How Viruses Attack Cells and Infiltrate DNA

Viruses: Genes Gone Rogue

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Viruses are packets of genes on the run. They don't have any fancy biological equipment of their own, and must hijack the cells of living organisms in order to replicate.

Some viruses go as far as integrating with our DNA to become part of us forever. Depending on your mood, you might call them intracellular parasites, mobile genetic elements, or freeloading gits.

What are Viruses?

Viruses have three main components:

  • Nucleic Acid. The storage medium of genes, taking the form of DNA or RNA.
  • Capsid. A protein coat that protects the genetic material in transit, made of individual capsomeres.
  • Envelope. An optional extra coating made of lipids, sugars, and studded with proteins.
Virus cartoon

Cross-section of SARS-CoV-2, an enveloped virus with single stranded RNA.

Viruses have evolved to parasitised bacteria, plants, fungi, and animals throughout the course of evolution.

And there are an awful lot of them: vertebrates alone carry ~3.6 million species, while the human gut contains 140,000 species that infect our symbiotic gut bacteria.

Science cartoon of the four major types of viruses

Viruses come in four flavours: helical (eg rabies), polyhedral (eg adenovirus), spherical (eg coronavirus), and complex (eg bacteriophage).

When viruses infect us, they damage our cells and trigger an immune response, both of which create the symptoms of infectious disease.

Are Viruses Alive?

Traditionally, biologists said viruses are not alive because they lack the equipment to metabolise, grow, and self-replicate.

But viruses do possess genes, allowing them to mutate, adapt, and evolve. They also share a common genetic code with all living cells, suggesting they branch from the universal tree of life.

So how did viruses evolve to be relegated to the world of the undead? There are three main hypotheses of viral origins.

Virus Origins: The Virus First, Regressive, and Escape Hypotheses

Classical hypotheses of viral origins. (1) The Virus First Hypothesis says viruses preceded all cellular life. (2) The Reduction Hypothesis says some primitive cells spun-off into the first viruses, while others became modern cells. (3) The Escape Hypothesis says viruses are genes that evolved to survive outside modern cells.

Recent comparisons of viral and cellular proteins reveal intricate overlaps in their proteomes (protein sets). This favours the reduction hypothesis, where early parasitic cells dropped their standard equipment to become the first viruses.

Fast forward a couple billion years. Modern viruses are so streamlined as to have just 4-200 genes. This compares to 180-12,000 genes in bacteria, and around 20,000 genes in humans. (Just to mix things up a bit: water fleas have 31,000 genes.)

So the question—are viruses alive—is somewhat open. We might think of viruses in the wild as dormant, coming to life only when they hijack cells. While some simply redirect our biological machinery, others set up compartmentalised virus factories where they metabolise and reproduce with autonomy.

It's life, Jim, but not as we know it.

The Great Cell Hijack

What do viruses actually do inside our cells? And are all infected cells doomed?

Cells are the multipurpose biological factories that make up our tissues. They're up to 1,000 times bigger than viruses, and have complex internal structures bustling with organelles and enzymes.

Our DNA is stored in the nucleus of almost every cell

Our DNA is stored in the nucleus of almost every cell.

If you like analogies, consider that DNA serves as a kind of recipe book for making proteins, which in turn make up our cells as well as the essential molecules secreted beyond.

Proteins are large, complex molecules like hormones, antibodies, and enzymes, used around the body all the time. So DNA isn't only relevant during foetal development; it's actually expressed throughout the lifetime on a moment-to-moment basis.

This expression is a two step process that takes place first inside, and then outside, the cell nucleus. Being devious little wretches, viruses sneak right into this pathway to replicate their own protein body parts.

DNA expression sees our genetic information converted into proteins

DNA expression sees our genetic information converted into proteins.

Some viruses inject their genes in the nucleus, right alongside our own DNA, which can have major consequences as we'll see in a moment. But first, let's look at common viruses like SARS-CoV-2 which deposit their genes on the factor floor: the cell cytoplasm.

The viral pathway in cells: how coronavirus infects cells

The pathway of a coronavirus in cells. (1) A virion binds with a cell receptor to gain entry. (2) The entire unit is engulfed inside a lipid bubble called an endosome, which it escapes to (3) release its RNA into the cytoplasm. (4) The RNA is translated into chains of amino acids which fold up to form proteins. (5) The viral proteins self-assemble in new virions and are packaged into a secretory vesicle for (6) exocytosis out of the cell.

Cells that succumb to viral infection are doomed. That's usually because the viral genes are translated at the expense of host genes, damaging or destroying the cell in the process. Then the nanoscale army continues on its path of destruction.

Fortunately, this operation isn't completely covert. When viruses enter cells, they leave molecular calling cards on the cell surface. These are antigens. And they provide our immune system with was to identify viral invaders.

Over several days, our immune cells multiply and target the invading pathogen. Based on the antigen, cytotoxic T-cells identify and destroy contaminated cells. Meanwhile, B-cells release antibodies into the blood and mucus membranes to neutralise roaming virions.

Key cells of the adaptive immune system

Key cells of the adaptive immune system.

But this adaptive immune response takes time. Until then, the viral army scales to extraordinary volumes.

For instance, at peak COVID infection, just one millilitre of saliva contains 200 million SARS-CoV-2 virions. Supercarriers can host up to 6 trillion virions per ml. And yet, viruses are so small that the entire mass of SARS-CoV-2 in the global population is estimated to be just 1-10kg.

