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From the online Merriam-Webster Dictionary:

 Evade: to elude by dexterity

 Modulate: to adjust to or keep in proper measure or proportion

The phrase “immune evasion” pervades the virology literature. It is intended to describe the viral mechanisms that thwart host immune defense systems. However, this phrase is imprecise and even misleading. The term “evasion” implies that host defenses are ineffective, similar to a bank robber evading capture by a hapless police force. In reality, a virus does not necessarily need to be invisible to the host response throughout its reproduction cycle; it simply must delay or defer detection for a time sufficient to produce progeny virus particles. If viruses really could evade the immune system, we might not be here discussing such semantic issues.

Perhaps a more accurate term to describe viral gene products that delay or frustrate host defenses is “immune modulators.” The principle is that, given the speed of viral reproduction, an infection can be successful even if host defenses are suppressed only transiently or partially.

From the moment of ectromelia virus entry, the host mounts a response to counteract the virus. The impact of such countermeasures is revealed by the effects of specific immune deficiencies, which lead to different kinds of disease. If the mouse lacks CD8⁺ T lymphocytes, a major immune cell population critical for destroying virus-infected cells, it will die of extensive liver destruction by 4 to 5 days after infection. If instead the host lacks the potent antiviral cytokine interferon gamma, the virus may be controlled in the liver, even though death will occur by 10 to 12 days after infection as a consequence of uncontrolled viral reproduction in the skin. Even in mice with intact immune responses, viral movement from tissue to tissue means that the immune response is continually playing catch-up: as infection is controlled in the liver, infection of the skin appears. Furthermore, while mice of a certain strain can control the infection and survive, mice of a different strain may not, underscoring the critical involvement of more subtle genetic regulators of immune control.

Just as ectromelia advances through various permissive tissues of the host, the host defenses are deployed in a coordinated, stepwise manner (Fig. 2.2). All surfaces of the mammalian body where pathogens may enter are protected by defensive layers provided by fur, skin, and mucus, or are acidic environments. Once these barriers are crossed and cells become infected, intrinsic cellular defenses including cell-autonomous responses, such as autophagy and cell suicide, are engaged. Because the virus may reproduce faster than an infected cell can control it, the “professional” immune response is also induced, beginning with the early innate response (Chapter 3). Eventually, virus-specific cells of the adaptive response arrive at the site of infection, targeting infected cells and extracellular virus particles for destruction or elimination (Chapter 4).

While this text generally avoids imparting actions to viruses, the impression one may have gained from the ectromelia virus example is that viruses are on a seemingly preordained, step-by-step path to gain access to their target cells of choice (for example, hepatitis viruses in hepatocytes, measles virus in epithelia, or human immunodeficiency virus type 1 in CD4⁺ T cells). Likewise, one might think that the immune response is deployed in a synchronized and choreographed manner, much like actors performing a play night after night. These impressions would be wrong. As every game of chess is constrained by the same rules, but each game differs in execution and outcome, so too are viral infections and host immunity influenced by random, or stochastic, events. For example, tissues and the immune system may impose bottlenecks on the dissemination of a virus population. The diversity of viral populations enables some particles to pass through the bottleneck, while others are lost as the virus spreads (Chapter 10). Such bottlenecks include not only access to tissues but also immune restriction (Fig. 2.3). The stochastic view does not reject the idea that infections generally follow a predictable course, but rather adds random elements to the consequences of each step that could affect the speed of viral transmission throughout the host, the immunological control of the virus, or the magnitude of illness experienced by the infected host.

Figure 2.1 Ectromelia virus infection of mice. Infection begins with a break in the skin, allowing the virus to access susceptible and permissive cells, with ensuing local viral reproduction and dissemination via the lymphatics within 1 to 2 days of exposure. Experimentally, virus can be injected into the footpad. Primary viremia occurs when the virus is released into the bloodstream, permitting infection of the spleen, liver, and other organs, greatly amplifying the number of viral particles within the host. Secondary viremia occurs as a consequence of release of virus from these organs, resulting in infection of distal sites of the skin. In certain inbred strains, as well as in wild mice, a severe rash may develop. Adapted from Fenner F et al. 1974. The Biology of Animal Viruses (Academic Press, New York, NY), with permission.