Viruses

Viruses

Moises starf

Moises Starf

Moises Starf

ontents

Preface ix

Acknowledgments xiii

Introduction xiv

The Origin of Viruses 1

The First Cells Set the Stage 2

Mobile Genetic Elements 11

Plasmids 13

Summary 14

Viral Structure and Behavior 15

DNA Viruses 16

RNA Viruses 22

Retroviruses 26

Summary 29

Viral Taxonomy 31

Viral Families 32

Bacterial Viruses 33

Plant Viruses 38

Human Viruses 41

Summary 55

A Brief History of Virology 57

Viral Diseases in the Ancient World 58

Smallpox in Europe and the New World 60

The First Vaccine 61

The Microscope 62

The Germ Theory 66

Future Prospects 68

Viruses in the Sea 70

Viromes and Microbiomes 71

Virus-mediated Gene Transfer 72

Marine Viruses Are Novel Gene Banks 74

Viruses as Marine Predators 75

Marine Viruses and Disease 76

Summary 76

Viruses in Biomedical Research 77

Biotechnology 77

Gene Therapy 81

Stem Cell Therapy 86

Summary 89

Viral Diseases 90

AIDS 91

Cancer 96

Chicken Pox 98

Common Cold 100

Hemorrhagic Fever 100

Herpes Simplex 102

Influenza 103

Measles 104

Polio 106

Rabies 108

SARS 109

Smallpox 110

West Nile Fever 111

Yellow Fever 112

Summary 113

Viral Pandemics 114

AIDS 115

Polio 120

Smallpox 123

Spanish Flu of 1918 124

SARS 127

Swine Flu 129

Summary 131

Fighting Viral Infections 132

Antiviral Drugs 132

Interferons 136

Vaccines 138

Immunization Policies 142

Summary 143

Resource Center 145

Cell Biology 145

Biotechnology 166

Methods in Virology 175

Understanding Clinical Trials 177

Protein Gene Nomenclature 179

Weights and Measures 180

Glossary 181

Further Resources 210

Web Sites 215

Index 218

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Moises Starf

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The Origin of Viruses

ifty years ago, scientists thought that viruses were examples of the most primitive of all life-forms, giving rise to prokaryotes (bacteria) and eukaryotes (cells that formed plants and animals). Today, researchers know this is not true. Viruses appeared after the emergence of prokaryotes, the most ancient form of cell, and it is believed they evolved from mobile genetic elements known as transposons and bacterial minichromosomes known as plasmids. Because of their small size, transposons and plasmids could leak out of a bacterial cell after which they could enter, or infect, other cells. Over time these genetic elements acquired a protein coat that protected their DNA and made it easier for them to infect cells. It is thought that transposons evolved into eukaryote viruses while plasmids evolved into prokaryote viruses. Some of the ancestral eu- karyote viruses simply took up residence in the genome where they were able to move from one chromosome to another, but stayed

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within the nucleus. Other ancestral viruses, however, went on to evolve into complex viruses that could leave a cell, often destroying it in the process, and could then reinfect others.

This chapter discusses the origin of viruses within the context of the origin of the cell. The first cells had many problems to solve before they could flourish in what was almost certainly a hostile environment. Perhaps the biggest problem to overcome was the es- tablishment of some form of inheritance system long before genes and sexual reproduction had evolved. The first cells accomplished this simply by swapping molecules with their neighbors. But this process, so essential for the emergence of life, set the stage for the appearance of the first viruses.

THE FIRST CELLS SET THE STAGE

Life appeared on Earth for the first time as single cells about 3.5 billion years ago. At that time Earth was a hot and stormy planet with surface temperatures exceeding 150° F (65° C), and an atmo- sphere that consisted primarily of methane and ammonia. The vio- lent electric storms that were common in those days were crucial for the origin of life for they provided the necessary energy for the synthesis of organic compounds from the methane and ammonia. Scientists have shown that the organic compounds so produced in- cluded amino acids, nucleic acids, sugars, and fats, all of which are essential ingredients in living things today. The heat fused many of these molecules into macromolecules (chains of molecules) such as protein, deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and a fatty substance called phospholipid. These compounds enriched the water, turning the oceans into a nutrient broth. The phospho- lipid, unlike the other macromolecules, could not dissolve in water but spread out on the surface, producing Earth’s first oil slick (for more detail see chapter 10).

In addition to the heat and electrical discharges, the storms provided something else that was essential for the appearance of

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life: thunderous waves, breaking on the shores. Anyone who has watched a wave break on a shore has witnessed one of the most im- portant mechanisms for the formation of life on this planet. The foam that rolls onto the shore after the wave breaks is composed of billions of bubbles. In the prebiotic coastal waters, each bubble that formed collected a different sample of the water and, therefore, represented a unique individual, a separate experiment that could be acted upon by the forces of natural selection.

