mcg/kg of IL-7 (using a preparation called CYT107) or else placebo for twelve weeks. All participants were men and amongst those receiving IL-7, the median age was just over 40 years. All had a viral load below 50 copies/ml.

CD4 count at enrollment ranged from 101 to 400 cells/mm³ (median of about 270 cells/mm³), but the median nadir, or lowest-ever level was 100 cells/mm³. The median CD8 count was about 750 cells/mm³ and the median CD4/CD8 ratio was 0.35.

Dr Levy reported twelve-week interim results from 22 participants receiving the two lower IL-7 doses. Overall, IL-7 appeared safe and was well tolerated over a short period. There were no serious adverse events or toxicities that caused patients to reduce their dosages, though some reported mild or moderate injection site reactions. Viral load generally remained suppressed, but four people in the 20 mcg/kg group experienced low-level temporary viral "blips."

Participants experienced significant increases in both CD4 and CD8 cell numbers. Those in the 10 mcg/kg group had about a 150% increase in CD4 cells at Week 4, which fell back to about a 90% increase by Week 12 (from a median 268 to 643 to 419 cells/mm³). In the 20 mcg/kg group, the corresponding increases were about 200% at Week 4 and 135% at Week 12 (from a median 240 to 709 to 563 cells/mm³).

One of seven of participants in the 10 mcg/kg group and five of eight in the 20 mcg/kg group reached a CD4 cell level above 500 cells/mm³ - the lower end of the normal range for HIV-negative people.

CD8 cell counts showed a similar pattern. In the 10 mcg/kg group, the level rose by 91% at Week 4, but dropped back to a 42% increase by Week 12 (from a median 761 to 1434 to 1081 cells/mm³). In the 20 mcg/kg group, the corresponding increases were 131% and 65% (from a median 659 to 1695 to 1210 cells/mm³).

The researchers saw increases in both naive T-cells, which are not yet committed to fighting a specific disease-causing pathogen, and central memory cells, which "remember" invaders encountered in the past. It also appeared that patients' thymus glands were producing more cells. But another type of memory cell (effector memory cells) did not increase. Dr Levy suggested that the most mature cell types seemed to benefit least from IL-7.

These findings led the researchers to conclude that a three-injection cycle of IL-7 "induces a dose-dependent and sustained increase of CD4 T-cells."

While the findings from this small study are encouraging, they must be confirmed in larger, longer studies. Recently reported final results from two large and expensive trials of another cytokine, interleukin-2, failed to reproduce promising early data. While IL-2 did increase CD4 counts, this did not translate into clinical benefits or improved survival.

Addressing this risk, Dr Levy noted that the types of CD4 T-cells expanded by IL-7 are completely different from those expanded by IL-2. While the IL-2 trials (known as ESPRIT and SILCAAT), designed in the late 1990s, looked at progression to AIDS, he suggested that today it may be possible to see beneficial clinical outcomes sooner using different types of endpoints.