Basic Virology. Martinez J. Hewlett

        Viral and subviral diseases with long incubation periods Rabies HIV/AIDS Prion diseases

        SOME VIRAL INFECTIONS TARGETING SPECIFIC ORGAN SYSTEMS

        Viral infections of nerve tissue

        Examples of viral encephalitis with grave prognosis Rabies Herpes encephalitis

        Viral encephalitis with favorable prognosis for recovery

        Viral infections of the liver (viral hepatitis) Hepatitis A Hepatitis B Hepatitis C Hepatitis D Hepatitis E

        QUESTIONS FOR CHAPTER 4

THE DYNAMICS OF HUMAN–VIRUS INTERACTIONS

      We have seen that the process of infection and consequent disease is controlled by a number of factors ranging from the effect of specific genes controlling aspects of pathogenesis to more subjective factors that can be classified as important in overall virulence of the disease. The nature of the viral disease – or more accurately, the viral infection, its severity, the fate of the host, and the fate of the virus causing the disease – is important from a purely medical point of view. But, as importantly, the features of the dynamic interaction between virus and host provide important clues as to how long a particular virus has been associated with its host. Further, the nature of the interaction provides clues as to the evolutionary history of the host.

The stable association of viruses with their natural host places specific constraints on the nature of viral disease and mode of persistence

      As noted in Chapter 3, viruses are maintained by active rounds of infection somewhere in their reservoir. We have seen that a virus infection leading to immunity to re‐infection will lead to virus extinction in a small population once the pool of susceptible individuals is exhausted. Also, even in a large reservoir, if the virus infection directly or indirectly leads to death of a large enough number of individuals, the host population of the reservoir will crash and, in extreme cases, may become extinct. Clearly, a virus that can only replicate within that population will also become extinct. These limitations, which can be described with precision using the mathematics of population biology and epidemiology, lead to a number of evolutionary constraints on the dynamics of the virus–host interaction. Viruses whose infection leads to an acute disease followed by clearing and immunity need a large host population, while the outcome of the disease cannot be too lethal or the virus cannot be maintained. If infection results in mild or inapparent symptoms, however, there still must be efficient spread. This latter pattern of virus infection is a common feature of viruses with animal reservoirs that contain large populations, such as flocks of migratory birds or herds of ungulates. Since the agricultural/urban revolution starting about 10 000 years ago, which engendered rapid increases in our population, urbanized human populations fit these criteria also.

The early history of humans, however, was not one of large sedentary populations. Rather, our ancestors lived in small, nomadic groups organized along familial lines. This organization is similar in broad outline to that of predators such as wolves and large cats. In such a population, no virus that is cleared with resulting immunity can persist; therefore, only a virus that can establish a persistent infection of its host, with little or no diminution of the host's ability to survive and propagate, can persist. Furthermore, this persistence must allow for infectious virus to be present at opportune moments for infection of new, susceptible individuals (i.e., infants and occasional adults encountered from other groups). A number of viruses have replication strategies and genetic capacities to establish such infections, and it is striking that genetic analysis of such viruses demonstrates ancient associations with humans.

These two basic, non‐exclusive strategies of virus replication are diagrammed in Figure 4.1. Of course, not all viruses are constrained by their narrow host range to infect just one species or type of host. Some, notably a number of viruses using RNA as their genetic material, have a broad host range and can readily jump from one species of host to another. With such a virus, the constraints on the mortality of the disease caused in the novel or ancillary host target population are counterbalanced by less severe disease and therefore persistence in a different species that the virus infects. It is not particularly surprising, then, that mortality rates of some diseases caused by zoonotic viruses are quite high.

Figure 4.1 Virus maintenance in small and large populations. (a) In a small population, virus infection can only occur when there is an immunologically naive individual available. This requires a virus within such a population to be able to maintain itself in an infectious state in individuals long after they have been infected. A favored mode of infection would be from parent to child. Clearly, high mortality rates or severe disease symptoms would be selected against. (b) In a large population, there will be a large number of susceptible individuals appearing at the same time. This can result in local episodic infections of such individuals. The large size of the host population insures that some virus is available from actively infected adults at all times. While persistence is not excluded, it need not be strongly selected for, especially if the course of the acute phase of the disease is relatively long compared to the generation time of the population.

      Other factors further complicate the simple patterns of virus infection and persistence outlined here. A notable one is that if the period of time between the initial infection and the appearance of symptoms (the incubation period) is longer than the generation time of the host, constraints on mortality are lost. This is the case for rabies, which exhibits essentially a 100% mortality rate in infected carnivores – its natural host – but has a very long incubation period that allows reproduction even after infection. The lifespan of humans is so long that this might not seem to be a major factor in maintaining virus infections with high mortality rates, but the association between certain persistent human virus infections and the very much later appearance of tumors and immuno‐pathologies is a consequence of a long incubation period between initial infection and ultimate pathology.

Classification of human disease–causing viruses according to virus–host dynamics

      We can use the nature of the virus–host interaction to generate a simple classification of viruses, especially those of humans. These criteria are a useful aid for organizing detailed information concerning diseases with a viral etiology