The prebiotic bubbles were stabilized by the phospholipids that coated the surface of the water. But when a new wave arrived, many of the bubbles burst open from the turbulence, thus releasing their contents back into the environment. Over time, evolution selected for stable bubbles that spent longer periods of time experimenting with captured molecules. Presumably, this happened when a bubble managed to synthesize a compound that increased the stability of its lipid membrane. As a consequence, that bubble not only enjoyed a longer existence but the fruit of its labors, the membrane-stabilizing molecule, was eventually made available to the community as a whole. With billions of bubbles being formed, it is conceivable that within the population many other useful molecules could have been produced and then eventually released into the environment. When new bubbles formed, they may have captured some, or all, of those molecules and thus were given a head start. This simple form of genetic inheritance, acted upon by natural selection, likely trans- formed the prebiotic bubbles into the first cells, but it also paved the way for the appearance of the first viruses.

Two types of cells have evolved on Earth, and they in turn have given rise to different types of viruses. The first type of cell is called a prokaryote (meaning before the nucleus). These cells have the simplest structure and have diverged into the archaea and the bac- teria. The second type of cell is called a eukaryote (meaning true nucleus). These cells evolved from the prokaryotes and are the type

Plants Animals

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Fungi

Protozoans

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Eukaryotes

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Archaea

Bacteria

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Ancestral prokaryotes

First cells

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Cell classification. The first cells evolved into the ancestral prokary- otes, which gave rise to the archaea, bacteria, and eukaryotes, the three major divisions of life in the world. The archaea and bacteria are very similar anatomically but differ biochemically. Eukaryotes, anatomically and biochemically distinct from both the archaea and bacteria, gave rise to plants, animals, protozoans, and fungi.

of cell that all plants and animals are made from. There are also single-cell eukaryotes known as protozoans. Although the main focus of this book is on animal viruses, there are many different kinds of viruses that only infect prokaryotes and plants; these will be discussed in chapter 3.

Prokaryotes have a simple structure that includes a cell mem- brane, a protoplasm that contains the cell’s DNA genome and all of the biochemical machinery that the cell needs for reproduction, energy metabolism, and the acquisition of nutrient molecules. Many of these cells also have a secondary genome, or minichromo- some, known as a plasmid. This important structure is discussed in a following section. Prokaryotes, particularly the bacteria, inhabit nearly every niche on Earth, including the soil, air, and water. There are also many different species that live on the skin or in the bodies of animals, the latter of which are confined to the mouth, throat, and digestive tract.

Eukaryotes are much bigger and much more complex than prokaryotes. In a prokaryote, all of the cell’s machinery and all of its biochemical activity take place in a single compartment, the protoplasm. By contrast, eukaryotes have special compartments, or organelles, for everything. The DNA is kept in the nucleus, and proteins are synthesized in the cytoplasm, some of which are modified in special organelles known as the Golgi complex and the endoplasmic reticulum. Energy is produced by the mitochondria, waste material is recycled in lysosomes, and noxious compounds are detoxified in peroxisomes.

The earliest cells to appear on Earth were submerged in an ocean full of nutrients that they could easily obtain by simple ab- sorption. But as the cell population increased two things began to happen: The availability of nutrients began to decrease and the complexity of the nutrients began to increase. The more com- plex nutrients could not be obtained by simple absorption. The increasing complexity of the nutrients was due to the fact that

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Circular chromosome

Cell membrane

Plasmid

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Cytoplasm Ribosome

Bacillus Coccus

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Spirillum

Prokaryotes. All prokaryotes have the same basic anatomy consisting of a cell membrane, a cytoplasm, and a circular DNA chromosome. Some bacteria have a second, smaller chromosome called a plasmid, which may be present in multiple copies. The cytoplasm contains a wide assortment of enzymes and molecules, as well as ribosomes, protein- RNA complexes that are involved in protein synthesis. The cells may be spherical (coccus), rod shaped (bacillus), or wavy corkscrews (spirillum), appearing singly, in pairs, or linked together into short chains.

Golgi complex

Endoplasmic Reticulum

Nucleus

Cell

membrane Mitochondrion

Cytoplasm

Golgi vesicle

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Lysosome

Peroxisome

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The eukaryote cell. The structural components shown here are present in organisms as diverse as protozoans, plants, and animals. The nucleus contains the DNA genome, and as assembly plant for ribosomal subunits (the nucleolus). The endoplasmic reticulum (ER) and the Golgi work together to modify proteins, most of which are destined for the cell membrane. These proteins are sent to the mem- brane in Golgi vesicles. Mitochondria provide the cell with energy in the form of adenosine triphosphate (ATP). Ribosomes, some of which are attached to the ER, synthesize proteins. Lysosomes and peroxi- somes recycle cellular material and molecules. The microtubules and centrosome form the spindle apparatus for moving chromosomes to the daughter cells during cell division. Actin filaments and a weblike structure consisting of intermediate filaments (not shown) form the cytoskeleton.

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Sugar

Sugar

Glycocalyx

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Ceramide

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Membrane

Glycoprotein Glycolipid

Membrane

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Cell

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The eukaryote glycocalyx. The eukaryotes molecular forest consists of glycoproteins and glycolipids. Two examples are shown at the top, a glycoprotein on the left and a glycolipid on the right. The glyco- protein trees have trunks made of protein and leaves made of sugar molecules. Glycolipids also have leaves made of sugar mol- ecules, but the trunks are a fatty compound called ceramide that is completely submerged within the plane of the membrane. The glycocalyx has many jobs, including cell-to-cell communication and the transport and detection of food molecules. It also provides recog- nition markers so the immune system can detect foreign cells.

