While immune-based therapies (IBTs) have been a focus in research for more than 15 years, we still do not fully understand how these therapies might best be used to control HIV. Data presented by Drs. Fred Valentine and Kendall Smith at a recent forum shed some light on two IBTs and the ways in which they work in conjunction with highly active antiretroviral therapy (HAART). At the monthly Community Forum on March 10th sponsored by ACRIA, AIDS Treatment Data Network, Gay Men's Health Crisis, and Treatment Action Group, Dr. Valentine presented data from his studies of Remune (HIV-1 immunogen). This was followed by a presentation by Dr. Smith, who reviewed aspects of his ongoing work with interleukin-2 (IL-2).

The Problem with HAART

The antiviral drugs that are commonly used to treat HIV have a simple mission: to suppress viral replication (reproduction) by disrupting various stages of the life cycle of HIV. Reducing the amount of virus in an individual's body is beneficial, as it results in fewer T-cells being infected and destroyed. However, as HIV mutates and becomes resistant to various drug treatments, the level of virus in the blood eventually increases and the number of T-cells decreases. IBTs represent an entirely different approach to controlling HIV. Instead of attacking the virus itself and stopping its replication, IBTs can bolster the body's immune response to the virus so that cells infected with the virus are destroyed.

In order to understand how IBTs work, it is important to know some of the basics of immune function. When a typical virus -- such as the virus that causes mumps -- enters the body, it is detected by cells called macrophages. Macrophages consume the virus and then "present" pieces of the virus (also known as the antigen) to other cells of the immune system, including helper T-cells (CD4+ cells). Helper T-cells have special receptors on their surfaces that receive the antigens. When they connect, the T-cells begin reproducing at an extraordinary rate. This process is called the lymphocyte proliferative response (LPR). These T-cells spread throughout the rest of the body and, using chemical messengers called cytokines, notify other cells-such as cytotoxic CD8+ cells-to attack and kill cells in the body infected with the mumps virus. Also activated are a large number of B-cells, which produce antibodies to neutralize free virus floating around the body.

As a result of the immune system's hard work, the virus is wiped out. In addition, cells called memory T-cells and memory-B cells are produced, which essentially quicken the immune response if the body is ever exposed again to the same virus.

The Lymphocyte Proliferative Response (LPR)

In his presentation at the Forum, Dr. Fred Valentine emphasized the difference between the body's immune response to a typical virus (as described above) to that of the immune response to HIV. HIV is not a typical virus, and the typical immune response does not usually occur when an individual is infected with HIV. The virus attaches to CD4+ cells and uses these cells to replicate. Since the virus replicates more quickly than the immune system can respond, the immune system eventually becomes unable to fight off any kind of infection at all, and full-blown AIDS develops. Dr. Valentine noted that the development of an effective immune response to HIV would mean the development of a full immune response against HIV, i.e., the kind of immune response that the body generates to a typical virus.

Treatment with HAART, while it can increase the number of CD4+ cells, does not necessarily improve the LPR against HIV, which, according to Dr. Valentine, is a key component of the immune response. Dr. Valentine and others have noticed that HIV-infected patients who live many years without seeing their CD4+ cell counts decrease or develop any kind of AIDS-related infections (>10 years) -- called long-term nonprogressors (LTNPs) -- have a robust LPR, compared to typical HIV-infected patients who don't. As explained by Dr. Valentine, the absence of an LPR generally renders the immune system unable to control HIV, and the immune system will eventually lose its ability to function as replicating virus destroys CD4+ cells.

The increase in CD4+ cells achieved with HAART treatment can lead to an increased LPR to certain disease-causing microorganisms, such as those responsible for PCP, MAC, and CMV disease. Consequently, many patients who once had very low CD4+ cells are now able to go off their prophylactic drugs (such as Bactrim) if their immune system has responded well to HAART. Interestingly, Dr. Valentine has noticed that most HIV-infected patients, even after two or more years of HAART, do not appear to have a strong LPR to HIV. This might explain why the immune system is unable to maintain control of HIV once HAART is stopped.

Remune

Perhaps Remune will be the answer. Remune is a compound consisting of infectious HIV that has been inactivated and partially modified. Remune is created by inactivating HIV using chemical baths and irradiation. As a result of these two processes, gp120, the protein on the outer shell of HIV that binds to the helper T-cell's surface protein, is removed. While the virus is no longer infectious, many other HIV-specific proteins remain intact, and the inactivated virus can stimulate cellular immune response (LPR), leading to the production of cells which can destroy HIV-infected cells.

