Basic Virology. Martinez J. Hewlett

genes. Second, this same vast majority of viruses do not contain genetic evidence of ever having encoded enzymes involved in energy metabolism. This is convincing evidence that the viruses currently investigated did not evolve from free‐living organisms. This finding distinctly contrasts with two eukaryotic organelles, the mitochondrion and the chloroplast, which are known to be derived from free‐living organisms.

Figure 1.1 A phylogenetic tree of selected species from the three domains of life: Eukaryota (or Eukarya), Eubacteria, and Archaea. The tree is based upon statistical analysis of sequence variation in seven universally conserved protein sequences: arginyl‐t‐RNA synthetase, methionyl‐t‐RNA synthetase, tyrosyl‐t‐RNA synthetase, RNA pol II largest subunit, RNA pol II second largest subunit, PCNA, and 5′‐3′ exonuclease.

      Source: Based upon Raoult, D., Audic, S., Robert, C., et al. (2004). The 1.2‐megabase genome sequence of mimivirus. Science306: 1344–1350.

      Genetics also demonstrates that a large number of virus‐encoded enzymes and proteins have a common origin with cellular ones of similar or related function. For example, many viruses containing DNA as their genetic material have viral‐encoded DNA polymerases that are related to all other DNA polymerase isolated from plants, animals, and archaea.

Statistical analysis of the divergence in three highly conserved regions of eukaryotic DNA polymerases suggests that the viral enzymes, including those from herpesviruses and from poxviruses and relatives (including mimiviruses), have existed as long as the three domains themselves. Indeed, convincing arguments exist that the viral enzymes are more similar to the ancestral form. This, in turn, implies that viruses or virus‐like self‐replicating entities (replicons) had a major role, if not the major role, in the origin of DNA‐based genetics. The phylogenetic tree of relationships between two forms of eukaryotic DNA polymerase (alpha and delta), two forms of the enzyme found in archaebacteria, as well as those of three groups of large DNA viruses and some other DNA viruses infecting algae and protists is shown in Figure 1.2.

      Another example of the close genetic interweaving of early cellular and viral life forms is seen in the sequence analysis of the reverse transcriptase enzyme encoded by retroviruses, which is absolutely required for converting retroviral genetic information contained in RNA to DNA. This enzyme is related to an important eukaryotic enzyme involved in reduplicating the telomeres of chromosomes upon cell division – an enzyme basic to the eukaryotic mode of genome replication. Reverse transcriptase is also found in cellular transposable genetic elements (retrotransposons), which are circular genetic elements that can move from one chromosomal location to another. Thus, the relationship between certain portions of the replication cycle of retroviruses and mechanisms of gene transposition and chromosome maintenance in cells is so intimately involved that it is impossible to say which occurred first.

      A major complication to a complete and satisfying scheme for the origin of viruses is that a large proportion of viral genes have no known cellular counterparts, and viruses themselves may be a source of much of the genetic variation seen between different free‐living organisms. In an extensive analysis of the relationship between groups of viral and cellular genes, L. P. Villarreal points out that the deduced size of the Last Universal Common Ancestor(LUCA) of eukaryotic and prokaryotic cells is on the order of 300 genes – no bigger than a large virus – and provides some very compelling arguments for viruses having provided some of the distinctive genetic elements that distinguish cells of the eukaryotic and prokaryotic kingdoms. In such a scheme, precursors to both viruses and cells originated in a pre‐biotic environment hypothesized to provide the chemical origin of biochemical reactions leading to cellular life.

      At the level explored here, it is probably not terribly useful to spend great efforts to be more definitive about virus origins beyond their functional relationship to the cell and organism they infect. The necessarily close mechanistic relationship between cellular machinery and the genetic manifestations of viruses infecting them makes viruses important biological entities, but it does not make them organisms. They do not grow, they do not metabolize small molecules for energy, and they only “live” when in the active process of infecting a cell and replicating in that cell. The study of these processes, then, must tell as much about the cell and the organism as it does about the virus. This makes the study of viruses of particular interest to biologists of every sort.

Figure 1.2 A phylogenetic tree of selected eukaryotic and archaeal species along with specific large DNA‐containing viruses based upon sequence divergence in conserved regions of DNA polymerase genes.

      Source: Based upon Villarreal, L.P. and DeFilippis, V.R. (2000). A hypothesis for DNA viruses as the origin of eukaryotic replication proteins. Journal of Virology74: 7079–7084.

Viruses have a constructive as well as destructive impact on society

      Often the media and some politicians would have us believe that infectious diseases and viruses are unremitting evils, but to quote Sportin’ Life in Gershwin's Porgy and Bess, this “ain't necessarily so.” Without the impact of infectious disease, it is unlikely that our increasingly profound understanding of biology would have progressed as it has. As already noted, much of our understanding of the mechanisms of biological processes is based in part or in whole on research carried out on viruses. It is true that unvarnished human curiosity has provided an understanding of many of the basic patterns used to classify organisms and fostered Darwin's intellectual triumph in describing the basis for modern evolutionary theory in his Origin of Species. Still, focused investigation on the microscopic world of pathogens needed the spur of medical necessity. The great names of European microbiology of the nineteenth and early twentieth centuries – Pasteur, Koch, Ehrlich, Fleming, and their associates (who did much of the work with which their mentors are credited) – were all medical microbiologists. Most of the justification for today's burgeoning biotechnology industry and research establishment is medical or economic.

Today, we see the promise of adapting many of the basic biochemical processes encoded by viruses to our own ends. Exploitation of viral diseases of animal and plant pests may provide a useful and regulated means of controlling such pests. While the effect was only temporary and had some disastrous consequences in Europe, the introduction of myxoma virus – a pathogen of South American lagomorphs (rabbits and their relatives) – had a positive role in limiting the predations of European rabbits in Australia. Study of the adaptation dynamics of this disease to the rabbit population in Australia taught much about the co‐adaptation of host and parasite.

      The exquisite cellular specificity of virus infection is being adapted to generate biological tools for moving therapeutic and palliative genes into cells and organs of individuals with genetic and degenerative diseases. Modifications of virus‐encoded proteins and the genetic manipulation of viral genomes are being exploited to provide new and (hopefully) highly specific prophylactic vaccines as well as other therapeutic agents. The list increases monthly.

Viruses are not the smallest self‐replicating pathogens

      Viruses are not the smallest or the simplest pathogens able to control their self‐replication in a host cell – that distinction goes to prions. Despite this, the methodology for the study of viruses and the diseases they cause provides the basic methodology for the study of all subcellular pathogens.

      By the most basic definition, viruses are composed of a genome and one or more proteins coating that