Lecture 24: patterns of infection
Flint et al, Chapter 16
BSCI 437
General points
• Infection can be
– Acute
– Persistent
• Effects can range from
– Unnoticeable
– Deadly
Viral life cycles
 Cytopathic: rapidly kill the cell while producing a burst of new particles
 Non-cytopathic: infection yields virions without causing immediate cell death
Incubation period
 The time between the initial infection and the onset of disease symptoms.
 Can range from a few days (cold viruses) to years (HIV)
Stages of viral infection
1. Primary infection- Infection of cells in the general location where virus enters.
Common for example with cold viruses and Diarrhea causing viruses. Many viruses
including HIV initially infect cells in the infected area.
2. Viremia- Virus enters the blood system and can be detected in the blood stream.
Not all viruses do this. Some remain only localized.
3. Secondary infection- Infection of other organ of cell types by the virus.
Many viruses have high affinity for specific organs due to the presence of receptors or
specific cell metabolic functions. Examples are infection of salivary glands by mumps
virus, brain tissue by encephalitis virus, and liver tissue by hepatitis virus.
Stages of viral infection – Varicella zoster infection (Fig. 16.3)
• Primary infection: VZV infects via conjunctiva and upper respiratory tract
• Days 0 – 3: Replicates in primary lymph nodes
• Days 4 – 6: primary viremia,
• Days 6 – 13: replication in liver, spleen, other organs
• Day 14: infection of skin and appearance of rash. Infection of sensory ganglia
and establishment of latent infection
Virulence
 The ability of an infectious agent to cause disease. A relative term in the sense
that it depends on the particular host that is infected and the state of that host as
well as the site of infection.
o Rabies and Ebola are highly virulent.
o Some viruses infect animals but are virulent only when the host immune
response is suppressed. Examples are certain herpes and hepatitis B virus
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that become virulent when human hosts are treated with
immunosuppressant drugs after organ transplant.
General patterns of infection (Fig. 16.1)
 Acute
 Persistent
 Latent, reactivating
 Slow
Acute Infections
• Acute infections only detected by clinical symptoms.
• Can be acutely infected but assymptomatic…subclincal.
• Viruses usually produce large amounts of progeny
• Rapid onset of symptoms
• Rapid resolution of infection either by
– Immune clearance or
– Death
Defense against acute infections
Most acute infections are rapidly resolved
Limited by the intrinsic and innate immune responses
Localization to the immediate site of infection,
Clearance by macrophages, NK cells, polymorphonuclear cells, complement.
Adaptive immune response provides memory against subsequent infection.
Virus-specific humoral and cellular responses
If not quickly limited, acute infections are resolved by host death
e.g. many haemorragic viruses, severely immunocompromised patients
Antigenic variation – the viral response
• Survival of acute infection  lifelong immunity to that specific virus
• How is it that we get sick from other acute viruses over and over?
o e.g. common cold, influenza
• Answer: viruses capitalize on high rates of mutation to evolve around immune
response
• Structural plasticity: virions that can tolerate many amino acid substitutions yet
remain infections.
o Rhinoviruses and Influenzaviruses are incredibly structurally plastic.
o Limits ability to make effective vaccines
• Many viruses are not structurally plastic: e.g. poliovirus. One vaccination can
confer lifelong immunity
Structural plasticity: Antigenic variation
The immune system detects “epitopes” on “antigens”: structural features of molecules
• Antigenic variation:
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o Changes in the epitopes of viral proteins that are presented to the immune
system.
• Antigenic drift:
o Appearance of virions with slightly altered surface proteins following
passage in the natural host.
o An evolutionary process where natural selection is driven by the host
immune response
• Antigenic shift:
o A major change in a surface protein as a gene encoding a completely new
surface protein is acquired.
o Results from coinfection of one host with two different viral serotypes.
o Due to reassortment of genes among two or more viruses.
o Very commonly seen with viruses having segmented genomes.
o Reassortment and recombination of blocks of genetic information result in
viral hybrids that are immunologically new to the host.
Acute infections and Public Health
Acute infections are commonly associated with epidemics
e.g. polio, influenza, measles, common cold
Main problem: by the time symptoms emerge, the patient has passed on the infection
Difficult to control in large populations and crowded environments
e.g. work, daycare, dorms
Effective antiviral drug therapy requires early intervention, safe drugs with few side
effects…..not really practical for acute infections.
Cost: 90% of outpatient visits due to self-limiting acute viral infections.
Persistant Infections. Four general classes.
1) Infection by viruses which actively produce large amounts of progeny, but which
cause little cytopathology.
2) Infection by normally lytic virus but in which the extent of virus multiplication is
somehow limited, so that the yield of virus is small.
3) Limitation of reinfection by various viral and cellular factors, so that the proportion
of infected cells in the total cell population remains small but constant.
 Viral factors tend to be decreased virulence, and interference of virus
production by defective interfering particles.
 Cellular factors include differences in permissiveness to infection/virus
replication, and immune surveillance.
4) Chromosomal integration of proviral genomes
 Result in “silent” infections, infrequent or constant rounds of low level, and only
slight production of cytopathic virus.
Some persistent viral infections of humans (see Table 16.2)
VIRUS
SITE OF PERSISTENCE
CONSEQUENCE
Adenovirus
Adenoids, tonsils, lymphocytes None known
Epstein-Barr
B-cells, nasophayngial epithelia Lynphoma, carcinoma
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H.Cytomegalovirus Kidney, salivary gland, WBCs?
Hepatitis B virus Liver, lynphocytes
Hepatitis C virus Liver
HIV
CD4+ T-cells, macrophates,
microglia
HSV 1 and 2
Sensory and autonomic ganglia
HTLV 1 and 2
T-cells
Pneumonia, retinitis
Cirrhosis, liver cancer
Cirrhosis, liver cancer
AIDS
Papillomaviruses Skin, epithelial cells
Polyomavirus BK Kidney
Polyomavirus JC Kidney, CNS
Papillomas, carcinomas
Hemorrhagic cystitis
Progressive multifocal
leukoencephalopathy
Subacute sclersoing
panencephalitis
Progressive rubella
panencephalitis
Shingles, postherpetic neuralgia
Measoes
CNS
Rubella virus
CNS
Varicella-Zoster
Sensory ganglia
Cold sore, genital herpes
Leukemia, brain infections
Perpetuating a persistent infection by modulating the adaptive immune response:
Blocking display of viral antigen in context of MHC class I (See Fig. 16.5).
 CTL response clears out virus infected cells
 Requires CD8 interaction with MHC class I molecules displaying viral
peptides
 Blocking such display provides an advantage to a virus.
 Examples:
o HIV Tat protein blocks transcription of MHC class I and of 2
microglobulin
o hCMB US11 and US2 proteins route MHC class I protein out of ER to
proteosome
o HSV ICP47 blocks proteolytic processing of internal antigens by the
proteosome
o hCMV blocks transport of processed antigens to ER
o Many viral proteins block transport of MHC class I/antigen complexes
to golgi
o HIV Nef protein directs MHC class I/antigen complexes from plasma
membrane to the lysosome.
MHC Class II modulation after infection

