HIV Vaccines

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HIV Vaccines
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HIV gp120/gp41
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Obstacles to the Development of HIV Vaccines

• Antigenic diversity and hypervariability of the
  virus
• Transmission of disease by mucosal route
• Transmission of the virus by infected cells
• Resistance of wild-type virus to
  seroneutralization
• Integration of the virus genome into the host
  cell chromosomes
• Latency of the virus in resting memory cells
• Rapid emergence of viral escape mutants in the
  host
• Down-regulation of MHC class I antigens
• No spontaneous recovery from natural infection in
  spite of high-level immune responses of the host

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Principal Roles of the HIV Accessory Proteins

• Vpr
• Together with matrix protein, targets the viral
  preintegration complex to the nucleus
• Arrests dividing cells in G2 of the cell cycle
• Enhances HIV replication in macrophages
• Vpu
• Down-regulates expression of CD4 molecules by
  targeting them to the proteasome, leading to
  their degradation in the endoplasmic reticulum
• Forms ion channels in the cell membrane, thus
  helping to promote the release of virions to the
  nucleus
• Neutralizes APOBEC3G, an innate antiretroviral
  mechanism (CgtU mutase)
• Vif
• Plays a role in provirus formation and stabilizes
  newly synthesized DNA intermediates
• Associates with cytoskeleton intermediate
  filaments and helps transport incoming virions to
  the nucleus
• Neutralizes an APOBEC3G antiviral mechanism

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Principal Roles of the HIV Accessory Proteins

• Nef
• Associates with cellular protein kinases (PAK65,
  p56tck, p59Hck)
• Stimulates viral DNA synthesis and enhances virus
  infectivity in primary T cells and macrophages
• Enhances virus replication in vivo, contributing
  to high viral loads and pathogenesis
• Binds CD4 molecules at the plasma membrane and
  mediates their rapid endocytosis and lysosomal
  degradation
• Down-regulates cell surface expression of major
  histocompatibility complex class I antigens and
  of immune costimulatory molecules of CD80 and
  CD86, a cytotoxic T-lymphocyte escape mechanism
• Activates the expression of FasL, which induces
  apoptosis in bystander cells that express Fas

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Clinical Progression of HIV Disease
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Antigenic determinants and epitopes of interest

• A major obstacle in effective vaccines is the
  elicitation of Nabs
• The principal neutralizing determinant appears to
  b the hypervariable V3 loop of gp120
• Antibodies against one strain often are not cross
  reactive to other strains
• HIV X4 vs. HIV R5 strains
• Other epitopes include V1, V2 and CD4-binding
  domain (competitive)
• gp41 has a three epitopes
• Antibodies to each inhibit gp41-mediated fusion

PDB ID 2B4C
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Antigenic determinants and epitopes of interest

• T cell epitopes are not restricted to virus
  surface antigens
• Any HIV polypeptide can contain T cell epitopes
• An effective antiviral immune response requires
  CD8 CTLs
• CTL responses are sustained by CD4 Th responses
• Unfortunately, this is precisely what HIV
  requires for virus replication
• Thus, an effective Th cell response leads to the
  depletion of those Th cells
• CTL escape mutants (peptide epitopes) always
  arise during HIV infection
• Since T cells cannot undergo affinity maturation,
  like B cells, these escape mutants evade the CTL
  response

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Candidate HIV vaccines

• The development of an HIV vaccine is a formidable
  challenge
• Most classical vaccines provide protection from
  disease but do not actually prevent infection
• They allow a limited but controlled replication
  of the pathogen at the portal of entry
• This raises the question of whether an HIV
  vaccine, if unable to prevent infection, could
  prevent development of disease
• The difficulties of HIV vaccine testing include
• Testing must be done in humans
• Since controlled experiments cannot be done, must
  reply on retrospective analysis
• Test population must be a high-risk group
• Must be able to document their activities
• Must be able to follow them for years (decades?)

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Whole inactivated vaccines and virus-like
particles

• Not currently being considered
• Regulatory and safety concerns (alloantigens,
  xenoantigens)
• All HIV strains are propagated in transformed
  human cell lines
• Transformed human cells cannot be used for virus
  propagation for vaccines
• Formalin damages HIV epitopes, such that they
  fail to elicit strong Nabs
• Virus-like particles
• Canarypox virus with all HIV proteins except RT
• Produced in primary cell culture
• Elicit strong Nab response with administered with
  cholera toxin B subunit (adjuvant)

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Live, attenuated vaccines

• All work has been conducted with strains of
  simian immunodeficiency virus (SIV) in monkeys
• SIVmac
• Directed nef deletion mutant
• Administration results in low-grade infection
  without clearance
• Provided protection against challenge with 1,000
  ID50 of virulent SIV
• However
• Some adult monkeys developed AIDS from vaccine
• Fatal to neonatal monkeys
• Additional deletions of LTR and vif are currently
  being tested
• Hybrid SHIV vaccines are also being examined

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Live recombinant vaccines
Potential vectors for HIV vaccine
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Subunit vaccines

• Subunit vaccines are composed of polypeptides
  from the virus that are antigenic and
  neutralizing
• Typically produced by recombinant DNA technology
• E. coli or other bacteria
• Yeast
• Baculovirus
• DNA vaccines
• Host cells for production must be able to perform
  post-translational modifications
• Soluble envelope glycoproteins
• Exclude transmembrane domains
• Coexpress gp120 and gp41
• Easy to include antigens from multiple HIV
  strains
• ?V2gp120 is currently being tested in humans
• Deletion provides better exposure of V3 loop

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DNA Vaccines

• Genetically engineered DNA molecules with
  nontransforming eukaryotic cis-elements
• Typically plasmids
• Easy to produce in large quantities
• Extremely heat stable
• Requires multiple boosters
• Often require delivery by gene gun
• Microscopic beads coated with DNA
• Injected into the skin/muscle with high pressure
• Presumably, the beads carry the DNA into cells,
  which then activate gene expression from the
  plasmid
• This produces antigen that is processed by the
  class I and class II pathways
• No DNA vaccine has been approved for any disease

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Human Clinical Trials

• More than 20 have been completed all have failed
• Many others are ongoing
• Trials to date (completed and ongoing)
• Subunit vaccines - 35 trials
• Viral vector vaccines - 35
• Bacterial vector (Salmonella typhi) - 3
• DNA vaccine - 27

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Human Clinical Trials

• VaxGen gp120 phase II trial (VAX004 candidate)
• gt5,095 volunteers
• Immunized with recombinant soluble gp120 from MN
  and GNA8 strains
• Injections at 0, 1, 6, 12, 18, 24 and 30 months
• Assessment at 36 months
• Objectives
• Does vaccine protect against HIV infection?
• What differences between vaccinated and placebo
  infections?
• Results
• Vaccine did not protect (6.7 vaccinated vs. 7.0
  placebo)
• No differences between between groups in regard
  to infection responses

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