🦠Virology Unit 3 – Viral Genomes and Genome Organization

What Are Viral Genomes?

• Viral genomes consist of the genetic material that encodes all the information required for viral replication and propagation within host cells
• Can be composed of either DNA or RNA, depending on the specific virus
• Vary significantly in size, ranging from a few thousand nucleotides to over a million base pairs
• Contain genes that code for essential viral proteins, such as capsid proteins, enzymes, and regulatory factors
• Viral genomes are typically compact and efficient, with minimal non-coding regions and overlapping genes to maximize the use of limited genetic space
• Genome organization and structure play crucial roles in viral replication, gene expression, and interaction with host cells
• Understanding viral genomes is essential for developing antiviral therapies, vaccines, and diagnostic tools

Types of Viral Genetic Material

• Viruses can have genomes composed of either DNA or RNA
  • DNA viruses (herpesviruses, poxviruses) have double-stranded DNA (dsDNA) genomes
  • RNA viruses (influenza, HIV) have single-stranded RNA (ssRNA) or double-stranded RNA (dsRNA) genomes
• RNA viral genomes can be further classified as positive-sense (+ssRNA), negative-sense (-ssRNA), or ambisense
  • Positive-sense RNA genomes (poliovirus) can directly serve as mRNA for protein synthesis
  • Negative-sense RNA genomes (Ebola virus) must first be transcribed into positive-sense RNA by viral RNA-dependent RNA polymerase
• Some viruses, such as retroviruses (HIV), have RNA genomes that are reverse transcribed into DNA during the replication cycle
• The type of genetic material influences the replication strategy and host cell interactions of the virus
• Differences in genetic material also impact the stability and mutation rates of viral genomes

Viral Genome Structures

• Viral genomes can exist in various structural forms, including linear, circular, or segmented
• Linear genomes are the most common and can be found in both DNA and RNA viruses (adenoviruses, influenza viruses)
  • Linear genomes may have terminal repeats or covalently linked proteins at the ends for stability and replication initiation
• Circular genomes are less common but can be found in some DNA viruses (polyomaviruses) and a few RNA viruses (hepatitis delta virus)
  • Circular genomes provide a more stable structure and facilitate rolling circle replication
• Segmented genomes consist of multiple, separate molecules of nucleic acid that are encapsidated together (Rotavirus, influenza viruses)
  • Segmentation allows for genetic reassortment and increased genetic diversity
• Genome structure can influence the packaging of genetic material into the viral capsid and the release of the genome during infection
• The structure of the viral genome also affects its susceptibility to host cell nucleases and the efficiency of replication and transcription

Genome Organization Strategies

• Viral genomes employ various strategies to organize and express their genetic information efficiently
• Some viruses have polycistronic mRNAs that encode multiple proteins from a single transcript (picornaviruses)
  • Polycistronic mRNAs are translated using alternative start codons or internal ribosome entry sites (IRES)
• Overlapping genes are common in viral genomes, where the same nucleotide sequence codes for different proteins in different reading frames (hepatitis B virus)
  • Overlapping genes maximize the coding capacity of the compact viral genome
• Alternative splicing is used by some viruses (adenoviruses) to generate multiple mRNAs and proteins from a single gene
• Ribosomal frameshifting and stop codon readthrough are mechanisms used by some viruses to express additional proteins (retroviruses)
• Viral genomes may also contain non-coding regulatory elements, such as promoters, enhancers, and packaging signals
• The organization of viral genomes reflects the evolutionary adaptation to efficiently replicate and express genes within the constraints of limited genetic material

