Immune-Based Therapies

Slowly but surely, immune-based therapies (IBTs) are beginning to steal some of the spotlight away from HAART. Given what is now known about the limitations of HAART, many researchers are now focusing on some of the impressive research involving IBTs. In recent months, numerous researchers have been suggesting -- with a hearty amount of bravura and confidence -- that IBTs will prove to be the answer to HAART's shortcomings.

Unfortunately, this new wave of research comes along with much of the same controversy and confusion that has plagued IBT research for years. Unlike antivirals, which have been clinically proven to keep HIV-infected people healthier and alive longer, no IBT has yet been proven to have the same effect. In essence, the burden of proof falls twice on IBTs: Not only must they live up to their suggested biological activities, they must also prove to have a safe and significant impact on the length and quality of patients' lives.

HAART and the Immune System: A Primer

We've come a long way from CD4 counts, baby. Not long ago, all researchers could hope for was that antivirals would boost the amount of an HIV-infected patient's T-cells. Then came combination therapy, viral load, and the quest towards maximal viral suppression. Today, the stakes are even higher: HAART must not only increase T-cells and suppress viral load, but must also aid in the restoration of some of the immune system's more complicated functions.

Many positive immunological effects of HAART have, in fact, been documented, including:

• The ability to reduce the number of hyper-active immune system cells, called CD38+ cells. A high CD38+ cell count can mean that the immune system is concentrating too heavily on HIV and not enough on other disease-causing pathogens; and

• The ability to correct the balance of memory CD4 cells (called CD45RO+ cells) and naive CD4 cells (called CD45RA+ cells), both of which are needed to help the immune system ward off new infections and keep old infections in check.

Some preliminary research has suggested that HAART can help at least temporarily rebuild a key part of the immune system's defense -- called the lymphoproliferative response (LPR) -- from infections like Candida, M. tuberculosis, and Pneumocystis. LPR is virtually nonexistent in almost all HIV-positive people except long-term nonprogressors.

Yet, HAART falls short of overcoming a few key immunological obstacles:

• The improved LPR associated with HAART is often short-lived. Moreover, the resulting LPR is very weak against HIV, meaning that the immune system remains incapable of initiating its own response to the virus.

• Eradication of HIV from the human host may prove to be impossible with HAART alone. Antiviral drugs are not active against latently infected, dormant immune cells harboring HIV, most of which can live for more than 10 years.

IBTs: The Final Frontier?

While HAART plays a large role in reconstituting the immune system, its activity is limited, at best. In striving towards more complete immune reconstitution, many research teams are now focusing on some of the following IBTs:

IL-2: Beyond the Basics

For many years, it has been known that recombinant interleukin-2 (IL-2) -- a synthetic version of the human cytokine responsible for stimulating CD4 cells -- can significantly increase CD4 counts in asymptomatic HIV-infected people (See Craig Sterritt's article in Volume 6, Number 4 of CRIA Update). Keeping up with the times, a great deal of data presented at the 12th World AIDS Conference confirmed that IL-2 combined with HAART increases CD4 counts more effectively than HAART alone. Yet, it is still not known whether or not these CD4 count increases are, in fact, clinically relevant. In other words, it's still not known whether or not IL-2 will keep patients alive healthier and longer.

While researchers continue to grapple with this fundamental question, some recent studies have zeroed in on some of the other immunological benefits of IL-2. According to Dr. Clifford Lane of the National Institutes of Health (NIH), IL-2 may play a role in eradicating HIV. According to Dr. Lane, IL-2 stimulates the cytokines IL-6, tumor necrosis factor, and GM-CSF, all of which can "turn on" latently infected cells harboring HIV. Once these cells are activated by IL-2, HIV is expelled and ultimately destroyed by antiviral drugs. Dr. Lane also suggests that IL-2 blocks T-cell death (apoptosis) caused by HIV. This, in turn, allows both naive and memory T-cells to proliferate and continue their important functions.

As promising as these theories are, they are currently based on test tube study results, imperfect mathematical models, and a healthy amount of optimism. Short of HIV eradication in a large number of patients, the utility of IL-2 therapy will remain unknown.

IL-10 and IL-12

Like IL-2, both IL-10 and IL-12 are synthetic versions of cytokines produced by the immune system. Both cytokines are currently being studied in clinical trials and both show great promise as IBTs.

