Table of Contents
The “central dogma” of molecular biology, in its simplest form, states that genetic information flows in one direction:
$$
\text{DNA} \;\rightarrow\; \text{RNA} \;\rightarrow\; \text{Protein}
$$
Retroviruses are fascinating because they use an additional, reverse step:
$$
\text{RNA} \;\rightarrow\; \text{DNA}
$$
This does not make the central dogma completely wrong, but it shows that there are important exceptions and extra routes of information flow.
What Retroviruses Are and What Makes Them Special
Retroviruses are RNA viruses whose genomes consist of single-stranded RNA. Typical examples are:
- Human Immunodeficiency Virus (HIV)
- Some tumor-causing viruses (e.g. certain animal leukemia viruses)
The key, defining feature of retroviruses:
- They convert their RNA genome into DNA inside the host cell.
- This DNA copy is then integrated into the host’s genome, becoming part of the host cell’s genetic material.
This strategy is unique among viruses and is the reason they “contradict” the simple form of the central dogma.
The Retroviral Life Cycle: Where the “Contradiction” Occurs
Many steps of the retroviral life cycle are similar to other viruses (attachment, entry, assembly, release), and are covered in viral biology elsewhere. The steps that matter here for the central dogma are:
1. Entry With Their Own Enzymes
Retroviruses carry, inside their capsid:
- Their RNA genome
- The enzyme reverse transcriptase
- Often other enzymes such as integrase
These enzymes are encoded in the viral genome and packaged into each viral particle.
2. Reverse Transcription: RNA → DNA
Once inside the host cell, the viral RNA is used as a template to synthesize DNA. This is the crucial “reverse” step:
- Reverse transcriptase performs:
- RNA-dependent DNA synthesis: builds a DNA strand using viral RNA as template.
- RNA degradation: removes the RNA strand once copied (RNase H activity).
- DNA-dependent DNA synthesis: synthesizes the second DNA strand, forming double-stranded DNA.
In symbolic form:
$$
\text{Viral RNA} \xrightarrow{\text{reverse transcriptase}} \text{Double-stranded viral DNA}
$$
This is the opposite direction to the usual transcription step (DNA → RNA).
3. Integration Into the Host Genome
The new viral DNA (often called proviral DNA) enters the cell nucleus. Another viral enzyme, integrase, cuts host DNA and joins viral DNA into it.
- The integrated viral DNA is now called a provirus.
- It behaves like a host gene:
- It is transcribed by the host’s RNA polymerase.
- Viral mRNAs and new viral genomes (RNA) are produced from it.
This means the cell’s own transcription machinery now reads the viral DNA as if it were part of its own genome.
4. Return to the “Normal” Direction: DNA → RNA → Protein
After integration, the information flow follows the usual scheme:
- Proviral DNA → viral RNA (transcription by host)
- Viral RNA → viral proteins (translation by host ribosomes)
Thus the retroviral life cycle includes both the standard and the “reverse” information flows.
How Exactly Retroviruses Challenge the Central Dogma
Original Simplification vs. Reality
The original, simplified central dogma:
- Implied that RNA is made from DNA, not the other way around.
- Suggested information does not flow from RNA to DNA in living systems.
Retroviruses clearly demonstrate:
- RNA can be used as a template for DNA synthesis in cells infected by these viruses.
- Therefore, RNA → DNA is a real, biologically important process.
What Does *Not* Change
Retroviruses do not overturn every aspect of the central dogma:
- Information still does not flow from protein back to nucleic acids (no protein → DNA or protein → RNA).
- Inside the host, once viral DNA is integrated, it is treated like normal DNA:
- DNA → RNA → Protein still applies to those viral genes.
So the central dogma is not entirely wrong; it must simply be expanded to include additional allowed routes of information flow.
Revised View of Information Flow
With retroviruses (and related processes in cells), the more complete picture is:
- DNA → DNA (replication)
- DNA → RNA (transcription)
- RNA → Protein (translation)
- RNA → DNA (reverse transcription)
Retroviruses were key in discovering and emphasizing the last route.
Reverse Transcriptase: The Key Enzyme
Reverse transcriptase is central to why retroviruses contradict the simple central dogma.
Important properties:
- It is a polymerase that reads RNA and synthesizes DNA.
- It is often error-prone, leading to frequent mutations in retroviral genomes.
- This contributes to rapid evolution of retroviruses (e.g. drug resistance in HIV).
- Reverse transcriptase activity is not normally present in most uninfected cells (some endogenous cellular enzymes with related activities exist, but viral RT is distinctive).
Because of its crucial role, reverse transcriptase is:
- A major target for antiviral drugs (e.g. HIV therapy).
- A powerful tool in genetic engineering (e.g. making DNA copies of RNA, cDNA).
Retroviruses and Genetic Engineering
Retroviral biology directly influences methods in genetic engineering:
1. cDNA Synthesis
Using reverse transcriptase in the lab, scientists can:
- Take mRNA from cells.
- Use it as template to synthesize complementary DNA (cDNA).
This mimics the retroviral RNA → DNA step and allows:
- Construction of cDNA libraries representing expressed genes.
- Cloning of genes without introns, since mRNA has had introns removed.
2. Retroviral Vectors
The ability of retroviruses to insert DNA into host genomes is exploited to deliver foreign genes:
- Modified retroviruses (retroviral vectors) are engineered:
- To carry therapeutic or experimental genes.
- To have pathogenic genes removed for safety.
- After infection, the retroviral DNA (with the inserted gene) integrates into the host genome.
- The host cell then expresses the introduced gene.
This is highly relevant to:
- Gene therapy (e.g. attempts to correct genetic defects).
- Long-term expression of transgenes in research.
The very property that challenges the central dogma (RNA → DNA integration) becomes a powerful genetic engineering tool.
Endogenous Retroviruses: Viral DNA in Our Genomes
Evidence of past retroviral infections is found in the genomes of many organisms, including humans:
- Endogenous retroviruses (ERVs) are remnants of ancient retroviral infections.
- When a retrovirus infects germline cells (sperm or egg precursors), the provirus can be passed on to offspring.
- Over evolutionary time, such sequences can:
- Accumulate mutations and become inactive.
- Occasionally be co-opted for host functions.
The very presence of ERVs in genomes is a long-term record of RNA → DNA transfer events, mediated by retroviruses.
How Retroviruses Changed the Conceptual Framework
Before retroviruses (and reverse transcriptase) were described:
- The central dogma was often viewed as a rigid, one-way rule.
- The idea of RNA serving as a template for DNA was not widely considered in cellular biology.
The discovery of reverse transcription showed that:
- Cells are more flexible in their information processing than previously thought.
- Viruses can hijack and extend the host’s molecular systems.
- The central dogma should be seen as a general framework with specific, well-defined exceptions, rather than an absolute prohibition.
In genetic engineering, this insight translates into:
- New routes to manipulate information (using RNA to generate DNA).
- New vectors and tools inspired by retroviral strategies.
- A deeper awareness of how viruses and hosts exchange and rearrange genetic information over evolutionary time.
Retroviruses therefore “contradict” the simple central dogma not by overturning the role of DNA, but by revealing an additional, reverse pathway of information flow—one that has become central to modern molecular biology and genetic engineering.