Interleukin-7 May Flush Out Latent HIV Reservoirs

By Megan Rauscher

Interleukin-7 (IL-7) is a potent inducer of HIV-1 replication in latently infected cells from individuals on virally suppressive highly active antiretroviral therapy (HAART), increasing the chances of viral eradication, a team of virologists reports.

The persistence of latent HIV-1 pools in virally suppressed infected individuals on HAART "remains a major therapeutic problem," Dr. Roger J. Pomerantz from Thomas Jefferson University in Philadelphia and colleagues note in the January 3rd issue of The Journal of Clinical Investigation.

Immune activation therapy with interleukin-2 (IL-2) in association with HAART with or without the monoclonal antibody OKT3 has been modestly successful in purging HIV-1 reservoirs (see Reuters Health report January 10, 2003).

Now, Dr. Pomerantz and colleagues report that IL-7 is more effective than IL-2 alone or in combination with phytohemagglutinin (PHA) in reactivating latent HIV-1 proviruses from freshly cultured CD8-depleted peripheral blood mononuclear cells (PBMCs) and quiescent CD4+ T lymphocytes from patients on virally suppressive HAART. Resting CD4+ T cells are thought to be a major hiding place for HIV-1.

In their experiments, IL-7 induced HIV-1 replication in 56% and 45.5% of PBMCs and resting CD4+ T lymphocyte cocultures, respectively, compared with 22% and 27.3%, respectively, for IL-2/PHA stimulation. IL-2 alone did not induce HIV-1 replication in any cocultures (0 of 6) while 3 of 5 cocultures treated with IL-7 were positive for viral outgrowth.

"IL-7 seems to be the best way to stimulate HIV out of latency," Dr. Pomerantz said in a telephone interview with Reuters Health.

Moreover, data from phylogenetic analyses of viral envelope gp120 genes from induced viruses show that IL-7 and the combination of IL-2 and PHA induce different viral isolates. "IL-7 seems to stimulate the virus in different ways than the typical ways of getting HIV out of latency with IL-2 and OKT3," Dr. Pomerantz explained.

This is important, he and colleagues note in their report, because it suggests that "different activators of proviral latency may perturb and potentially deplete only selected, specific portions of the proviral archive in virally suppressed individuals."

Therefore, "just as we use HAART to stop HIV replication, we think you're going to need what we call highly active anti-latency therapy, or HAALT, to purge all the reservoirs," Dr. Pomerantz said.

It is also worth noting, he said, that IL-7 is a "kinder and gentler IL-2, so it not only works the best against latent HIV, but we are going to predict that it's going to have even less side effects than IL-2."

01/07/05

J Clin Invest 2005;115:128-137.