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This book has specialized in the dynamics of killer cell responses to viral infections. That is, we investigated the principles according to which CTL responses develop against viruses in vivo, how they fight the infection, and how viruses can fight back and subvert the CTL response. In other words, we concentrated on the interactions between populations of viruses and species of immune cells within the body of a host. [ABSTRACT FROM AUTHOR]

Chapter 11 explored the topic of virus-induced suppression of specific immune responses. In particular, we concentrated on the importance of helper cell impairment because this is a central feature of several persistent human viruses, such as HIV, HBV, and HCV. As explained in chapter 4, helper cell responses can be crucial for the resolution of viral infections by CTL. Therefore, if the impairment of helper cell responses can be reversed by treatment, long-term immunological control of the infection could be achieved without the need for further therapy. Long-term immune mediated control is a particularly desirable outcome with these persistent human infections because drug therapy comes with severe side effects and is difficult to tolerate. The subject of this chapter is to explore how therapy can be used to achieve long-term immunological control of immunosuppressive infections. [ABSTRACT FROM AUTHOR]

Chapters 7, 8, and 9 have discussed effector molecules in relation to their direct antiviral activity: to kill infected cells or to inhibit the spread of the virus from cell to cell by nonlytic means. We discussed the role of the different types of effector mechanisms for the successful resolution of infection, and how the exact balance between lytic and nonlytic effector mechanisms can determine whether pathology is observed or not. However, experimental data indicate that the effector molecules might have a broader function than just antiviral activity [(2000)]. In addition, they might serve as regulatory molecules that determine the extent to which the population of CTL expands in response to antigenic stimulation. Experimental data indicate that the amount of effector molecules that are secreted by CTL can influence the peak size of the CTL response, as well as the number of CTL found in the memory phase after the infection has been resolved. Of particular interest in this respect are mice that have deficiencies in either perforin or IFN-γ. Perforin is the main effector molecule that is responsible for CTL-mediated lysis, while IFN-γ is known to be a CTL-secreted soluble mediator that inhibits viral replication in several infections, for example LCMV. A deficiency in either perforin or IFN-γ, or both, has been observed to result in higher levels of CTL both in the acute and the post acute phase of infections [(2000); (1999); (2000)]. [ABSTRACT FROM AUTHOR]

So far, this book has discussed how CTL responses can fight viral infections, leading to their successful resolution and clearance. On the other hand, viruses have the ability to avoid clearance by a variety of mechanisms. A very prominent mechanism that has been documented in the context of several pathogens is antigenic escape. Viral epitopes acquire mutations that prevent the CTL response from recognizing the epitope. Consequently, the infected cell is not attacked by the CTL. HIV is probably the best known virus that shows extensive antigenic escape [(1996); (1997); (2001); (1991); (1997a); (1999)]. Because HIV has a relatively high mutation rate, escape mutants are readily generated and this can contribute to the inability of the CTL response to fight HIV effectively, and it might contribute to the eventual development of AIDS. HCV infection is another example of a human pathogen that can readily acquire mutations, allowing it to escape from immune responses [(2000)]. Another mechanism to avoid immune-mediated clearance is to establish a latent infection [(1999)]. This means that cells can be infected by the virus, but once inside the cell, the virus is silent and does not produce further progeny viruses for prolonged periods of time. If the virus is silent, the CTL cannot recognize that the cell is infected, because no viral proteins are produced. If the cell is sufficiently long-lived, it can carry the virus and provide a reservoir for viral persistence. At certain time intervals, the virus can reactivate in the cells and start producing new virus particles. This is called the lytic phase of the infection, and the CTL response tends to prevent growth of the virus to high numbers. Thus, while the CTL manage to control the virus in this case, latent infection of cells prevents clearance of the virus. [ABSTRACT FROM AUTHOR]

