Principles of Virology. Jane Flint

from infected birds. The frightening possibility that it could gain the ability to spread among humans is a major incentive for monitoring for person-to-person transmission in case of infection by this and other pathogenic avian influenza viruses. Given the eons over which viruses have had the opportunity to interact with various species, today’s “natural” host may simply be a way station in viral evolution.

Viruses Are Unique Tools To Study Biology

      Because viruses are dependent on their hosts for propagation, studies that focus on viral reprogramming of cellular mechanisms have provided unique insights into genetics, cellular biology, and functioning of host defenses. Groundbreaking studies of viruses that infect bacteria (called bacteriophages) in the mid-20th century established the molecular basis of genetic inheritance. Through development and use of stringent, quantitative methods with these relatively simple biological entities, this research confirmed that DNA encodes genes and genes encode proteins. General mechanisms of genetic recombination, repair, and control of gene expression were also elucidated, laying the foundations of modern molecular biology and recombinant DNA technology. Subsequent studies of animal viruses established many fundamental principles of cellular function, including the presence of intervening sequences in eukaryotic genes. The study of cancer (transforming) viruses established the genetic basis of this disease.

      With the development of recombinant DNA technology and our increased understanding of viral systems, it has become possible to use viral genomes as vehicles for the delivery of genes to cells and organisms for both scientific and therapeutic purposes. The use of viral vectors to introduce genes into various cells and organisms to study their function has become a standard method in biology. Viral vectors are also being used to treat human disease, for example, via “gene therapy,” in which functional genes delivered by viral vectors compensate for faulty genes in the host cells (Volume II, Chapter 9).

The study of viruses has contributed in a unique way to the field of anthropology. As ancient humans moved from one geographic area to another, the viral strains unique to their original locations came along with them. The presence of such strains can be detected by analysis of viral nucleic acids, proteins, and antibodies from ancient human specimens and in modern populations. Together with archeological information, identification of these virological markers has been used to trace the pathways by which humans came to inhabit various regions of our planet (Fig. 1.2).

Figure 1.2 Tracking ancient human migrations by the viruses they carried. The polyomavirus known as JC virus is transmitted among families and populations and has coevolved with humans since the time of their origin in Africa. This virus produces no disease in normal, healthy people. Most individuals are infected in childhood, after which the virus establishes a persistent infection in the gastrointestinal tract and is shed in urine. Analysis of the genomes of JC virus in human populations from different geographic locations has suggested an expansion of ancient humans from Africa via two distinct migrations, each carrying a different lineage of the virus. Results from these studies are consistent with analyses of human DNAs (shown by the solid line). They also suggest an additional route that was undetectable in the human DNA analyses (indicated by the dashed line). Data from Pavesi A. 2005. J Gen Virol 86:1315–1326.

Virus Prehistory

      Although viruses have been known as distinct biological entities for only about 120 years, evidence of viral infection can be found among the earliest recordings of human activity, and methods for combating viral disease were practiced long before the first virus was recognized. Consequently, efforts to understand and control these important agents of disease began only in the last century.

Viral Infections in Antiquity

      Reconstruction of the prehistoric past to provide a plausible account of when or how viruses established themselves in human populations is challenging. However, extrapolating from current knowledge, we can deduce that some modern viruses were undoubtedly associated with the earliest precursors of mammals and coevolved with humans. Other viruses entered human populations only recently. The last 10,000 years of history was a time of radical change for humans and our viruses: animals were domesticated, the human population increased dramatically, large population centers appeared, and commerce and technology drove worldwide travel and interactions among unprecedented numbers of people.

      Viruses that established themselves in human populations were undoubtedly transmitted from animals, much as still happens today. Early human groups that domesticated and lived with their animals were almost certainly exposed to different viruses than were nomadic hunter/gatherer societies. Similarly, as many different viruses are endemic in the tropics, human societies in that environment must have been exposed to a greater variety of viruses than societies established in temperate climates. When nomadic groups met others with domesticated animals, human-to-human contact could have provided new avenues for virus spread. Even so, it seems unlikely that viruses such as those that cause measles or smallpox could have entered a permanent relationship with small groups of early humans. Such highly virulent viruses, as we now know them to be, either kill their hosts or induce lifelong immunity. Consequently, they can survive only when large, interacting host populations offer a sufficient number of naive and permissive hosts for their continued propagation. Such viruses could not have been established in human populations until large, settled communities appeared. Less virulent viruses that enter into a long-term relationship with their hosts were therefore more likely to be the first to become adapted to reproduction in the earliest human populations. These viruses include the modern retroviruses, herpesviruses, and papillomaviruses.

Evidence for knowledge of several diseases that we now know to be caused by viruses can be found in ancient records. The Greek poet Homer characterizes Hector as “rabid” in The Iliad (Fig. 1.3A), and Mesopotamian laws that outline the responsibilities of the owners of rabid dogs date from before 1000 B.C.E. Their existence indicates that the communicable nature of this viral disease was already well-known by that time. Egyptian hieroglyphs illustrate what appear to be the consequences of poliovirus infection (a withered leg typical of poliomyelitis [Fig. 1.3B]). Pustular lesions characteristic of smallpox have also been found on Egyptian mummies. The smallpox virus was probably endemic in the Ganges River basin by the fifth century B.C.E. and subsequently spread to other parts of Asia and Europe. This viral pathogen has played an important part in human history. Its introduction into the previously unexposed native populations of Central and South America by colonists in the 16th century led to lethal epidemics, which are considered an important factor in the conquests achieved by a small number of European soldiers. Other viral diseases known in ancient times include mumps and, perhaps, influenza. Europeans have described yellow fever since they discovered Africa, and it has been suggested that this scourge of the tropical trade was the basis for legends about ghost ships, such as the Flying Dutchman, in which an entire ship’s crew perished mysteriously.

Humans have not only been subject to viral disease throughout much of their history but have also manipulated these agents, albeit unknowingly, for much longer than might be imagined. One classic example is the cultivation of marvelously patterned tulips, which were of enormous value in 17th-century Holland. Such efforts included deliberate spread of a virus (tulip breaking virus or tulip mosaic virus) that we now know causes the striping of tulip petals so highly prized at that time (Fig. 1.4). Attempts to control viral disease have an even more venerable history.