How Viruses Integrate with Our DNA

Most viruses, including SARS-CoV-2, don't appear to integrate with our own DNA. But there are exceptions.

Retroviruses are hell-bent on eternal life, integrating their DNA alongside our own in the nucleus. Clinically, the most significant one is HIV which causes AIDS.

How does this happen? The HIV virus uses an enzyme called reverse transcriptase to convert its single-stranded RNA backwards into double-stranded DNA. It then injects the DNA into a nuclear pore complex so it can live permanently among the host DNA.

In this purely genetic form, the virus is known as a provirus. Nestled alongside the genes of its host, proviruses are expressed to reproduce HIV for life.

How retroviruses integrate their RNA into human DNA in cells

The retrovirus infection cycle. (1) The retrovirus binds to a cell receptor to gain entry. (2) Reverse transcriptase converts the viral genome from RNA to DNA. (3) The capsid injects the viral DNA along with an enzyme called integrase into the nucleus. (4) Integrase catalyses the insertion of viral DNA at target sites to create a permanent store. (5) To replicate, the provirus is then transcribed back into mRNA which is (6) exported out of the nucleus. (7) The mRNA is translated into viral proteins which self-assemble and (8) exit the cell.

Typically, the HIV virus targets immune cells, ultimately leading to acquired immunodeficiency syndrome (AIDS). But HIV attacks other cells too. When it infects germ cells (sperm and eggs), it hitches a ride within the genome of future generations.

Today, we all have proviruses inside our DNA—or at least, the fragmented remnants of their genes. But if natural selection prunes away useless genes, why are proviral sequences still with us today?

How Viruses Shaped Our Evolution

When proviral genes land in host DNA, they can be co-opted for new purposes, ultimately driving new adaptations.

For instance, a select group of retroviral genes were put to work in mammals 130 million years ago. They bestowed our ancestors with novel proteins that supported fusion between cells, facilitating the evolution of the placenta.

This is how viruses changed the course of animal evolution: they actually handed us cool new genes.

But there is a finite window in which we can take advantage of viral genes. Over time, the unused sequences become corrupted by random mutation, degrading into strings of non-coding DNA which clutter up our genetic bank.

What's more, viral elements have a propensity to replicate within our genome using a copy-and-paste style mechanism. It explains their astonishing abundance today: of the 3 billion bases in human DNA, up to 1.4 billion may have viral origins.

Once written off by geneticists as junk DNA, these non-coding snippets of As, Cs, Gs, and Ts are now thought to have valuable functions. For instance, they may provide a genetic sandbox from which novel genes can emerge.

Then there's the extraordinary facility of jumping genes.

Jumping Genes

Around half of our DNA consists of transposable elements—sequences of A, C, G, and T bases that move around within our genome, earning them the moniker of "jumping genes". A large portion of these elements have proviral origins.

When jumping genes copy-and-paste themselves within our DNA, the precise landing site determines whether our DNA is altered in a positive, neutral, or negative way.

Jumping genes can interrupt the sequence of coding DNA to cause disease

Jumping genes can interrupt the sequence of coding DNA to start, stop, and alter the expression of our genes. In evolutionary terms, this can be hugely beneficial. But as individuals, we're nature's guinea pigs.

Retroviruses have also littered our genome with extra promoter sequences, which serve as on-switches when located at the start of coding genes. We've successfully co-opted many viral promoters in our evolution.

And yet there are some genes we very much want to keep switched off under normal circumstances. This is where jumping promoters can cause problems.

Consider that we have around 40 genes that direct cell growth and repair. When they're not required, they're inactivated. Switching them on in error can lead to runaway cell growth—aka cancer.

For this to happen, a proto-oncogene must first undergo a mutation to become an oncogene. Now it's a gun, cocked and loaded. Although we have many checks and balances to avoid it firing, jumping promoters can pull the trigger.

When a promoter jumps and lands near the start of an oncogene, it can trigger cancer.
Jumping genes: a promoter sequence jumps downstream to activate transcription of an oncogene

Jumping genes: a promoter sequence jumps downstream to activate transcription of an oncogene.

Research is uncovering a growing number of mechanisms by which these self-appointed gene managers can trigger diseases like ALS, MS, haemophilia, and schizophrenia. So how often do genes jump?

The most abundant jumping gene, Alu, makes up around 10% of our DNA. At 300 base pairs long, Alu has copied and pasted itself a million times since it took up residence in our genome 65 million years ago. These mobile genetic elements are so active that new Alu insertions are estimated to affect 1 in 20 births.

Is this bad? Not always. In the course of evolution, Alu sequences have been co-opted as gene regulators, helping control gene expression throughout the lifetime. Unfortunately, Alu jumps can also trigger blood and neurological disorders.

However, for the most part, Alu elements usually land in non-coding regions, which rather adds value to that so-called junk DNA.

Final Thoughts

Viruses are everywhere. In supermarkets. In labs. In bacteria. In our DNA. We even use them in medicine: viruses can be adapted to carry genetic material to our cells, whether to cure disease with gene therapy or prevent it with genetic vaccines.

Viruses have been around for billions of years and, looking at the state of our genome, will be with us for a long time to come. Good or bad, dead or alive, if there's one thing you can say about viruses... it's that they're spectacularly successful at what we're all ultimately programmed to do: replicate our genes.

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Rebecca Casale, Creator of Science Me

Rebecca Casale is a science writer in New Zealand. If you like her content, please share it with your friends. If you don't like it, why not punish your enemies by sharing it with them?