Basic Virology. Martinez J. Hewlett

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.

Initial stages of infection – entry of the virus into the host

      The source of the infectious virus is termed the reservoir, and virus entry into the host generally follows a specific pattern leading to its introduction at a specific site or region of the body. Epidemiologists working with human, animal, and plant diseases often use special terms to describe parts of this process. The actual means of infection between individuals is termed the vector of transmission or, more simply, the vector. This term is often used when referring to another organism, such as an arthropod, that serves as an intermediary in the spread of disease.

      Many viruses must continually replicate to maintain themselves – this is especially true for viruses that are sensitive to desiccation and are spread between terrestrial organisms. For this reason, many virus reservoirs will be essentially dynamic; that is, the virus constantly must be replicating actively somewhere. In an infection with a virus with broad species specificity, the external reservoir could be a different population of animals. In some cases, the vector and the reservoir are the same – for example, in the transmission of rabies via the bite of a rabid animal. Also, some arthropod‐borne viruses can replicate in the arthropod vector as well as in their primary vertebrate reservoir. In such a case the vector serves as a secondary reservoir, and this second round of virus multiplication increases the amount of pathogen available for spread into the next host.

Some reservoirs are not entirely dynamic. For example, some algal viruses exist in high levels in many bodies of freshwater. It has been reported that levels of some viruses can approach 10⁷ per milliliter of seawater. Further, the only evidence for the presence of living organisms in some bodies of water in Antarctica is the presence of viruses in that water. Still, ultimately all viruses must be produced by an active infection somewhere, so in the end all reservoirs are, in some sense at least, dynamic.

Viruses (or their genomes) enter cells via the cooperative interaction between the host cell and the virus – this interaction requires a hydrated cell surface. Thus, initial virus infection and entry into the host cell must take place at locations where such cell surfaces are available, not, for example, at the desiccated surface layer of keratinized, dead epithelial cells of an animal's skin, or at the dry, waxy surface of a plant. In other words, virus must enter the organism at a site that is “wet” as a consequence of its anatomical function or must enter through a trauma‐induced break in the surface. Figure 2.4 is a schematic representation of some modes of virus entry leading to human infection.

The incubation period and spread of virus through the host

      Following infection, virus must be able to replicate at the site of initial infection in order for it to build up enough numbers to lead to the symptoms of disease. There are several reasons why this takes time. First, only a limited amount of virus can be introduced. This is true even with the most efficient vector. Second, cell‐based innate immune responses occur immediately upon infection. The best example of these is the interferon response.

Figure 2.4 Sites of virus entry in a human. These or similar sites apply to other vertebrates.

      Source: Adapted from Mims, C.A. and White, D.O. (1984). Viral Pathogenesis and Immunity. Boston: Blackwell Science.

This “early” stage or incubation period of disease can last from only a few days to many years, depending on the specific virus. In fact, probably many virus infections go no further than this first stage, with clearance occurring without any awareness of the infection at all. Also, some virus infections lead only to replication localized at the site of original entry. In such a case, extensive virus spread need not occur, although some interaction with cells of the immune system must occur if the animal host is to mount an immune response.

      Following entry, many types of viruses must move or be moved through the host to establish infection at a preferred site, the infection of which results in disease symptoms. This site, often referred to as the target tissue or target organ, is often (but not always) important in mediating the symptoms of disease, or the spread, or both.

      There are several modes of virus spread in the host. Perhaps the most frequent mode utilized by viruses is through the circulatory system (viremia). A number of viruses can spread in the bloodstream either passively as free virus or adsorbed to the surface of cells that they do not infect, such as red blood cells. Direct entry of virus into the lymphatic circulatory system also can lead to viremia. Some viruses that replicate in the gut (such as poliovirus) can directly enter the lymphatic system via Peyer's patches (gut‐associated lymphoid tissue) in the intestinal mucosa. Such patches of lymphoid tissue provide a route directly to lymphocytes without passage through the bloodstream. This provides a mode of generating an immune response to a localized infection. For example, poliovirus generally replicates in the intestinal mucosa and remains localized there until eliminated; the entry of virus into the lymphatic system via Peyer's patches leads to immunity. Virus invasion of gut‐associated lymphoid tissue is thought to be one important route of entry for HIV spread by anal intercourse, as infectious virus can be isolated from seminal fluid of infected males.

Infection of lymphoid cells can also be a factor in the spread of infectious virus. HIV infects and replicates in T lymphocytes and macrophages, leading to the generation of active carrier cells that migrate to lymph nodes. This facilitates spread of the virus throughout the immune system. Many other viruses infect and replicate in one or another cells of the lymphatic system. Some of the viruses known to infect one or another of the three major cells found in lymphatic circulation are shown in Table 2.1.

While spread via the circulatory system is quite common, it is not the only mode of general dissemination of viruses from their site of entry and initial replication in animals. The nervous system provides the other major route of spread. Some neurotropic viruses, such as HSV and rabies virus, can spread from the peripheral nervous system directly into the central nervous system (CNS). In the case of HSV, this is a common result of infection in laboratory mice; however, it is a relatively rare occurrence in humans, and is often correlated with an impairment or lack of normal development of the host's immune system. Thus, an initial acute infection of an infant at the time of birth or soon thereafter can lead to HSV encephalitis with high frequency.

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