Retroviruses are a unique class of viruses that carry their genetic material as ribonucleic acid (RNA) rather than deoxyribonucleic acid (DNA). The name “retro” reflects their unusual, backward method of genetic replication inside a host cell. These agents are enveloped in a lipid membrane derived from the host cell and contain a protein shell, or capsid, surrounding their RNA core. This structure allows the virus to bind to and enter target cells, initiating a process where the viral genetic code is permanently spliced into the host cell’s DNA. This mechanism of integration enables retroviruses to establish long-term, persistent infections.
The Unique Replication Cycle
The defining characteristic of a retrovirus is its ability to reverse the central dogma of molecular biology, reversing the typical flow of genetic information. Once inside the host cell, the virus releases its single-stranded RNA genome and viral enzymes into the cytoplasm. The primary enzyme is reverse transcriptase (RT), which uses the viral RNA as a template to synthesize a complementary DNA (cDNA) strand.
RT then degrades the RNA and synthesizes a second DNA strand, resulting in a complete double-stranded DNA copy of the viral genome. This viral DNA is transported into the host cell’s nucleus. There, the enzyme integrase cuts the host cell’s chromosomal DNA and permanently inserts the viral DNA into the host genome.
This integrated viral DNA is called a provirus, and it can remain dormant for extended periods in a state known as latency. The host cell’s machinery treats the provirus as its own genetic code, transcribing the viral genes into new RNA molecules. Some RNA is packaged as the genome for new viral particles, while other RNA is translated into the proteins needed to assemble the next generation of viruses. This integration makes retroviral infections challenging to eradicate because the provirus is replicated every time the host cell divides.
Major Retroviral Diseases
The most well-known retroviral disease is caused by the Human Immunodeficiency Virus (HIV), which leads to Acquired Immunodeficiency Syndrome (AIDS). HIV targets and destroys CD4+ T-lymphocytes, which are white blood cells that coordinate the immune system’s response. The progressive loss of these immune cells cripples the body’s ability to fight pathogens, resulting in AIDS.
A diagnosis of AIDS is made when the CD4+ T-cell count drops significantly or when the patient develops an opportunistic infection or cancer. The chronic nature of HIV infection is a direct consequence of the provirus integrating into the host genome, allowing the virus to persist despite the immune response. Another human retrovirus, Human T-lymphotropic Virus type 1 (HTLV-1), causes different forms of pathology.
HTLV-1 is associated with Adult T-cell Leukemia/Lymphoma (ATLL), a rare and aggressive cancer, and a progressive neurological disorder (HAM/TSP). Unlike HIV, which kills its target T-cells, HTLV-1 causes the proliferation and immortalization of infected T-cells. This uncontrolled cell growth is the underlying mechanism that can lead to the development of ATLL years or even decades after the initial infection.
Antiretroviral Drug Strategies
The pharmacological management of retroviral infections, particularly HIV, relies on Highly Active Antiretroviral Therapy (HAART), or combination therapy. This approach uses multiple drugs simultaneously to attack the virus at different stages of its replication cycle. Using a combination of agents is necessary to prevent the rapid development of drug resistance, a common problem with frequently mutating viruses.
Several major classes of drugs are used:
- Reverse Transcriptase Inhibitors (RTIs): These include Nucleoside/Nucleotide RTIs (NRTIs), which mimic DNA building blocks to cause premature chain termination, and Non-nucleoside RTIs (NNRTIs), which bind directly to the reverse transcriptase enzyme to prevent its function.
- Protease Inhibitors: These block the viral protease enzyme from cleaving large viral polyproteins into functional components, preventing the formation of mature, infectious virus particles.
- Integrase Strand Transfer Inhibitors (INSTIs): This class blocks the integrase enzyme, preventing the viral DNA from being spliced into the host chromosome.
- Entry or Fusion Inhibitors: These prevent the virus from physically attaching to or entering the host cell in the first place.
Use in Gene Therapy
The unique ability of retroviruses to permanently integrate their genetic material into a host cell’s chromosome has been repurposed for beneficial medical applications in gene therapy. Scientists engineer retroviruses into specialized tools called viral vectors to deliver therapeutic genes to target cells. The stability of the resulting provirus ensures that the corrective gene is passed on to all daughter cells, offering a long-term therapeutic effect.
To ensure safety, these vectors are modified to be replication-incompetent by removing the genes necessary for the virus to produce new infectious particles. The therapeutic gene is inserted into the vector in place of the viral replication genes. This system is particularly useful for treating monogenic disorders, which are caused by a single defective gene.
Retroviral and lentiviral vectors have shown promise in clinical trials for conditions like severe combined immunodeficiency (SCID), often referred to as “bubble boy disease.” The vector delivers a correct copy of the faulty gene into the patient’s hematopoietic stem cells outside the body, and these corrected cells are then infused back into the patient. While the risk of insertional oncogenesis, where the integration disrupts a host gene, remains a safety consideration, modifications like self-inactivating vectors are continually being developed to minimize this risk.