6.3 Theme 1 - Viruses & Antiviral Agents

What are the general characteristics of viruses?

• Can pass through a 2 µm filter and remain infectious

• Totally intracellular - relying exclusively on living cells for replication & persistence

• Possess either DNA or RNA as genetic material

• Have surface components to facilitate binding to host cells

What are the main morphological features of viruses?

• nonenveloped or enveloped, envelope = lipid membrane derived from the host

• Virus symmetry can be: Icosahedral, helical, complex

What are the 3 main methods of viral entry into host cells?

• Direct penetration – virus binds to the cytoplasmic membrane & releases genetic material into the cell

• Membrane fusion – virus binds to receptors, fuses with the membrane, & releases genetic material after capsid breakdown

• Endocytosis – virus binds to the cell, is engulfed into a vesicle, & releases genetic material inside the cell

How does a non-enveloped DNA virus replicate?

• Attachment – virus binds to host cell

• Entry & uncoating – viral DNA released

• Transcription – DNA transcribed to mRNA

• Replication – mRNA drives DNA & protein synthesis

• Assembly – capsid formed

• Release – mature virions exit cell

How does an enveloped DNA virus replicate?

• Attachment – virus binds to host cell

• Entry & uncoating – viral DNA released

• Transcription – DNA transcribed to mRNA

• Replication – mRNA drives DNA & protein synthesis

• Assembly – nucleocapsid forms in the cell

• Envelopment & release – virus acquires a lipid envelope from the host’s plasma membrane as it buds out of the cell

How do RNA viruses replicate?

• Positive-sense ssRNA (+ssRNA) virus: +ssRNA is directly translated into viral proteins. Viral RNA polymerase transcribes a complementary −ssRNA, which serves as a template to make more +ssRNA for further protein production or packaging

• Negative-sense ssRNA (−ssRNA) virus: −ssRNA is transcribed by RNA-dependent RNA polymerase into +ssRNA, which is translated into viral proteins and also copied back into −ssRNA for new virions

• Double-stranded RNA (dsRNA) virus: dsRNA is unwound; the + strand is translated into viral proteins, while viral RNA polymerase transcribes the − strand to form complementary RNA for assembly into new virions

How do retroviruses establish latency?

• Retrovirus RNA is converted to DNA

• Viral DNA integrates into the host chromosome

• Provirus may replicate when host cell replicates

• Provirus may be transcribed, producing RNA for new retrovirus genomes

• Viral protease produces viral proteins

• Later activation leads to viral particle production and recurrent infection

How do blood-borne viruses spread in the body?

• Enter blood and reach primary replication sites such as muscle, liver, spleen

• Cause secondary viremia, sometimes shedding virus

• Spread to other replication sites like skin, mucous membranes, lungs, kidneys

• Example: chickenpox enters via respiratory tract but causes symptoms (lesions) on skin

How can viral integration lead to cancer?

A virus can insert near a proto-oncogene acting as a promoter. If the proto-oncogene repressor is inactivated (e.g., by a second viral insertion), the oncogene is expressed, potentially leading to cancer.

How does acyclovir (ACV) inhibit viral replication?

• Acyclovir is a prodrug and nucleoside analogue that must be phosphorylated to be active

• Viral thymidine kinase (HSV-1 TK) adds the first phosphate, which host kinases cannot do

• Cellular GMP kinase adds the second phosphate forming acyclovir diphosphate

• Cellular NDP kinase adds the third phosphate forming acyclovir triphosphate

• Acyclovir triphosphate is incorporated by viral DNA polymerase into viral DNA

• Lacking a 3’-hydroxyl group, it causes chain termination and halts viral replication

How does AZT inhibit HIV replication?

• AZT targets HIV reverse transcriptase

• It is phosphorylated by host cell kinases in three steps to form AZT triphosphate

• The 3’ azido group blocks formation of phosphodiester bonds, terminating viral DNA synthesis

• Unlike acyclovir, activation occurs in any cell, not just infected cells

• Drug can accumulate in non-infected cells

• Resistance can develop, so AZT is used in combination therapy (HAART)

How do influenza neuraminidase inhibitors work?

• They block neuraminidase activity, preventing cleavage of sialic acid from viral glycoproteins

• Without neuraminidase, newly formed influenza virions cannot be released from infected cells

• Virus remains trapped in the host cell, preventing further replication and halting disease progression