Individuals treated with interleukin-2 (IL-2) plus highly active antiretroviral therapy (HAART) have significantly fewer resting CD4+ T cells in their bloodstream which harbor HIV than patients receiving HAART alone, according to a study of 26 patients conducted at the National Institute of Allergy and Infectious Diseases (NIAID). Resting CD4+ T cells are among the “safe havens” where HIV may persist for years - sewn into the cells’ genes - despite aggressive three-drug antiretroviral therapy.
In resting CD4+ T cells taken from the bloodstream (“peripheral blood”) of a small number of study patients receiving IL-2 plus HAART, the researchers have been unable to find HIV capable of replicating, even when they have looked for the virus in millions of cells with sensitive laboratory procedures.
Anthony S. Fauci, M.D., NIAID director and chief of the NIAID Laboratory of Immunoregulation (LIR), plans to present these new findings at the 36th Annual Meeting of the Infectious Diseases Society of America in Denver, Colo., on Sunday, November 15 at 8:30 a.m. Mountain Time. The lead LIR scientist on the new studies is Tae-Wook Chun, Ph.D., who, with Dr. Fauci and other colleagues, has published several seminal papers on latent reservoirs of HIV.
The NIAID team studied two different groups of HIV-infected patients, 12 receiving HAART (generally a combination of at least three antiretroviral drugs including a protease inhibitor) and 14 receiving HAART plus IL-2, administered either intravenously or subcutaneously. IL-2 is a regulatory protein of the immune system produced in the body by T cells. IL-2 has potent effects on the proliferation, differentiation and activity of a number of immune system cells, notably T cells. The 14 patients on HAART plus IL-2 received doses of IL-2 totaling 3 to 18 million international units per day during five-day treatment cycles, followed by a rest period of at least eight weeks before the next treatment cycle.
At the time samples were taken from the study patients, all 26 had plasma viral loads that were less than 50 HIV copies per milliliter (ml) of blood.
In six of the 14 HIV-infected individuals receiving IL-2 plus HAART, the NIAID researchers did not detect any HIV capable of replicating when they cultured 10 to 20 million peripheral blood resting CD4+ T cells from each patient. When they cultured much larger numbers of peripheral blood resting CD4+ T cells from these six individuals - up to 330 million cells per person - the researchers still could not find any replication-competent virus in three patients. In contrast, the investigators consistently have found replication-competent HIV in peripheral blood resting CD4+ T cells from each of 12 patients who received HAART alone.
The researchers then performed a lymph node biopsy on one of the three patients treated with IL-2 plus HAART in whom no virus was found in peripheral blood resting CD4+ T cells. Replication-competent HIV could not be isolated from the lymph node tissue that they examined.
“Our new data suggest that in HAART-treated patients, interleukin-2 may have a role in reducing this ‘reservoir’ of virus, where HIV would otherwise remain sequestered from the immune system,” says Dr. Fauci.
Scientists believe that other hidden reservoirs of HIV exist, and may include the brain, testes, CD4+ T cells in other lymphoid organs such as the gut, and other immune system cells such as macrophages. Together, these potential viral sanctuaries pose a formidable obstacle to the ultimate control or eradication of HIV from an infected person’s body. Investigators at NIAID and elsewhere are developing strategies to diminish the amount of virus in these hiding places, speculating that a smaller pool of latently infected cells would more likely be controlled by the immune system of the patient.
“We look forward to extending and elaborating on these observations,” says Dr. Fauci. “In particular, we hope to determine the mechanisms of the observed effects, which currently are unclear. It will also be crucial to determine the clinical relevance of reducing the size of the latently infected resting CD4+ T-cell pool.
“The final proof of the feasibility of effectively controlling replication-competent HIV in latently infected cells will be discontinuation of HAART and long-term follow-up,” Dr. Fauci notes.
NIAID is a component of the National Institutes of Health (NIH). NIAID conducts and supports research to prevent, diagnose and treat illnesses such as HIV disease and other sexually transmitted diseases, tuberculosis, malaria, asthma and allergies. NIH is an agency of the U.S. Department of Health and Human Services.
HIV-infected individuals interested in AIDS clinical trials at NIH, including studies involving IL-2, may call 1-800-AIDS-NIH.
Press releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.