Chapter 8 discussed how lytic and nonlytic CTL responses influence the outcome of infection, what balance of responses is required to control different infections, and how the occurrence of pathology can be avoided. Much of this discussion focused on one type of immune cell, the CTL, that can perform both lytic and nonlytic antiviral activity. As already mentioned in Chapter 8, however, nonlytic CTL responses effect viral spread in the same way as an antibody response. Like nonlytic CTL responses, antibodies also inhibit the rate of virus spread, without killing the infected cells. Antibodies are a major branch of the immune system, and contribute significantly to nonlytic antiviral activity. However, there is an important difference compared to nonlytic CTL responses. Antibodies are produced by B cells that are a separate population of cells from the CTL. Both B cells and CTL proliferate in response to stimulation by the same virus. Therefore, they are in competition with each other for antigenic stimulation [(2000); (1995a)]. For example, if the CTL response suppresses virus load to levels that are too low to stimulate the B cells, then a successful B cell/antibody response might not be generated. Conversely, if the B cells reduce virus load to levels that are too low to stimulate the CTL, a successful CTL response will not be established. These competition dynamics add complexity to the situation, because the outcome of competition will influence the relative balance between lytic and nonlytic immune responses that fight a given virus. [ABSTRACT FROM AUTHOR]

Chapter 7 discussed the concept of CTL-induced pathology, where CTL-mediated lysis of infected cells can lead to tissue damage and mortality of the host, instead of virus control. A fast rate of viral replication relative to the efficacy of the CTL was found to promote the occurrence of CTL-induced pathology. Lysis of infected cells, however, is not the only mechanism by which CTL can fight viral infections (Fig 8.1). CTL can also secrete soluble factors that bind to infected cells [(1994a)]. This triggers a reaction inside the cell that inhibits virus replication (Fig 8.1). Consequently, while the cell remains infected and is not killed, it stops producing virus particles and does not contribute to virus spread anymore. This type of mechanism is called nonlytic activity of CTL. There are examples of this mode of CTL-mediated activity across several infections. In LCMV infection, IFN-γ, secreted by CTL, can reduce the rate of viral replication [(2000)]. In HIV infection, a soluble factor has been identified that can stop virus production by infected cells. It has been termed CTL secreted antiviral factor (CAF), and its exact identity if subject to debate [(1996); (2002)]. In addition, HIV specific CTL can secrete chemokines that can inhibit the entry of certain HIV strains into their target cells [(1995); (1997); (1997); (1997)]. nonlytic CTL responses are thought to play an important role in HBV infection [(1994b); (1999a); (1996); (1996a); (1999b)]. [ABSTRACT FROM AUTHOR]

A major mechanism by which CTL fight viruses is the lysis or killing of infected cells. This removes the source of virus production and contributes to virus clearance. As discussed in Chapter 8, lysis of infected cells can be essential for the resolution of infection [(1999); (1996); (1995b); (1998); (1999)]. This form of antiviral activity can, however, also have a negative impact on the host [(1971); (1993c); (1996)]. If many cells are infected, then lysis of these cells can lead to a significant amount of tissue damage. This can result in pathology, and even in the death of the host. Such damage, brought about by CTL responses that fight an infection, is referred to as CTL-induced pathology. [ABSTRACT FROM AUTHOR]

When CTL dynamics are analyzed, we usually consider a CTL response in the context of a single specific virus. Upon infection, the CTL response expands, attains effector activity, fights the virus, and differentiates into memory cells. Memory cells survive at elevated levels for a prolonged period of time after the resolution of infection. However, hosts are exposed to a wide variety of infections over their lifespan. Each infection can potentially elicit CTL responses that expand and build memory. This brings up a problem. As the host gets infected by different pathogens, the total number of CTL would increase over time as more and more populations of memory cells are created. However, this does not occur. Instead, experiments have shown that a given infection can result in the decline of the CTL memory population that was established in response to a previous unrelated infection (Fig 6.1) [(2003); (1999; (1996); (1995)]. Thus, already established CTL memory is diminished upon exposure to heterologous antigen. It appears that the second infection activates the CTL memory population that was established in response to a previous infection trough bystander effects. Once activated, however, these CTL do not receive any further survival signals because they are not specific for the antigen that is currently present in the system. Consequently, they die and the population of memory cells declines. [ABSTRACT FROM AUTHOR]

