as well characterized in plants as in animal and bacterial cells.
Stages of virus replication in the cell
Various patterns of replication as applied to specific viruses, as well as the effect of viral infections on the host cell and organism, are the subject of many of the following chapters in this book. The best way to begin to understand patterns of virus replication is to consider a simple general case: the productive infection cycle – this is shown schematically in Figure 2.2. A number of critical events are involved in this cycle. The basic pattern of replication is as follows:
1 The virus specifically interacts with the host cell surface, and the viral genome is introduced into the cell. This involves specific recognition between virus surface proteins and specific proteins on the cell surface (receptors) in animal and bacterial virus infections.
2 Viral genes are expressed using host cell processes. This viral gene expression results in synthesis of a few or many viral proteins involved in the replication process.
3 Viral proteins modify the host cell and allow the viral genome to replicate using host and viral enzymes. While this is a simple statement, the actual mechanisms by which viral enzymes and proteins can subvert a cell are manifold and complex. This is often the stage at which the cell is irreversibly modified and eventually killed. Much modern research in the molecular biology of virus replication is directed toward understanding these mechanisms.
4 New viral coat proteins assemble into capsids, and viral genomes are included. The process of assembly of new virions is relatively well understood for many viruses. The successful description of the process has resulted in a profound linkage of knowledge about the principles of macromolecular structures, the biochemistry of protein–protein and protein–nucleic acid interactions, and the thermodynamics of large macromolecule structures.Figure 2.2 The virus replication cycle. Most generally, virus replication can be broken into the stages shown: (a) initial recognition between virus and cell and introduction of viral genetic material into the host cell, (b) virus gene expression and induction of virus‐induced modification of host, allowing (c) virus genome replication. Following this, (d) virus‐associated proteins are expressed, and (e) new virus is assembled and released, often resulting in cell death.
5 Virus is released where it can infect new cells and repeat the process. This is the basis of virus spread, whether from cell to cell or from individual to individual. Understanding the process of virus release requires knowledge of the biochemical interactions between cellular organelles and viral structures. Understanding the process of virus spread between members of a population requires knowledge of the principles of epidemiology and public health.
PATHOGENESIS OF VIRAL INFECTION
Most cells and organisms do not passively submit to virus infection. As noted in Chapter 1, the response of organisms to virus infection is a major feature of evolutionary change in its most general sense. As briefly noted, a complete understanding of pathogenesis requires knowledge of the sum total of genetic features a virus encodes that allows its efficient spread between individual hosts and within the general population of hosts. Thus, the term pathogenesis can be legitimately applied to virus infections of multicellular, unicellular, and bacterial hosts.
A major challenge for viruses infecting bacteria and other unicellular organisms is finding enough cells to replicate in without isolating themselves from other populations of similar cells. In other words, they must be able to “follow” the cells to places where the cells can flourish. If susceptible cells can isolate themselves from a pathogen, it is in their best interest to do so. Conversely, the virus, even when constrained to confine all its dynamic features of existence to the replication process per se, must successfully counter this challenge or it cannot survive.
In some cases, cells can mount a defense against virus infection. Most animal cells react to infection with many viruses by inducing a family of cellular proteins termed interferons that can interact with neighboring cells and induce those cells to become wholly or partially resistant to virus infection. Similarly, some viral infections of bacterial cells can result in a bacterial restriction response that limits viral replication. Of course, if the response is completely effective, the virus cannot replicate. In this situation, one cannot study the infection, and in the extreme situation, the virus would not survive.
Viruses that infect multicellular organisms face problems attendant with their need to be introduced into an animal to generate a physiological response fostering the virus's ability to spread to another organism (i.e., they must exhibit virulence). This process can follow different routes.
Disease is a common result of the infection, but many (if not most) viral infections result in no measurable disease symptoms – indeed, inapparent infections are often hallmarks of highly coevolved virus–host interactions. But inapparent or asymptomatic infections can be seen in the interaction between normally virulent viruses and a susceptible host as a result of many factors. A partial list includes the host's genetic makeup, host health, the degree of immunity to the pathogen in the host, and the random (stochastic) nature of the infective process.
Stages of virus‐induced pathology
Pathogenesis can be divided into stages – from initial infection of the host to its eventual full or partial recovery, or its virus‐induced death. A more‐or‐less typical course of infection in a vertebrate host is schematically diagrammed in Figure 2.3. Although individual cases differ, depending on the nature of the viral pathogen and the immune capacity of the host, a general pattern of infection would be as follows:
Initial infection leads to virus replication at the site of entry, and multiplication and spread into favored tissues. The time between the initial infection and the observation of clinical symptoms of disease defines the incubation period, which can be of variable length, depending on many factors.Figure 2.3 The pathogenesis of virus infection. Typically, infection is followed by an incubation period of variable length in which virus multiplies at the site of initial infection. Local and innate immunity, including the interferon response, counter infection from the earliest stages; and if these lead to clearing, disease never develops. During the incubation period, virus spreads to the target of infection (which may be the same site). The adaptive immune response becomes significant only after virus reaches high enough levels to efficiently interact with cells of the immune system; this usually requires virus attaining high levels or titers in the circulatory system. Virus replication in the target leads to symptoms of the disease in question and is often important in spread of the virus to others. Immunity reaches a maximum level only late in the infection process and remains high for a long period after resolution of the disease.
The host responds to the viral invasion by marshaling its defense forces, both local and systemic. The earliest defenses include expression of interferon and tissue inflammation. Ultimately the major component of this defense – adaptive immunity – comes into play. For disease to occur, the defenses must lag as the virus multiplies to high levels. At the same time, the virus invades favored sites of replication. Infection of these favored sites is often a major factor in the occurrence of disease symptoms and is often critical for the transmission to other organisms. As the host defenses mount, virus replication declines and there is recovery – perhaps with lasting damage and usually with immunity to a repeat infection. If an insufficient defense is mounted, the host will die.
