Host-Virus Relationships

Introduction and Definitions

Viruses that infect humans are animal viruses

Viruses that infect plant cells are bacteriophages, or phages

Naked capsid virus (nonenveloped): no lipid coating

some have spikes, others don’tÞ bind cell surface receptor

capsid: protein coat assembled from capsomers (smaller protein subunits)

dots signify viral proteins are closely linked to genetic info

Enveloped virus: lipid membrane surrounding capsid

nucleocapsid: viral nucleic acid plus surrounding capsid

matrix protein: supplied by virus to aid in assembling new viruses
genetic material is closely linked to many proteins

Common outcomes

Productive infection resulting in lytic cell death

can be quantitated by plaque assay (see figure below)

bacteriophages (A) vs. adenovirus (B, human virus) Þ different viruses

produce different plaques (size and shape vary)

examples of lytic viruses (promotes cell lysis/death)

virus infects cell Þ replicates Þ lyses cell Þ white spot; shows how many viral particles are active

cytopathic effect (CPE): change in cell morphology due to lytic viruses

Persistant virus production leading to chronic asymptomatic infection, chronic disease state, or relapse to a more aggressive state

Latency, which may be associated with:

integration of viral genome into host genome, or maintenance as plasmid (in the case of bacteriophages)
reactivation at a later time
may change the genotype of the infected cell

Hit and run infection: virus infects cell Þ replicates, causes some damageÞ all evidence of virus is lost from the cell

Determinants of infection outcomes: particular host-virus combination, extracellular environment, multiplicity of infection, physiology and developmental stage of the cell (ie. some viruses only replicate in actively dividing host cells)

Virus has intimate assoc with host cell so it is hard to target medically, but can target the viral enzyme used for replication

Genome structure

Much variation: ss/ds, RNA/DNA, linear/circular, covalently attached terminal proteins

circular genome and covalent proteins aid in resolving problem assoc with replicating the ends of the genome

Most viruses have a single nucleic acid molec (unsegmented), but some RNA viruses have several molec (segmented)

For viruses with ss genomes, the polarity relative to viral mRNA can be either:

the same polarity (+) or called the coding or mRNA sense
the opposite polarity (-) or called the noncoding or mRNA antisense
in this case, virus must generate its own enzymes (prepackaged) in order to replicate in the host

Many pathways for synthesizing viral mRNA are related to genomic structure (see figure below)

red arrows indicate genetic material not normally read by the host cell so must supply their own enzymes

convert (+)RNA Þ (-)DNA Þ (+)DNA Þ then use host

Capsid structure

All viruses encode their own capsid proteins

Viral genomes too small to encode single protein to encapsulate a viral genome so produce capsids composed of repeating protein subunits (i.e., the simplest spherical virus contains 60 identical protein subunits)

Viral capsids assume one of two basic shapes:

cylindrical: subunits have helical arrangement

ex: tobacco mosaic virus (TMV); influenza; poxviruses

spherical: subunits arranged as an icosahedron (20 identical faces)

Most viruses have structures protruding from their surfaces that are often involved in absorption to cell surface

ex: bacteriophage tail; adenovirus spikes; glycoprotein spikes in memb of some enveloped viruses

Some capsids package virally-encoded enzymes essential for early steps in viral replication

Classification of viruses

Classify according to size and composition of genetic material

Classify according to shape of virus

Huge range in sizes

smallest: needs active replicating cell
largest: supplies virtually all of the enzymes it needs to replicate

Viral replication cycle

Adsorption to surface of cell

highly specific, involves virion attachmnt proteins and cellular receptors
host range: cell types which can be infected by a given virus. Most viruses are species-specific

Penetration and uncoating

viruses 1^st enter cell cytoplasm by receptor-mediated endocytosis
for enveloped viruses, low pH of endosomal compartment induces conformational changes in viral proteins which can then mediate fusion between endosomal and virus envelope membs, releasing virus into host cell cytoplasm
nonenveloped viruses (ie adenovirus) must also be released from endosomes (ie penetrate), but mechanisms unclear
some viruses avoid endosomes and enter cytosol immediately
viruses may undergo further uncoating (loss of capsid structure) in cytoplasm

Amplification of viral nucleic acids and proteins

Processing and assembly of new viral proteins and nucleic acids into progeny particles

viral proteins may be cleaved (proteolysis), glycoslated (addition of CHO), or fatty acylated (addition of fatty acids) by viral enzymes or host cell machinery
formation of new capsid structures generally involves self-assembly of protein subunits
In general, capsids and new nucleic acids of cylindrical viruses undergo co-assembly. For spherical viruses, new genomes are inserted into pre-assembled capsid structures

Release

nonenveloped viruses are released by cell death (cell lysis)

enveloped viruses bud thru the cell memb (usually plasma memb) Þ does not kill host cell so can bud indefinitely

envelope composed of lipid from host cell memb and protein made from viral genome

Host-virus interactions

Acquisition of viral infections

direct infection (of respiratory, alimentary, and genital tracts; skin; oropharyngeal mucosa; or conjunctiva)
insect vectors or animal bites (ie rabies)
blood or blood products/blood transfusions (ie hepatitis)
some viruses (ie rubella, cytomegalovirus) can traverse the chorionic barrier (mother to neonate)

Virus spread in the host

cell to cell via cell-free virus (local infections)

release into bloodstream (systemic infections)

cell-cell fusion without touching extracellular matrix (difficult to attack these viruses)

travel thru axons

for enveloped viruses, site of budding determines how virus spreads: apical Þ local; basolateral Þ systemic

Common outcomes

inapparent or asymptomatic infection Þ no clinical symptoms

disease Þ viral damage to tissues/organs; loss of function; tissue damage due to host immune responses

Host antiviral responses

humoral and cellular immune responses

Ab neutralize the virus

virally derived peptides trigger cytotoxic T-cell response

Interferon production by infected cell – early, nonspecific antiviral defense triggered by ds-RNA Þ blocks viral replication by either blocking protein synthesis (ie PKR) or by chewing up mRNA

Phosphorylated PKR phosphorylates and inactivates EIF-2a which is needed for protein synthesis

Interferon activates dependent RNase which chews up mRNA

Infected cells display virally-derived peptides on their cell surface becoming targets for complement-fixing Ab and cytotoxic T-cells

Neutralizing Ab prevent virus attachment or uncoating. Usually directed against envelope or capsid proteins; protect against repeated cycles or virus infection