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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.

Table 2.1 Some viruses that replicate in cells of the immune system.

Cells Infected	Virus
B lymphocytes	Epstein–Barr virus (herpesvirus)
Some retroviruses
T lymphocytes	Human T‐cell leukemia virus
HIV
Human herpesvirus 6
Human herpesvirus 7
Monocytes	Measles virus
Varicella‐zoster virus (herpesvirus)
HIV
Parainfluenza virus
Influenza virus
Rubella (German measles) virus
Cytomegalovirus (herpesvirus)