AIDSWEEKLY Plus, 19 August 1996
Daniel J. DeNoon, Senior Editor

Paul's comments carry substantial weight, as he is director of the Office of AIDS Research at the National Institutes of Health.

"It must be said that our application of advances in immunoregulation has been disappointing, to say the least," Paul said. "In principle, we are using immunization techniques that might have been employed 50 years ago with products that could not have been available even five years ago."

Paul spoke as part of the Distinguished Lecturer Series at the XI International Conference on AIDS, held July 7-12, 1996 in Vancouver, British Columbia, Canada.

He noted that the world faces "a dreadful duality" wherein increasingly successful therapies against HIV and opportunistic infections are available only to wealthy nations and not to the rest of the world, where more than 90 percent of new HIV infections occur.

"This unacceptable duality can only be addressed by the introduction of truly effective prevention measures and a reinvigorated vaccine effort," he said.

"We must explore two issues: why natural immunity against HIV has failed, in the great number of individuals, to protect them against the development of AIDS; and why our initial efforts to develop protective vaccines have been so disappointing."

Paul pointed to the successful protection of macaque monkeys by a live attenuated SIV vaccine as "persuasive evidence" that a protective HIV vaccine is possible.

"During the past decade, immunoregulation has become an independent field of immunological science, providing us with cellular and molecular explanations for aspects of the immune response that were previously simply observations," he said. "I believe that the vaccine research agenda ... must include a detailed examination of the components of the response and of how we can intervene to maximize the effectiveness of vaccines."

Exposure to natural or vaccine antigens, Paul noted, ideally would result in an immune response characterized by three principal phases:

• A period of activation and expansion of immune cells specific for the antigen. These cells not only become more numerous but also undergo an event critical to the establishment of immunity: differentiation. During this process, immune cells acquire new functions such as the ability to produce cytokines or to mediate the activities of killer cells.
• Researchers have only recently begun to appreciate the period following expansion, Paul suggested. This is the period characterized by the death of the vast majority of the expanded cells via a process known as programmed cell death or apoptosis. "This death is a physiological process, presumably evolved to deal with the potentially negative consequences of preserving very large numbers of cells specific to an individual antigen and so limiting the diversity of future response the immune system may be required to mount," he said.
• In the third phase of the ideal immune response, the relatively few antigen-specific immune cells that escape apoptosis (either by chance or because they have differentiated to a memory state) form the basis for long-term immunologic memory.

But in HIV infection, the ideal immune response obviously does not take place. Paul suggested that this is because the rapid rate of HIV replication bombards T cells with a very high level of antigenic stimulation.

"These cells have not yet adapted or tuned themselves to confronting such stimuli," Paul said. "The biochemical consequence of such interaction is that a large fraction of the cells enter a state of immunologic unresponsiveness or anergy and fail to fully participate in the response. These anergic cells may survive and recover their activity, but the overall consequence of anergy induction is a response of substantially muted magnitude."

To prevent HIV from interfering with the first phase of the immune response, Paul recommended taking advantage of new insights into the process of co-stimulation.

Antigen-presenting cells (APCs) are far more likely to induce anergy if they lack the B7.1 or B7.2 surface molecules that interact with the CD28 stimulatory receptor on most T cells. APCs bearing B7.1 or B7.2 greatly increase the activation process with increased production of cytokines.

"The magnitude of normal responses can be strikingly enhanced by providing additional CD28-mediated signals, a process that can be achieved by agonist anti-CD28 antibodies," Paul said. "Such an interaction increases the magnitude of the primary response and thus markedly enhances the stabilized level of memory, providing a more effective response against a subsequent challenge."

On the other hand, Paul noted, T-cell activation is suppressed or even terminated when B7 molecules interact with the CD28 cogener known as CTLA-4. CTLA-4 is produced by a T- cell only after activation, thereby providing a natural termination of the immune response.

"To enhance the expansionary phase of the primary response, we could diminish the expression of CTLA-4, delay its appearance, or block its activity," Paul suggested. "Any or all of these approaches could be anticipated to result in a primary response of greater magnitude than normally achieved, and thus to induce an enhanced state of immunologic memory."

Another way to regulate the immune response to an infection such as HIV would be to intervene in the second phase of the immune response: apoptosis.

"Research on apoptosis is now one of the most exciting areas of immunological science, and advances in its understanding are occurring rapidly," Paul said.