The chapters so far have investigated the dynamics between CTL and viral infections, assuming that a single population of CTL fights a population of viruses. The situation is, however, more complex than this (Fig 5.1). The immune system can generate a huge diversity of T cells that are specific to different antigens. A given virus consists of many parts that can all be potentially recognized by CTL. These are called viral epitopes. Therefore, several different CTL can exist that can recognize different epitopes of the same virus. Each of these CTL can become activated and undergo clonal expansion upon infection. Consequently there is not a single CTL response against an infection. Instead, there are multiple CTL responses or clones that fight the same virus population. [ABSTRACT FROM AUTHOR]

The two main branches of the adaptive immune system that directly fight infections are the CTL and the antibodies. The adaptive immune system, however, contains another branch: the CD4 T helper cells. Just as the CTL, they bear a T cell receptor that can specifically recognize antigen. Instead of the CD8 surface receptor that is found on CTL, the helper cells bear the CD4 receptor. Upon antigenic stimulation, the helper cells become activated, undergo clonal expansion, and differentiate into memory cells. While it has been documented that CD4 T cells can have direct antiviral activity [Doherty et al. (1997)], this is thought to be not their main function. As their name implies, their prevalent function is to help the CTL and antibody responses to develop and to fight the infection. This chapter investigates the dynamics of CD4 T cell help in the context of CTL responses. [ABSTRACT FROM AUTHOR]

Immunological memory is a central characteristic of the immune system [(1996); (1996); (1996; (2000a)]. Nevertheless, there is no simple definition of this concept. The easiest definition is on the functional level: a host is protected more ef- ficiently against a second infection if it has previously been infected with the same pathogen, and survived the infection. Before the host has encountered a pathogen it is said to be naive. This means that the number of immune cells that are specific for this pathogen is relatively low. When the host is infected with this pathogen for the first time (primary infection), the population of specific immune cells expands, fights the pathogen, and subsequently settles around a relatively stable level that is much higher than in the naive host. This population of cells is referred to as memory cells, and memory persists in the long-term after pathogen clearance. Upon reinfection with the same pathogen (secondary infection or rechallenge), this population of memory cells can react more efficiently against the invading virus compared to a naive host. Consequently, the host suffers less or no pathology. Memory is found in all adaptive branches of the immune system: B cells (or antibody) responses, as well as T cell responses. Vaccinations rely on the generation of memory: the immune system is artificially exposed to a pathogen (or an immunogenic part of the pathogen), and this results in the generation of immunological memory and in protection against infection. While the population of memory cells is maintained in the long-term after clearance of a pathogen, it declines slowly, and this can lead to a loss of protection over time. It is unclear for how long hosts are protected against reinfection, and this may vary from case to case. [ABSTRACT FROM AUTHOR]

This chapter will introduce basic mathematical models that have been used to study the dynamics between virus infections and CTL responses. These models range from very simple and phenomenological to more complicated models that try to capture many biological details explicitly. This range also represents the development of these models over time, as more and more biological information became available from experimental research. Yet, even the models that are based on latest biological information still include uncertain assumptions because the appropriate biological and molecular details have not been fully worked out so far. [ABSTRACT FROM AUTHOR]

One of the most complicated organs of higher organisms is the immune system. The function of the immune system is to fight off pathogenic organisms that enter and grow within the host (for example viruses, bacteria, unicellular eukaryotic parasites such as malaria, and multicellular parasites such as worms). Detailed molecular research has elucidated how immune cells function, that is, how they recognize an invading pathogen and mount orchestrated responses that fight the infection and protect the host. In addition to understanding how the individual components of the immune system work, it is also important to take a "systems approach" and to investigate how the complex interactions between the many components of the immune system work together and determine the outcome of an infection. In a nutshell, this is the subject of this book. In particular, the interactions between pathogens and the immune system can be viewed as an ecological system within the body of an organism. Specifically, the area of population ecology or population dynamics has relevance. Several species of immune cells interact with populations of pathogens in various ways. Two especially important population dynamic interactions that are found in the immune system are predator-prey interactions and competition. (i) When predators capture and kill their prey, they reproduce such that their population size grows. This in turn has a negative impact on the prey population. In the absence of prey, predators die. The outcomes of such interactions can involve cycles in the population sizes of predators and prey that can dampen over time. [ABSTRACT FROM AUTHOR]