Host-Pathogen Strategies #1
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Transcript of Host-Pathogen Strategies #1
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Host-Pathogen Strategies #1
MICROBE:
• Frontal attack strategy – agents that cause acute diarrhea, common cold, influenza, etc.
HOST RESPONSE:
• Innate immunity – interferon
• Adaptive immunity – antibody production
• Cellular response – eliminate infected cells
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Host-Pathogen Strategy #2
MICROBE:
Stealth attack strategy - agents such as herpes viruses and retroviruses:– Persistence of genetic information in host cells– Modulate cytopathicity in time and space– Evade host immune responses
HOST RESPONSE:
Long term battle between host and pathogen.
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HIV Strategies
Stealth attack strategy:
• Forward escape – high mutation rate alters viral recognition by host CTL’s and antibodies
• Timing is everything – glycosylation of viral envelope and last minute unfolding upon cell entry inhibits host antibody attack.
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Human Immunodeficiency Virus
• Human retrovirus similar animal lentiviruses
• 10 kb genome
• 16 proteins
• Causative agent of AIDS
http://rds.yahoo.com/S=96062883/K=hiv/v=2/SID=w/l=IVR/SIG=131q4t235/EXP=1114187376/*-http%3A//www.life.umd.edu/CBMG/progrms/department/webpages378h/Adams/daniel.htm
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Conserved proteins
All retroviruses need several structural and enzymatic protein coding regions:
• gag – group specific antigen genes
• pol – polymerase genes
• env – envelope genes
http://rds.yahoo.com/S=96062883/K=hiv/v=2/SID=w/l=IVR/SIG=11opqm3ab/EXP=1114187467/*-http%3A//osms.otago.ac.nz/bur_AIDS.htm
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HIV Proteins
HIV REGULATORY PROTEINS:• Tat – transcriptional transactivator• Rev – regulator of viron gene expression
HIV ACCESSORY PROTEINS:• Nef – negative effector• Vif – viral infectivity• Vpr – viral protein R• Vpu – viral protein U
http://www.firstcoastnews.com/health/articles/2002-06-27/images/hiv_testing.jpg
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Rev – regulates transition between early and late phases of viral gene expression by allowing transport of viral mRNA from the nucleus to the cytoplasm.
Tat & Nef – required for high levels of viral replication and help the virus evade the host immune response.
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HIV Host Entry
• Transmission via bodily fluids
• HIV infects T helper cells, macrophages, microglial cells, dendritic cells:– CD4 primary receptor– CCR5 coreceptors present on macrophages, Dendritic
Cells, T cells (HIV R strain)– CSCR4 coreceptor only on T cells (X4 strain)
• R strain predominates early in infection, X4 strain is detected later, T cell counts drop.
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HIV Replication
• After internalization, HIV uncoats and RNA is reverse transcribed into cDNA.
• HIV uses IN, MA, and Vpr proteins to enter the nucleus through nuclear pores.
• cDNA is integrated into the host chromosome as an LTR-flanked provirus.
In resting lymphocytes, reverse transcription is inefficient and minimal energy available for viral translocation to nucleus. After activation, T cells are fully permissive.
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HIV Transcription• LTR contains enhancer and promoter sequences.
• Upstream Inr initiator and TATA box help position the RNA Polymerase II.
• Other enhancers bind upstream such as NF-KB and ETS factors.
• Regulatory element Tar downstream of Inr binds Tat and makes elongation efficient.
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HIV Viral Assembly
• Viral structural and enzymatic proteins are assembled in cholesterol-rich lipid rafts at the plasma membrane.
• Carboxy terminus of Gag is ubiquitylated and recruits TSG101 and PVS4 to release virion progeny.
• Accessory proteins Vpr and Nef, and cellular components MHCI and II are incorporated in new virions. Envelope glycoprotein and cholesterol are necessary for infection of new cells.
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Immunological Sanctuaries
• Persistent infections can be established in microglial cells of the CNS and resting T cells.
http://rds.yahoo.com/S=96062883/K=microglial+cell+photo/v=2/SID=w/l=IVR/SIG=11vh83bs0/EXP=1114193053/*-http%3A//www.webvision.med.utah.edu/glia.html
http://rds.yahoo.com/S=96062883/K=t+cell+photo/v=2/SID=w/l=IVR/SIG=13eurb0ob/EXP=1114193181/*-http%3A//www.dynapure.net/kunder/dynal/dynalpub401.nsf/$all/CCDF126C0556FEFAC1256C5400485069
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Proviral Latency
• 1990’s: High HIV replication occurs during asymptomatic period, so no viral latency?
• However, lab studies showed that HIV production can still be stimulated under certain conditions.
• Now it is thought that memory T cells and possibly other cells are infected with intact provirus that can be induced after cell activation.
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HIV Invisibility• Normally MHC I present viral peptides on host cell that allow
for viral-specific CTL recognition and killing.
• HIV used Nef protein to decrease the expression of MHC I on host cell surfaces.
• Nef interferes with migration of MHC I to cell surface by degradation in endosomes.
• To avoid killing by Natural Killer Cells that target cells without MHC I, HIV selectively inhibits HLA expression so that NK cells inhibitory receptors can still be bound.
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HIV Subversion of Host Cells
• HIV enhances apoptosis of bystander cells.
• Nef upregulates Fas Ligand expression on the surface of infected cells, triggering apoptosis in CTL’s and other cells bearing Fas receptors.
• Tat and Env proteins are also involved in apoptosis of bystander cells.
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HIV Protection of Infected Cells
• Nef inhibits ASK1 kinase that is involved with apoptosis signalling.
• Nef inactivates the pro-apoptotic Bad protein, thereby blocking mitochondrial release of cytochrome c. (Inhibition of Bad reduces inhibition on anti-apoptotic Bcl-2).
• Nef binds p53 and suppresses the apoptotic actions.
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HIV Treatment
HAART – highly active anti-retroviral therapy
• Helps to control viremia during treatment.
• After treatment, viremia usually returns.
• It could take longer than a human’s lifetime to completely clear infection!
• HIV is constantly evolving to evade the host immune response.
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Newer HIV Approaches
STI – structural treatment interuption:– Drug holiday to reduce cost and side effects, as well as to
expose immune system to short periods of viremia.
HAART-cytokine combo treatment:– Cytokines such as IL-2 and antibodies to activate T cell
receptors, so that viruses come out of latency to face the immune response and drug therapy.
Gene therapy to create viral-resistant cells?
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Methods of HIV Evasion
• Prevent host defenses from eliminating virus.
• Immunologic sanctuaries.
• Proviral latency.
• Altered antigen processing and presentation.
• Counter-attack against host lymphocytes.