1The idea in one paragraph

A virus is a few genes in a protein coat. It has no cytoplasm, no ribosomes and hardly any enzymes, so it cannot do anything by itself; it can only get into a host cell and use the host's machinery to make copies of itself. That is how a virus can exist with so few genes: the host supplies everything else. Beyond that shared minimum, viruses vary enormously. Their genetic material can be DNA or RNA, single- or double-stranded; some are wrapped in a stolen piece of host membrane and some are not. Phage lambda, which infects bacteria, can either destroy its host at once (the lytic cycle) or hide its DNA in the host's chromosome for generations (the lysogenic cycle). Viruses probably arose more than once, and some of them, influenza and HIV among them, evolve so quickly that vaccines and drugs struggle to keep up.

2What all viruses share

Very few features are shared by every virus. The guide lists five, and Figure 1 shows them.

• A small, fixed size. Most viruses are 20–300 nm across, far smaller than a bacterium, and they do not grow: each virus particle is assembled at its final size.
• Nucleic acid as the genetic material. Either DNA or RNA, never both.
• A capsid made of protein. A coat of many identical protein subunits that protects the nucleic acid and, in many viruses, helps it attach to the right host cell.
• No cytoplasm. There is no watery interior in which metabolism could happen.
• Few or no enzymes. Some viruses carry one or two enzymes they need at the very start of infection, such as the reverse transcriptase of HIV, but none carries the enzymes of metabolism.

Now the guiding question answers itself. How can viruses exist with so few genes? Because a virus does not need genes for ribosomes, for ATP production, for membrane building or for nutrition. It relies on the host cell for its energy supply, its nutrition, its protein synthesis and every other life function. It only needs genes to hijack a cell and to build more of itself. Some viruses have fewer than ten genes; a bacterium has thousands.

3How viruses differ

Beyond those five features, viruses are highly diverse in shape and structure. They vary in three ways the guide names.

• Genetic material. It may be DNA or RNA, and either can be single-stranded or double-stranded. No cell has single-stranded DNA or double-stranded RNA as its genome; viruses have all four types.
• Envelope or no envelope. Some viruses are enveloped: as they leave a host cell, they wrap themselves in a piece of the host's plasma membrane, studded with their own proteins. Others have no envelope and are just a capsid.
• Shape. Capsids can be helical rods, many-sided spheres, or complex shapes such as the head and tail of many bacteriophages.

The guide's three examples cover the range, and Figure 2 draws them.

4The lytic cycle of phage lambda

A bacteriophage (or phage) is a virus that infects bacteria. Phage lambda infects E. coli, and the guide uses it to show both of the ways a virus can use a cell. The first is the lytic cycle, which ends in the destruction (lysis) of the host. Figure 3 goes round it.

1. Attachment. The tip of the phage's tail binds to a specific receptor protein on the outer surface of E. coli. The fit is specific, which is why lambda infects E. coli and not your cells.
2. Injection. The phage injects its DNA through the tail into the bacterium. The empty capsid stays outside. Once inside, the linear lambda DNA joins its ends to form a circle.
3. Replication and synthesis. The phage genes are transcribed and translated by the host. Host enzymes and the host's supply of nucleotides and ATP copy the phage DNA many times; host ribosomes and amino acids make phage proteins for new heads and tails.
4. Assembly. New capsids form, each is packed with a copy of the phage DNA, and tails attach.
5. Lysis. A phage-coded enzyme breaks down the bacterial cell wall. The cell bursts and releases around a hundred new phages, each able to infect another cell.

Every one of those stages except attachment and injection runs on the host's resources. The phage brings instructions; the bacterium supplies the energy, the raw materials and the machinery. The whole cycle takes about an hour.

5The lysogenic cycle of phage lambda

Lambda has a second option. In the lysogenic cycle it does not destroy the host straight away, and Figure 4 shows what it does instead.

1. Injection. As before, the phage attaches and injects its DNA, which forms a circle.
2. Integration. An enzyme coded by the phage inserts the phage DNA into the bacterial chromosome at a particular site. Inserted phage DNA is called a prophage.
3. Dormancy and division. A phage protein, a repressor, switches off the genes that would start the lytic cycle. The bacterium lives, grows and divides normally, and every time it copies its chromosome it copies the prophage too, so all its descendants carry the virus.
4. Induction. If the bacterium is stressed, especially if its DNA is damaged, for example by ultraviolet light, the repressor is destroyed.
5. Excision and lytic cycle. The prophage cuts itself out of the chromosome and the phage enters the lytic cycle, making new phages and bursting the cell.