Replication Mechanisms

• Viral genome replication mechanisms vary depending on the type of genetic material and the specific virus
• DNA viruses typically replicate their genomes using viral or host cell DNA-dependent DNA polymerases
  • Some DNA viruses (herpesviruses) replicate in the nucleus, while others (poxviruses) replicate in the cytoplasm
• RNA viruses replicate their genomes using virus-encoded RNA-dependent RNA polymerases (RdRps)
  • Positive-sense RNA viruses (poliovirus) can directly use their genome as a template for replication and translation
  • Negative-sense RNA viruses (influenza) must first transcribe their genome into positive-sense RNA using viral RdRp
• Reverse-transcribing viruses (retroviruses) use a viral reverse transcriptase to convert their RNA genome into DNA, which is then integrated into the host cell genome
• Viral genome replication often involves the formation of replication intermediates, such as concatemers or hairpin structures
• The replication of segmented viral genomes requires the packaging of multiple genome segments into a single virion
• Viral replication mechanisms are often targeted by antiviral drugs, such as nucleoside analogs or polymerase inhibitors

Gene Expression in Viruses

• Viral gene expression involves the transcription of viral genes into mRNA and the translation of mRNA into viral proteins
• The expression of viral genes is tightly regulated to ensure the proper timing and levels of protein production
• Many viruses employ a temporal regulation of gene expression, with early genes expressed before genome replication and late genes expressed after
  • Early genes often encode regulatory proteins and enzymes required for genome replication
  • Late genes typically encode structural proteins, such as capsid and envelope components
• Some viruses use alternative splicing, ribosomal frameshifting, or polycistronic mRNAs to express multiple proteins from a single gene
• Viral gene expression can be regulated by viral or cellular transcription factors, as well as by RNA secondary structures and non-coding regulatory elements
• Host cell factors, such as translation initiation factors and chaperones, are often hijacked by viruses to facilitate viral gene expression
• Viral proteins can also modulate host cell gene expression to create a favorable environment for viral replication
• Understanding viral gene expression mechanisms is crucial for developing targeted antiviral therapies and vaccines

Genomic Evolution and Variability

• Viral genomes are highly dynamic and undergo rapid evolution due to high mutation rates and short generation times
• RNA viruses have particularly high mutation rates due to the lack of proofreading by viral RdRps
  • High mutation rates contribute to the genetic diversity and adaptability of RNA viruses (influenza, HIV)
• Recombination between related viruses can lead to the emergence of novel viral strains with altered virulence or host range (SARS-CoV-2)
• Reassortment of segmented viral genomes during co-infection can generate new combinations of genes and antigenic properties (influenza viruses)
• Viral genomes can acquire host cell genetic material through horizontal gene transfer, leading to the acquisition of new functions (oncogenic retroviruses)
• Positive selection pressures, such as immune responses and antiviral drugs, drive the evolution of viral genomes towards increased fitness and resistance
• Understanding viral genomic evolution is essential for monitoring the emergence of new viral strains, predicting pandemics, and designing effective vaccines and therapies

Key Viral Genome Examples

• Human immunodeficiency virus (HIV): A retrovirus with a single-stranded RNA genome that undergoes reverse transcription and integration into the host cell genome
  • HIV genome encodes structural proteins (Gag, Env), enzymes (reverse transcriptase, integrase), and regulatory proteins (Tat, Rev)
• Influenza A virus: An RNA virus with a segmented, negative-sense genome that undergoes reassortment and antigenic drift
  • Influenza genome consists of 8 RNA segments encoding surface proteins (hemagglutinin, neuraminidase), polymerase subunits, and other viral proteins
• Herpes simplex virus (HSV): A DNA virus with a large, linear, double-stranded genome that establishes latent infections in neurons
  • HSV genome encodes numerous structural proteins, enzymes, and immune evasion factors
• Hepatitis B virus (HBV): A DNA virus with a partially double-stranded, circular genome that replicates through an RNA intermediate
  • HBV genome has overlapping open reading frames encoding surface antigens, core protein, and a reverse transcriptase
• SARS-CoV-2: An RNA virus with a large, single-stranded, positive-sense genome that encodes both structural and non-structural proteins
  • SARS-CoV-2 genome has a unique organization with overlapping genes and a large replicase gene encoding multiple enzymes and regulatory proteins
• Understanding the genomes of specific viruses is crucial for developing targeted diagnostic tests, antiviral therapies, and vaccines