Over the past two decades, effective antiviral drugs have transformed AIDS from a death sentence to a manageable disease. But can something be done to restore the immune system after it has been compromised by infection with HIV? Researchers in the laboratory of Dr. Laura Napolitano at the Gladstone Institute of Virology and Immunology have begun to provide some answers.

The immune system protects us from infection and is vital to our health. An army of immune cells, positioned strategically throughout our body, act as sentries to guard against bacteria, viruses, and other infectious agents that may threaten us. These sentry cells may eliminate infectious agents on their own, or they may activate a second class of immune cells, the lymphocytes, which mount a powerful and specific response to destroy the invaders.

One class of lymphocytes, the T cell, is especially important in controlling and eradicating infection. There are two types: killer T cells (also called CD8 T cells) seek out infected cells and kill them, and helper T cells (also called CD4 T cells) provide essential help to many cells of the immune system.

 
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Changes in thymic weight and composition with age. The thymus sits in the middle of the chest just above the heart. In infancy, it consists almost entirely of thymic tissue filled with developing T cells. This tissue consists of two regions: cortex and medulla. In the teen years, fat tissue begins to replace the cortex and medulla. By middle age, the thymus space consists chiefly of fat surrounding small patches of cortex and medulla.

 
Our body is normally protected by millions of T cells. Remarkably, each T cell recognizes a unique target, providing us with a broad and strong defense. T cells are produced by the thymus, where they develop and are educated to recognize anything foreign to our body. Most T cells are made before birth or during the early years of childhood.

Because T cells are intended to last for life, the thymus undergoes a process during childhood termed thymic involution, in which fat gradually replaces functional thymic tissue. Thus, the number of newly made T cells declines steadily with age, and adults have very little functional thymus. The absent thymus is not a problem for most adults. However, for some individuals who develop T-cell deficiency due to HIV infection, chemotherapy, or bone marrow transplantation, the lack of a functional thymus makes it difficult to rebuild a strong immune system.

 
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T-cell development and infection by HIV. Newly made CD4 and CD8 T cells leave the thymus and circulate through the blood and into the lymph nodes, where they rest until they “see” the specific target they are designed to destroy. T cells that have not yet seen their target are called naive T cells. Naive T cells may spend minutes or decades lying in wait for their specific target. Once a naive T cell sees its designated target (also called an antigen), it proliferates, creating many copies of itself so that it can successfully fight off infection. Proliferating CD4 and CD8 naive T cells mature into CD4 and CD8 memory/effector T cells that eradicate infection and remain in our body, allowing our immune system to quickly “remember” and remove infectious agents if they reappear. HIV may infect CD4 cells at all stages, including developing cells in the thymus, naive cells, and memory/effector cells. By infecting cells in the thymus, HIV interferes with the production of new T cells. If new T cells cannot be made to replace those that are destroyed, immune system failure is inevitable.

 
Destruction of the Immune System by HIV

By infecting and destroying CD4 helper T cells, HIV compromises the immune system in a variety of ways. Without the “help” provided by the CD4 helper T cells, the CD8 killer T cells and other types of immune cells cannot do their jobs effectively. In addition, HIV may disrupt the production of new T cells by infecting and killing immature CD4 helper T cells that are developing in the thymus. As more and more CD4 helper T cells are lost, the immune system eventually fails, leading to illness or death from infection.

Potent new medical therapies can partially reverse the destructive effects of HIV, but recovery of the immune system is often incomplete. Consequently, there is growing interest in identifying ways to rebuild the immune system. CD4 T cells—the primary immune targets of HIV—are not easily replaced. The thymus, which produces these cells, is relatively inactive in adults, making it especially difficult to fully reconstitute the adult immune system. Thus, agents that stimulate the thymus to produce T cells may have a therapeutic role in HIV infection or other conditions.

