HostPathogen Strategies

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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 CTLs 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

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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

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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

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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.

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Proviral Latency

• 1990s 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 CTLs 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 humans 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.