Exogeneous antigenprocessing in the antigen-presenting cell: the pathway for
MHC class II peptide presentation. (see Fig. 15.20)

Antigen presenting cells – Macrophages, dendritic cells, B-cells. Gobble up
antigens from outside, process them, present them to CD4 T-cells in the
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

context of MHC class II. Presentation of viral antigen in this contact activates
T-helper cells, activating specific immune response.
Any viral protein that can modulate the MHC class II antigen presentation
pathway would therefore interfere with T-helper cell activation.
Examples:
 HIV Nef: triggers rapid internalization of CD4 and MHC class I and II.
 EBV BZLF2: Physically blocks MHC class II molecules
Killing activated CTLs
 Activated CTLs express the membrane-bound Fas receptor: related to TNF
receptor
 Fas binds the Fas-Ligand (FasL)
 Binding of FasL on target cells by Fas on activated CTLs activates T-cell aptosis.
 Many viruses, e.g. HIV-1 increase expression of FasL on the surfaces of infected
cells.
Direct infection of cells of the immune system
 Allows viruses to suppress the immune response, e.g. HIV
 Mobility of immune cells allows viruses to disseminate through host – e.g. CMV
Infections of tissues with reduced immune surveillance
Tissues with surfaces exposed to environment
 Higher thresholds of immune activation,
 e.g. skin, glands, bile ducts, kidney tubules.
o Cytomegalovirus infects cells on the surfaces of glands and ducts (kidney,
salivary, mammary), ensuring constant shedding of new virus into
environment.
o Papillomaviruses: Productive replication of only occurs in the outer,
terminally differentiated skin cells. The result is skin warts.
Other compartments of the body can’t mount inflammatory responses
 To do so would be to severely damage them.
 e.g. CNS, eye, areas of lymphoid drainage.
 Persistent infection of these tissues by viruses is common.
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