The current understanding of apoptosis is that as immune cells are constantly restimulated, they express ever larger amounts of cell-surface receptors that transmit the message to self-destruct. Two types of these receptors have been studied in some detail: fas (a molecule that is mutated in the lymphoproliferative disease known as ALPS, and tumor necrosis factor receptors (TNFR).

At some point, expansion of immune cells leads to increased production of ligands for fas and TNF with subsequent initiation of apoptosis.

"To upregulate a suboptimal response, particularly one that induces modest degree of memory, I would propose diminishing the degree of apoptosis through the use either of general inhibitors of the process of programmed cell death, administered at an appropriate time in the immune response, or through the development of specific fas or TNF inhibitors," Paul said. "Such inhibitors should be used at a specified time in the response to achieve a diminished degree of programmed cell death and enhanced memory without the overall negative effects of blocking the physiologically important process of apoptosis over long periods of time."

Paul also suggested another manipulation to improve immune responsiveness to HIV and HIV vaccine antigens: the control of the relative numbers of CD4(+) T cells with the T helper type 1 (Th1) and Th2 phenotypes and the relative numbers of CD8(+) T cells with Tc1 and Tc2 phenotypes.

Th1 CD4(+) T cells are primed to secrete interferon gamma (IFN-g), lymphotoxin, and interleukin 2 (IL-2). These cells fight infections with intracellular pathogens such as viruses. Th2 CD4(+) T cells are primed to produce IL-4 and its cogeners; this enhances antibody responses that are most effective against infections by extracellular pathogens. However, Th2 responses also block Th1 responses.

Recently, Tc1 and Tc2 CD8(+) T cells have been recognized. Tc1 cells are cytotoxic T cells that secrete IFN-g.

"Enhancing Th1 and Tc1 responses at the outset of infection, as might be achieved in an appropriate vaccination protocol, appears to be a very desirable goal," Paul said.

He noted that the presence of IL-4 is the main factor determining whether a CD4(+) T cell will develop into a Th2 IL-4 producer, and that IL-12 primes T cells to become Th1 cells.

"One can therefore control the quality of immune responses by manipulating the cytokine environment," he suggested. "Thus, priming T cells with antigen in the presence of IL-4 and anti-IL-12 antibodies produces a highly polarized Th2 response. Priming in the presence of IL-12 and anti-IL-4 creates very striking Th1 and Tc1-like responses.

"A vaccine-induced anti-HIV response dominated by IFN-g producers could, therefore, be achieved by priming in the presence of IL-12 and an inhibitor of IL-4. Today, that would involve anti-IL-4 antibody and IL-12, but if this proved to be a useful strategy in preparing individuals to make a more effective anti-HIV response, we would almost certainly want to find molecules that could inhibit IL-4 and mimic IL-12 function that would be more suitable for wide use."

Paul was emphatic that implementation of any of the approaches he suggested will required "major investment in both basic and targeted investigation."

However, he also stressed the need for continuation of ongoing efforts to find the best targets for an HIV vaccine, to overcome HIV heterogeneity and mutability, to develop the best delivery systems for HIV antigens, and to find products practical for global use.

"With such advances we will have the potential to revolutionize vaccine development for HIV and other pathogens," he said.

Paul praised the "spectacular progress" already made in basic immunology and in immunoregulation and suggested that this progress has set the stage for an aggressive HIV vaccine research agenda.

"The development of such a research agenda and its implementation, coupled with strong encouragement for advances in the preparation of key proteins, in vector development, and in DNA immunization techniques, gives me great hope that a truly effective anti-HIV vaccine can be achieved," he said.

Paul embraced the recommendations of the recently completed review of the NIH AIDS research program chaired by Arnold Levine of Princeton University.

"I am committed to a restructured, redirected vaccine research program under the leadership of an eminent non- government scientist and to a strong prevention sciences research portfolio," he said. "In parallel, as OAR director, I am proposing budgets that emphasize investigator-initiated research and the acquisition of new knowledge in human immunology."

Paul also stressed that the U.S. vaccine-research initiative would have as a central goal the development of a globally accessible product.

"We cannot neglect the effort to produce a highly effective vaccine that can be made available to all populations at risk throughout the world," he said. "Through the use of all the scientific tools at our disposal I believe we can, and we must, develop the means to end this human scourge."

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