The logic makes sense from the virus's point of view. Lysis multiplies the virus fast but destroys the host. Lysogeny lets the virus be copied, free, with every division of a healthy host, and it can switch to lytic when the host looks likely to die anyway.

6Where did viruses come from?

Viruses leave no fossils, so their origins are worked out from their structure and their genes. The guide's key point is that the diversity of viruses suggests several possible origins, not one. Figure 5 sets out the main hypotheses.

• The escape hypothesis. Viruses began as pieces of a cell's own genetic material, such as a few genes, that gained the ability to leave one cell and enter another, collecting a protein coat along the way.
• The reduction hypothesis. Viruses descend from cells that became parasites inside other cells. Living inside a host, they no longer needed their own ribosomes or metabolic genes, lost them over many generations, and were reduced to the minimum.
• The virus-first hypothesis. Viruses arose before, or alongside, the first cells. This is hard to square with the fact that every virus needs a host cell to reproduce.

Different groups of viruses may have come about in different ways; the evidence does not force a single answer. Two further points from the guide make the argument.

Shared features may be convergent evolution. Viruses share an extreme form of obligate parasitism: they cannot reproduce at all without a host. Any line of genetic parasites that adopted this way of life would face the same problems and tend to arrive at the same solutions: a protective protein coat, a small genome, no metabolism. So the features all viruses share do not prove they share an ancestor. They may be convergent evolution, the independent evolution of similar features in unrelated groups under similar selection pressures, just as the wings of birds and bats evolved separately.

The genetic code is shared with living organisms. Viruses use the same genetic code as cells. They have to, because their genes are read by the host's ribosomes. That places viruses firmly within the same history as cellular life: whatever their origins, they arose from, or together with, cells that already used this code. (The linking question asks whether life's history is one of rising complexity. The reduction hypothesis is a reminder that evolution can simplify as well.)

7Rapid evolution in viruses

Some viruses evolve faster than any cellular organism, fast enough to change noticeably within a year or within one patient. The guide asks for the reasons, two examples, and the consequences for treatment.

Why some viruses evolve so fast.

• High mutation rates. Many RNA viruses copy their genomes with enzymes that make frequent errors and cannot check and correct them, unlike the DNA polymerases of cells, which proofread. HIV's reverse transcriptase and influenza's RNA polymerase are both error-prone. Almost every new virus particle differs slightly from its parent.
• Very short generation times. A new generation can be produced within hours.
• Enormous numbers. One infected person can carry billions of virus particles, so even rare mutations appear somewhere every day.
• Strong selection. The host's immune system and antiviral drugs kill most viruses, so any variant that escapes them multiplies rapidly and replaces the rest. This is natural selection at high speed.
• Mixing of genes. When two strains infect the same cell, their genetic material can be shuffled together into new combinations.

Influenza. The influenza virus is enveloped, with an RNA genome in eight separate segments. The proteins on its surface, haemagglutinin and neuraminidase, are what the immune system recognises. Figure 6 shows the two ways they change.

• Antigenic drift. Mutations accumulate in the genes for the surface proteins, slowly changing their shape. After a year or two, antibodies made against last year's virus fit this year's less well, so people can be infected again. This is why flu returns every winter.
• Antigenic shift. When two different influenza strains, for example one from birds and one from humans, infect the same cell (pigs can host both), their RNA segments can be swapped, producing a virus with a new combination of surface proteins. Almost nobody has immunity to it, and it can spread worldwide as a pandemic.

Consequences for treatment. A flu vaccine trains the immune system to recognise particular surface proteins, and because of drift those proteins keep changing. Scientists therefore monitor circulating strains and update the vaccine every year to match the strains they predict will dominate. A shift can produce a virus that no existing vaccine covers, so a new vaccine has to be developed quickly. Antiviral drugs can also lose their effect as resistant strains are selected.

HIV. HIV evolves even faster, and it does so inside each infected person. Its reverse transcriptase makes errors as it copies the viral RNA into DNA, and it replicates constantly, so a single patient carries a huge and ever-changing population of variants.

Consequences for treatment. This is the reason HIV is never treated with one drug. Among the billions of viruses in a patient, a few will already carry a mutation that makes them resistant to any single drug. Give that drug alone and it kills the susceptible viruses, the resistant ones multiply, and within months the drug no longer works. Figure 7 shows the selection.

The answer is combination therapy: three or more antiretroviral drugs, acting on different viral targets, taken together. To survive, a virus would need resistance mutations against all three at once, which is extremely unlikely, so the virus stays suppressed. It cannot be eliminated, though, and treatment must be taken every day for life, because any lapse lets the virus replicate and evolve again. Rapid evolution is also one reason there is still no effective HIV vaccine: the surface proteins a vaccine would target keep changing.