Investigating Therapies to Rebuild the Immune System

Although it has been long assumed that the thymus cannot be reactivated in adults, recent research by Dr. Napolitano, her Gladstone colleague Dr. Joseph M. McCune, and collaborators at the University of California, San Francisco, has challenged this assumption. These investigators have been conducting innovative research into therapies to stimulate immune recovery.

Effects of GH therapy in HIV-infected adults assessed by computed tomography scans of the thymus and analysis of naive T cells. (A) Before treatment, the thymus was nearly black, consistent with the density of fat. (B) After 6 months of GH treatment, thymic density was markedly increased, and the formerly black tissue was replaced by brighter tissue consistent with cellular thymus. Arrows indicate the thymus. Flow cytometric analysis before (C) and after (D) therapy showed a corresponding increase in the number of naive CD4⁺ T cells (upper right quadrant). These results are representative of changes seen in all GH-treated individuals in the study.

 
Based on promising animal studies suggesting that growth hormone (GH) enhances thymic function in aged mice, Dr. Napolitano led a research study that yielded an exciting observation: GH appears to reverse thymic involution and to facilitate immune reconstitution in HIV-infected adults. The investigators treated five HIV-infected adults with GH for 6–12 months. Immune analyses were performed before initiation of GH therapy and every 3 months during therapy. Thymic mass was assessed by computed tomography, and the numbers and types of lymphocytes circulating in the blood, including naive and memory T-cell subsets, were determined by an advanced method called multiparameter flow cytometry.

The results were striking. Thymic mass increased markedly in the GH recipients. Circulating naive CD4 T cells also increased significantly, suggesting an enhancement of thymic function. These promising results suggest that it may be possible to turn on T-cell production in immunodeficient individuals. A larger study of HIV-infected adults is under way at the Gladstone Institute of Virology and Immunology to further investigate the effects of GH on the immune system.

Interleukin (IL)-7 is another potential enhancer of T-cell production. Research led by Dr. Napolitano and her Gladstone colleagues indicated that IL-7 may be an important regulator of the number of T cells in the body. IL-7 enhances T-cell production by providing crucial survival signals to developing human T cells. IL-7 also appears to increase the number of T cells in the body by stimulating the expansion of existing mature T cells. Preliminary tests of IL-7 in humans are just now getting under way. The potent effects of IL-7 on T cells make it an attractive future candidate to increase T-cell production during HIV infection.

 
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New T-cell production by the thymus versus expansion of mature T cells. Each T cell recognizes a different target. In this figure, the diversity of targets is represented by different colors and letters of the alphabet. For instance, a T cell that recognizes target “A” may fight the flu virus, whereas a T cell that recognizes target “B” may fight a bacterial infection. T-cell diversity lost to HIV infection is not repaired by expansion of pre-existing mature T cells but can be improved by new synthesis of T cells in the thymus.

 
Immune-Based Therapies: Further Considerations

Exploration of immune-based therapies for the treatment of immune deficiency is growing, but much remains to be learned about the specific effects of these therapies on the recovery of the immune system. Research at Gladstone is exploring how GH works to improve human T-cell production. IL-7 may act by stimulating new T-cell production or by promoting mature T-cell expansion. Knowledge of the specific effects of these agents on the immune system may provide important information to devise therapeutic strategies in the future.

T cells in the body normally recognize 100 million unique targets. With HIV-related T-cell depletion, much of this diversity can be lost. Therapies that promote expansion of existing T cells will increase the number of mature cells that recognize a set number of potential targets. In contrast, therapies that promote new T-cell production by the thymus may restore the diversity of the T-cell repertoire that is lost during HIV infection. It remains unclear, however, what the best therapeutic approaches to immune system reconstitution might be.

Additional studies of potential immune therapies are ongoing at the Gladstone Institute of Virology and Immunology. Those studies will help to answer critical questions about the immune system and contribute to therapies to rebuild the immune system in HIV-infected persons. In the future, these therapies may become a valuable part of treatment for human immunodeficiency from HIV and perhaps other immunodeficiency conditions as well.

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