In a randomized study consisting of 43 patients, Dr. Valentine has found that subjects who received HAART and Remune had stronger immunologic response to laboratory strains of HIV than those who received HAART alone. Moreover, Dr. Valentine noticed that, after 32 weeks, more patients receiving Remune/HAART had undetectable viral loads than those patients receiving HAART alone.

These data are important, as they are the first to demonstrate that cellular immune responses to HIV can be improved using an IBT in the presence of HAART. As Dr. Valentine is quick to point out, however, much more information is needed. For starters, it is still not known whether Remune increases LPRs to non-laboratory strains of HIV, such as the strains that are actually found in a patient's body. Dr. Valentine is interested in examining whether the LPR achieved using Remune can be as effective as the LPR observed in LTNPs. It will also be important to determine how long Remune can keep LPR activity going strong and whether or not this will actually keep patients alive longer and healthier. Additional trials have been started, and the results are eagerly awaited.

IL-2: A Cytokine with a History

IL-2 is not a newly discovered substance. In fact, Dr. Kendall Smith has been working with this cytokine since the 1970s, when it was known as "T-cell growth factor" and its therapeutic applications were first examined. IL-2 is a chemical messenger protein produced by T-cells that have been exposed to an antigen (such as a virus). Newly formed IL-2 attaches to receptors on the T-cell, which are also created after antigen stimulation. When IL-2 attaches to these receptors, it activates T-cells and gets the immunologic ball rolling. The activated T-cells produce DNA and divide, resulting in exponential T-cell growth and full immunologic response to an infection.

IL-2 has been given to patients with HIV in an attempt to mimic the process explained above. The basic principles of IL-2 therapy are to stimulate innate and acquired immunity, to increase the number of CD4 and natural killer cells, and to augment the function of these cells. IL-2 was first used in extremely high doses (10 mg/dose) in cancer patients to destroy malignant tumors, and has also been used for the treatment of HIV in a low dose (1 mg/dose) in 5-day cycles given intravenously every two months (as in ACTG trial 328). For over four years, Dr. Smith and his colleagues have been testing ultralow dose IL-2 (<.1 mg/dose) administered daily by sub-cutaneous injection for the treatment of HIV. They have seen none of the side effects or toxicity present at higher dosing levels. When IL-2 is dosed intravenously, the doses clear the body quickly, and must be given twice a day to maintain an adequate concentration of the substance. Subcutaneous doses do not immediately enter the extracellular body space and can therefore remain in the body for a longer period. A lower overall concentration of IL-2 is achieved when it is dosed by subcutaneous injection at a low dose daily than when the substance is given intravenously, but Dr. Smith noted that a low concentration is all that is needed to saturate the IL-2 receptors on the body's T- and B-cells.

IL-2 in Clinical Trials

Results from an early study of IL-2 in HIV-infected patients were published in 1996 by Dr. Elizabeth Jacobson and Dr. Smith. The trial examined ultralow dose IL-2 in 16 patients with CD4 counts between 200 and 500 who had taken antiretroviral therapy for at least a month. After 6 months of subcutaneous daily IL-2 dosing, a mean increase of 27 CD4 cell counts per month was observed in the treatment group. There was no significant change in viral load for these patients. More recent studies have shown that people who begin treatment with an undetectable viral load can maintain that undetectable viral load.

Dr. Smith views therapy with low-dose IL-2 as synergistic with HAART therapy, and believes that if a person's viral load can be reduced by HAART and immune system function is boosted with IL-2, it may be possible to discontinue HAART. No one is sure if immune therapy can keep the virus under control, but long-term treatment with IL-2 without side effects is certainly a more appealing option than long-term treatment with HAART. Other questions remain, however. Dr. Smith mentioned the issue of latent provirus, that is, virus that is not immediately expressed, and thereby cannot be destroyed by HAART. He wishes to examine whether the immune system will be able to destroy this virus when it is expressed even if HAART has been discontinued. It is not known whether treatment with IL-2 will boost the immune system's memory, that is, its ability to respond to a virus to which it was previously exposed.

The Next Steps

As research with Remune and IL-2 continues in large-scale trials, some of the questions posed by forum speakers will certainly be addressed. Perhaps the most important issue is determining how to use IBTs in conjunction with HAART. One possibility for long-term management is to combine chronic IBT with intermittent HAART, and there are other combinations to be examined. The work of these two physicians has provided important background information for the trials yet to come.