Lecture 16

Define a virus.

Metabolically inert pathogens that are incapable of reproducing outside a host cell.

Describe the structure of a virus.

An inner core of nucleic acid (DNA or RNA), which may be surrounded by a protein coat and an external lipid envelope.

How are viruses classified?

Based on chemical and physical properties, including genome sequence, nucleic acid type, number of proteins encoded, virion shape, capsid shape and presence of an envelope.

Describe the steps of virus replication.

1. Binding and fusion: Virus binds to and enters the host cell.

2. Uncoating: Viral genetic material is released

3. Integration: Viral DNA integrates into the host genome

4. Genome replication and transcription: Viral genome is replicated and transcribed into RNA; this can occur before integration

5. Protein synthesis and processing: Viral proteins are produced and processed

6. Assembly and release: New virions are assembled and released.

Why must antiviral treatment be specific to the causative virus?

Different viruses have different structures and replication mechanisms, so treatment must target the specific virus rather than relying on one broadly effective treatment.

Define HIV and explain why it can lead to AIDS.

HIV is a chronic infection that targets T cells in the blood. As T-cell numbers decrease, the immune system weakens, making the person vulnerable to other diseases that may become life-threatening.

What are the main classes of HIV treatment, in order?

Entry inhibitors > NRTIs > NNRTIs > integrase inhibitors > assembly inhibitors.

How do HIV entry inhibitors work?

They interfere with receptor binding, fusion and entry of virions into host cells.

What are examples of HIV entry inhibitors?

maraviroc and enfuvirtide

How do NRTIs work?

They mimic natural nucleotides and are incorporated into developing viral DNA by reverse transcriptase, stopping further DNA synthesis and preventing viral DNA from being integrated into the host genome

What are examples of NRTIs?

tenofovir

How do NNRTIs work?

They bind to an allosteric site on reverse transcriptase, causing a conformational change that distorts the nucleotide-binding pocket and catalytic site, preventing viral DNA synthesis

What is an example of a NNRTI?

etravirine

How do HIV integrase inhibitors work?

They bind to the catalytic site of viral integrase and chelate two Mg²⁺ ions, inhibiting strand transfer and preventing viral DNA from integrating into the host genome.

What is an example of a HIV integrase inhibitor?

dolutegravir

How do HIV assembly inhibitors work?

They inhibit viral protease, preventing HIV polypeptides from being cleaved into the individual proteins needed to assemble mature, functional viral particles

What is an example of a HIV assembly inhibitor?

ritonavir

Why must drug interactions be checked before prescribing medication to a patient with AIDS?

Patients may take multiple medications to treat HIV, opportunistic infections and cancers, increasing the risk of drug interactions.

Why does ritonavir have a high risk of drug interactions, and which drugs can be affected?

Ritonavir inhibits CYP3A4 and P-glycoprotein, increasing exposure to other drugs, including protease inhibitors, statins, benzodiazepines, digoxin, cyclosporine and tacrolimus.

Define HSV and explain how it causes recurrent infections.

HSV enters through the epithelium, causing a localised infection at the entry site. It then travels along sensory nerves to nerve ganglia, where it remains latent. Stress or other triggers can reactivate the virus, which travels back along the nerves to the original site and causes recurrent infections.

What is the treatment for HSV, and how does it work?

NTIs: Prodrugs are activated by viral TK in infected cells. The phosphorylated drug is incorporated into growing viral DNA by viral DNA polymerase, causing chain termination and preventing further viral DNA synthesis. Activation is specific to infected cells

What is an example of an NTI?

acyclovir

Define HBV and describe its treatment.

HBV can cause chronic liver disease and is preventable by vaccination. Treatment may require lifelong therapy; there is no cure, but NRTIs reduce liver damage and the risk of hepatocellular carcinoma

Define HCV and describe the goals and classes of treatment.

HCV can cause acute or chronic liver disease and can be successfully treated. Drug combinations eliminate the virus, reduce liver damage and lower cancer risk. Treatment classes include NTIs, NNTIs and assembly inhibitors.

Define influenza and explain the benefits of early antiviral treatment.

Influenza is a highly contagious viral respiratory infection that can cause severe complications in high-risk individuals. Antiviral treatment started early can shorten symptom duration and reduce viral spread.

What are the main classes of influenza treatment?

Uncoating inhibitors, NNTIs and release inhibitors.

How do influenza uncoating inhibitors work?

They block the viral M2 proton channel in endosomes, preventing the viral genome from dissociating from the viral matrix and stopping replication

what is an example of uncoating inhibitor?

amantadine, which is no longer routinely used because of widespread resistance and off-target effects

How do influenza release inhibitors work?

They mimic sialic acid and inhibit viral neuraminidase, preventing newly formed viral particles from being released from infected cells

what is an example of an influenza release inhibitor?

oseltamivir

Define COVID-19.

An infectious disease caused by SARS-CoV-2, an RNA virus that enters host cells and replicates using RNA-dependent RNA polymerase

What are the main classes of COVID-19 treatment?

Entry inhibitors, NTIs and assembly inhibitors.

How do casirivimab and imdevimab work as COVID-19 entry inhibitors?

They are monoclonal antibodies that target the viral spike protein, preventing binding to the ACE2 receptor on host cells and inhibiting viral entry

What are the risks of casirivimab and imdevimab?

They can cause severe infusion and hypersensitivity reactions and may worsen outcomes in hospitalised patients in certain circumstances.

How does remdesivir work as an NTI?

It targets viral RNA-dependent RNA polymerase. It allows three nucleotides to be added to the growing RNA chain before causing chain termination, stopping further viral RNA synthesis.

What are the risks of remdesivir?

Drug interactions can reduce efficacy, while impaired excretion may cause liver or kidney toxicity.

How does molnupiravir work as an NTI?

It mimics cytidine and uridine and is incorporated into viral RNA, causing mutations to accumulate in the viral genome and preventing effective viral replication.

What are the risks of molnupiravir?

It has significant reproductive and developmental safety concerns, including potential embryo-foetal harm, and is generally avoided during pregnancy.

What is a possible mechanism of resistance to nucleotide-based antivirals?

Changes in nucleotide selection or incorporation can reduce the effectiveness of nucleotide analogues and allow viral replication to continue.