In the early 1990s, AIDS was a leading cause of death among young adults in many North American cities. Today a young person diagnosed with HIV who starts treatment early can expect close to a normal lifespan, and hepatitis C, a liver infection that used to smoulder for decades, is cured with 8 to 12 weeks of pills. Both changes came from knowing, molecule by molecule, how a virus uses a cell: which receptor it grabs, which enzymes it carries, and which steps a human cell would never do on its own. Every virus-only step is a drug target. This lesson applies membranes, enzymes and inhibitors to modern medicine.
Viruses: parasites of the cell's machinery
A virus is a package of DNA or RNA inside a protein capsid, sometimes wrapped in an envelope of lipid stolen from its last host cell. It has no ribosomes, no ATP supply and no metabolism, so it is an obligate intracellular parasite. Every virus follows the same plan: attach to a specific receptor, enter, copy its genome and make proteins with the host's ribosomes and ATP, assemble new particles and leave. Attachment is as specific as an enzyme binding its substrate, which is why HIV infects immune cells and hepatitis C infects liver cells. It also explains why viruses are hard to treat. Antibiotics hit structures human cells lack (peptidoglycan walls, 70S ribosomes), but a virus uses the cell's own machinery, so a safe antiviral must hit something the virus brings with it, usually a viral enzyme. Hitting the invader but not the host is called selective toxicity.
How HIV enters and hijacks a helper T cell
- Binding: the envelope glycoprotein gp120 binds the CD4 receptor on helper T cells, then changes shape and binds a co-receptor, usually CCR5 (sometimes CXCR4).
- Fusion: a second glycoprotein, gp41, anchors in the cell membrane and folds back, pulling the two fluid bilayers together until they merge and the capsid enters the cytoplasm.
- Reverse transcription: the viral enzyme reverse transcriptase copies the single-stranded RNA genome into double-stranded DNA. This runs the central dogma backwards, which is why HIV is called a retrovirus.
- Integration: the viral DNA enters the nucleus, where integrase cuts the host chromosome and splices the viral DNA in. The inserted provirus is now a permanent part of that cell's DNA.
- Making viral parts: host RNA polymerase transcribes the provirus; host ribosomes make long polyproteins.
- Assembly and budding: viral RNA and polyproteins bud out wrapped in host membrane carrying gp120 and gp41.
- Maturation: the viral enzyme protease cuts the polyproteins into working enzymes and capsid proteins. Without this cut the particle is immature and cannot infect.
HIV causes disease by destroying the CD4 helper T cells that coordinate the whole immune response. A healthy person has roughly 500 to 1500 CD4 cells per microlitre of blood; below 200 the person has AIDS and develops opportunistic infections and cancers that a working immune system would control. Two features make HIV hard to beat. Reverse transcriptase has no proofreading, and an untreated person makes on the order of virions a day, so nearly every single mutation, including drug-resistant ones, appears daily. And in resting memory cells the provirus is silent; no drug can touch a gene that is not being used, so this latent reservoir lets the virus rebound whenever treatment stops.
| Life-cycle step | Viral target | Drug class | Example | How it works |
|---|---|---|---|---|
| Binding | CCR5 co-receptor (a host protein) | CCR5 antagonist | Maraviroc | Occupies CCR5 so gp120 cannot use it; useless against CXCR4-using virus |
| Fusion | gp41 | Fusion inhibitor | Enfuvirtide | Stops gp41 folding back, so the membranes never merge |
| Reverse transcription | Reverse transcriptase active site | NRTIs | Tenofovir, emtricitabine, zidovudine (AZT) | Fake nucleotides with no 3′–OH: once added, the DNA chain stops |
| Reverse transcription | A pocket away from the active site | NNRTIs | Efavirenz, rilpivirine | Noncompetitive (allosteric) inhibition |
| Integration | Integrase | Integrase inhibitors | Dolutegravir, bictegravir | Viral DNA is never spliced into the chromosome |
| Maturation | Protease active site | Protease inhibitors | Darunavir, atazanavir | Competitive inhibitors mimicking the cut site; virions stay immature |
Monoclonal antibodies: made-to-order binding proteins
An antibody is a Y-shaped protein of two heavy and two light chains. The tips of the Y are variable regions whose shape fits one specific antigen; the stem (Fc region) signals immune cells and complement proteins to destroy whatever the antibody has coated. Each B cell makes just one antibody. In 1975, Georges Köhler and César Milstein fused antibody-making B cells from an immunized mouse with myeloma (cancer) cells, which divide indefinitely. The resulting hybridoma cells live forever in culture and secrete one identical (monoclonal) antibody. Mouse antibodies trigger an immune reaction in people, so modern ones are engineered to be mostly or fully human (-ximab chimeric, -zumab humanized, -umab human). As large proteins they would be digested in the gut, so they are injected. The targeted cancer drugs you met in Organelles, the Fluid Mosaic Model and Membrane Transport (trastuzumab and its drug-carrying version) are one use; the table shows the main strategies.
| Strategy | Example | Target | Used for |
|---|---|---|---|
| Neutralize a virus | Palivizumab | RSV fusion protein | Protecting high-risk premature babies from RSV |
| Block entry into cells | Ibalizumab | CD4 on T cells | Multidrug-resistant HIV |
| Mop up a signal molecule | Adalimumab | TNF-α, an inflammatory signal | Rheumatoid arthritis, Crohn's disease |
| Flag cells for destruction | Rituximab | CD20 on B cells | B-cell lymphoma and leukemia |
| Release the immune brakes | Pembrolizumab | PD-1 on T cells | Melanoma, lung and other cancers that use PD-L1 to switch T cells off |