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they were coming from cells that had died, rather than the pool of simple prebiotic nutrients. In addition, by this time many cells had learned how to capture energy from the Sun. These were the

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A panoramic view of the glycocalyx. The glycoproteins in the cells’s forest come in many different shapes and sizes, and they dominate the surface of most cells. The glycolipids all have the same ceramide trunks, but the molecular foliage varies considerably. All but three of the structures in this image are glycoproteins, but in nerve cells glycolipids are much more common.

first autotrophs, cells that could photosynthesize, and with that ability came an ever-increasing population of complex macro- molecules that were released into the water when those cells died. Consequently, the eukaryotes, like the prokaryotes before them, developed cell-surface receptors that could capture and ingest large molecules. The receptors are glycoproteins (proteins with sugar molecules attached) that are part of a forest of macromol- ecules called the glycocalyx that cover the surface of the cell. This structure also gives the cell its ability to communicate with other cells. Viruses have learned how to exploit the normal function of the glycocalyx in order to gain access to the cell.

Transporters, and their associated receptors, are the specific glycocalyx structures used by viruses to enter a cell. These struc- tures consist of several glycoproteins arranged in a porelike con- figuration and are in effect doorways into the cell. Some of these receptors are associated with a process called endocytosis whereby large macromolecules and even whole cells are brought into the cell by the invagination of the cell membrane. Viruses have discovered the keys to these ports of entry, and they use them every time they infect a cell. The details of these transporters, as they pertain to viral infections, will be discussed in a later chapter.

MOBILE GENETIC ELEMENTS

The first cells are believed to have had a small RNA genome that encoded fewer than a dozen genes. (Modern cells all have DNA genomes.) When these cells died, they released their genome into the water along with everything else. Because their genomes were so small, it is possible that other cells could have picked them up in their entirety. The host cell could have kept them as a second chro- mosome, but after a period of time biochemical systems evolved that incorporated the captured genes into the host’s genome. Thus, early cells were not only involved in swapping useful construction materials but were also involved in swapping genes. Once captured, some of these genes were able to move around from one location in

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the genome to another. Scientists believe that these genetic elements gave rise to viruses that infect eukaryotes.

When first proposed by the American geneticist Barbara McClintock in 1951, the idea that genes could move from one loca- tion in the genome to some other location was greeted with disbelief and disdain. For more than 20 years, this idea was dismissed as wild speculation until the advent of recombinant technology made it possible to prove the existence of these wandering genes, also known as transposons, transposable elements, and jumping genes. McClintock’s work was eventually given the recognition it deserved, and in 1983, at the age of 81, she was awarded the Nobel Prize in physiology or medicine. She died on September 2, 1992.

McClintock’s research provided the first clues into the origin of viruses, particularly those that infect animal cells. Somehow, mil- lions of years ago, a jumping gene learned how to jump right out of the cell (that is, the genetic element did not have to wait for the cell to die before it could leave). It acquired this ability in small steps as it moved from one place in the genome to another. A jumping gene could conceivably reinsert next to a gene that codes for a potential capsid protein (a protein that surrounds and protects a virus’s ge- nome). In effect, the capsid gave the virus a body, with structure and form. The next time such a transposon moved it could take a copy of the potential capsid gene with it. Eventually, by moving from place to place, the transposon would have collected a large number of genes that not only made it possible for it to escape from the cell but also gave it the power to reinfect other cells. When that happened, a simple mobile genetic element went from being a molecular curios- ity to a living thing, equipped with a life cycle and the power of reproduction.

Viruses, and the transposons they evolved from, have had a pro- found effect on the evolution of the animal genome. For example, only about 2 percent of the human genome contains genes, with the rest of the DNA consisting of intervening sequences. These are

gene-free areas of the genome that may be thought of as safe zones, within which a virus or a transposon may settle without causing any damage. If a virus does happen to insert within a gene, the resulting damage, known as insertional mutagenesis, can have serious con- sequences and is known to be the cause of certain forms of cancer. In order to minimize this problem, the human genome, and indeed all animal genomes, have evolved into a form that accommodates mobile genes. In such a genome, the odds of a virus or a transpos- able element damaging an existing gene are extremely small.

Transposons move by being replicated (duplicated) by nuclear enzymes. Thus, the original transposon stays put, while the daugh- ter strand moves to a new location. Consequently, over time the genome becomes sprinkled with many copies of transposable ele- ments. These copies of the original element are then free to mutate into genes that may eventually become useful to the organism. Thus, transposons are the source of many of the genes now present in the human genome. When certain viruses infect a cell, they too take up residence within an intervening sequence. Recent studies have shown that the human genome is littered with viral genomes. Fortunately, most of these have been inactivated by slow mutational changes and are effectively locked in to the genome.

The flexibility of a transposable genome is perhaps the single most important characteristic that led to the explosive adaptabil- ity of eukaryotes and the many life-forms they produced. Such a genome is also