Researchers at the National Institute of Allergy and Infectious Diseases (NIAID) have helped answer an important question in the treatment of HIV-infected individuals: why, in patients receiving aggressive antiretroviral therapy who have no easily detectable HIV in their blood, does the virus rapidly rebound to high levels if the drugs are discontinued?
"Our new data suggest that the virus comes roaring back because of the normal stimulatory factors present in the environment of a patient's lymph nodes, notably signalling molecules called cytokines," says Anthony S. Fauci, NIAID Director and Chief of the NIAID Laboratory of Immunoregulation (LIR). "In the absence of antiretroviral therapy, these factors activate HIV that is hiding in a latent form in immune system cells."
In a series of in vitro experiments, the NIAID researchers found that inductive factors can activate reservoirs of latent HIV in resting CD4+ T cells, if potent combinations of antiretroviral drugs are not present. Such drug combinations, which generally include a protease inhibitor and two or three other drugs, are commonly referred to as "highly active antiretroviral therapy" or HAART.
Dr. Fauci's team and two other groups recently demonstrated that reservoirs of latent HIV can be found in resting CD4+ T cells of patients who have taken HAART for many months (see, for i.e., Chun et al., PNAS, Nov. 25 1997). Among Dr. Fauci's new findings are data that suggest that it may prove possible to purge these reservoirs of latent HIV by activating resting, latently infected CD4+ T cells with cytokines, resulting in the death of these cells, while preventing further viral spread with HAART.
Dr. Fauci will present his laboratory's new observations at the 5th Conference on Retroviruses and Opportunistic Infections in Chicago, Ill., on Wednesday, February 4 at 6:30 p.m. in the Sheraton Chicago Ballroom. The lecture is part of a special symposium chaired by Dr. Fauci called "Host Factors in HIV Infection: Implications for Therapy." The symposium also features Drs. Stephen O'Brien of the National Cancer Institute, Barton Haynes of the Duke University School of Medicine, and Giuseppe Pantaleo of Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland.
When an HIV-infected patient is taking HAART, inductive cytokines and other factors which can boost HIV production are still present in their lymph nodes and related organs. However, the powerful effects of HAART nonetheless can reduce viral replication dramatically, sometimes to the point where HIV can be found only in a latent form in resting CD4+ T cells. The new data suggest that when HAART is withdrawn, the effects of HIV-inducing cytokines and other factors once again promote the active production of virus.
"The findings underscore the risks involved in discontinuing antiretroviral therapy, even if a patient feels better and has a viral load that is 'undetectable' using standard assays," Dr. Fauci says. "Our data also stress the importance of developing comprehensive treatment strategies which not only block HIV replication but also modulate the host factors that drive such replication.
In studies dating back to the mid-1980s, Dr. Fauci and his team have shown that certain cytokines normally secreted by immune cells, particularly in the lymph nodes, can boost the replication of HIV. Blocking these so called "inductive" cytokines, such as tumor necrosis factor-alpha (TNF-alpha), interleukin 1-beta (IL-1 beta), and interleukin-6 (IL-6), can markedly reduce viral replication. Conversely, as LIR scientists first described in 1987, even resting, latently infected cells can be induced to actively produce HIV when cytokines such as TNF-alpha are added. More recent LIR experiments have shown that other stimuli, such as the activation of immune system cells by immunization, can also induce latently infected cells to actively produce HIV. In addition to these factors, a group of molecules called CC-chemokines, which suppress the replication of certain strains of HIV, can enhance the replication of HIV in some circumstances.
"HIV disease is a multifactorial process controlled by the complicated interplay of stimulatory and inhibitory factors concentrated in the lymphoid tissue, the centers of immune activity in the body," Dr. Fauci notes.
At the Chicago symposium, Dr. Fauci will present data from in vitro experiments involving latently infected CD4+ T cells drawn from HIV-infected, HAART-treated individuals, as well as from HIV-infected patients not receiving HAART.
In one series of experiments, the researchers found that after adding HAART to cultures of latently infected, resting CD4+ T cells, they were unable to induce with cytokines the production of HIV from the cells of either group of patients.
"However, when we took HAART out of the cultures, we were able to rapidly induce HIV replication with cytokines, even in cells from patients who had been on HAART for many months," says Dr. Fauci.
In another in vitro experiment, the researchers sought to determine if they could purge HIV from latently infected CD4+ T cells. They exposed the cells to the inductive cytokine interleukin-2 (IL-2) for six days, both with and without HAART added to the cultures.
The researchers reasoned that if they induced latently infected CD4+ T cells with IL-2 in the absence of HAART, the cells would make virus and die, but would still infect other cells. Thus, inducing HIV with a cytokine but without HAART would have a detrimental effect. In the presence of HAART, the thinking went, cells induced to make virus would also die, but would be unable to infect new cells because of the powerful antiviral effects of the drugs. Thus, HAART together with IL-2 would lead to a depletion of latently infected cells.
In the experiments, the researchers found that latently infected CD4+ T cells that contained inducible virus and were treated with both IL-2 and HAART did, indeed, dramatically decline in number.
"This work provides the rationale to attempt to purge latently infected CD4+ T cells in HIV-infected patients by using a similar approach, i.e., by deliberately inducing virus expression in the setting of HAART," says Dr. Fauci.
NIAID researchers are currently testing this approach in HIV-infected volunteers receiving IL-2 and antiretroviral drugs at the NIH Clinical Center in Bethesda, Md.