Unlike IL-2 and IL-12 (discussed below), both of which are responsible for stimulating healthy anti-HIV functions of the immune system, the primary role of IL-10 is to suppress potentially harmful immune functions. In test tube and human studies, IL-10 has been shown to effectively reduce the levels of the following cytokines: IL-1a and b, IL-6, IL-8, GM-CSF, G-CSF, and TNFa, along with monocytes and other key cells. The reason for wanting to play down these cytokines is simple; they all have been shown to increase HIV production and to cause certain HIV-related symptoms, such as fever, fatigue, diarrhea, and weight loss. IL-10 is still in the early stages of clinical development, thus it has not yet been determined how effective it will be in terms of boosting the immune system, reducing viral load, and delaying disease progression. Results from studies thus far, however, have demonstrated IL-10 to be a relatively safe and well-tolerated regimen.

While there are a number of potentially useful roles of IL-12 therapy, the most plausible in terms of HIV is its ability to promote the growth of "TH1" cells. T-cells generally fall under two categories: TH1 cells and TH2 cells. The former are typically found in the earlier stages of disease and are synonymous with proper immune function, whereas the latter are frequently associated with disease progression. By stimulating the production of TH1 cells, IL-12 facilitates production of IL-2 and gamma-interferon, two cytokines that aid substantially in the immune response to HIV and other infections. Researchers studying IL-12 are being cautious; previous studies involving non-HIV-infected patients with kidney disease resulted in a high number of hospitalizations and a few deaths. As a result, several small safety studies are now being conducted prior to the development of larger efficacy studies.

HIV-1 Immunogen (Remune®)

Given what is known about the lack of a lymphoproliferative response (LPR) in people infected with HIV, even among those receiving HAART, researchers have been questioning whether or not HIV-1 immunogen (Remune®) can bolster the immune system's response, not only to opportunistic infections, but also to HIV. HIV-1 immunogen is also known as Salk immunogen, in honor of its inventor, Dr. Jonas Salk. Like Dr. Salk's polio vaccine, HIV-1 immunogen consists of whole virus (in this case, HIV) that has been slightly altered and killed. In earlier clinical trials of the compound, it was found to be extremely safe and associated with very few side effects.

Most recently, data from an efficacy study was presented at the 12th World AIDS Conference by Dr. Fred Valentine, an immunologist at New York University Medical Center. Dr. Valentine's study compared HIV-1 immunogen to placebo in 43 HIV positive patients, all of whom received HAART for the study's duration. After five months, patients receiving HIV-1 immunogen had moderately lower viral loads and higher T-cell counts than those receiving placebo. According to Dr. Valentine, patients receiving HIV-1 immunogen also showed "profound" increases in their anti-HIV LPR, a first for any type of anti-HIV or immune-based therapy.

As promising as these data seem, they remain controversial and have been subject to a litany of commentary. According to a powerful article written by treatment advocate Mike Barr in the August/September issue of TAGLine, published by the Treatment Action Group, very few conclusions can be drawn from Dr. Valentine's study. For starters, HIV-1 immunogen proved only to increase the LPR to the immunogen itself, along with a laboratory-derived strain of HIV; there is no evidence to suggest that the immunogen increased the immune system's sensitivity to the actual HIV strains in the patients' bodies. Moreover, it is unclear whether or not the LPR changes associated with HIV-1 immunogen are associated with any sort of clinical benefit (i.e., delayed diseased progression).

Cell Transfer Therapy

While there are many different types of cell transfer therapies being developed and studied, their basic premise is the same: Cells provided by the HIV-infected patient or a donor are collected, allowed to grow (and, sometimes, genetically modified in a laboratory), and then infused into the patient. If the cells are provided by and infused into the same patient, the process is known as an "autologous" infusion. Cells provided by another human or an animal donor are known, respectively, as "allogeneic" and "xenogeneic" infusions.

The intent of this process is to grow and infuse cells that will significantly boost the immune system's response to HIV. Researchers have also found that by genetically altering and infusing immune cells -- a process known as gene transfer therapy -- it may be possible to restart an immune system that has been altered or weakened due to HIV. Clinical trials of various cell transfer therapy techniques continue to yield promising results.

Conclusion

It is clear that many of the recent IBT research findings will provide research teams with a reinforced foundation from which to build new eradication and immune reconstitution models. Perhaps there is something good to be said for the controversy and confusion surrounding IBT research after all. as new avenues of research -- any of which may result in ground-breaking results -- are being generated.

Tim Horn is the Executive Editor of The PRN Notebook, published by Physicians' Research Network in New York.

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