The Influence of Cytopathic and Antigenic Simian Immunodeficiency Virus on AIDS Progression (Kimata J.T. et al.)

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The Influence of Cytopathic and Antigenic Simian
Immunodeficiency Virus on AIDS Progression(Kimata
J.T. et al.)

• By Emmanuel Jean-Jacques
• Seminar Presentation 2

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Rationale

• To determine whether genetic variants and simian
  immunodeficiency virus (HIV and SIV) that evolve
  during the course of infection and progression of
  AIDS are distinct from their parent viruses
  present at early stages of infection.

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The Difference Between Early Stages of Infection
and Late Stages of Disease Progression

• In HIV-1-infected populations, viruses in the
  early asymptomatic stages of infection are
  macrophage-tropic (M-tropic), slowly replicating
  and nonsyncytium-induncing (NSI) in T-cells.
• As disease develops the viruses replicate rapidly
  in T-cells and T-lymphocyte cell lines (T-tropic)
  and cause cytopathic effects and
  syncytium-induction (SI) in the cells.

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AIDS Progression Continued

• The development of AIDS and the decline in the
  host immune system allow the T-tropic,
  cytopathic, SI viruses to replicate rapidly and
  dominate late-stage infection.

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The Question that is Addressed

• Are T cell-tropic, cytophatic variants that
  evolve from M-tropic infecting viruses more
  pathogenic?

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Role of Pathogenic Variants that Evolve during
AIDS Progression

• Both the late stages of HIV-1 infection in humans
  and the late stages of SIV infection in macaques
  are characterised by
• An increase in viral load
• CD4 T lymphocyte decline
• Consequent immunodeficiency

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Using SIV as a Model to Determine the Role of
Pathogenic Variants that Evolve during AIDS
Progression

• Viruses that evolve in macaques infected with an
  M-tropic, NSI SIV clone derived from Macaca
  nemestrina (SIVMneCL8) become rapidly
  replicating, highly cytopathic and SI, closely
  resembling HIV-1 infection.

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Hypothesis

• Late-stage cytopathic, SI variant viruses are
  more pathogenic than the parent virus that
  initially established persistent infection in the
  host.

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Methods

• Infection of Macaques
• Pig-tailed macaques (Macaca nemestrina) were
  inoculated intravenously with
• Early virus, SIVMneCL8
• Intermediate virus, SIVMne35wkSU,
• Late blood-derived virus, SIVMne170
• Late lymph node-derived virus, SIVMne027

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Methods Contd

• Confirmation of infection
• Virus isolation was done by co-cultivating in
  stimulated macaque peripheral blood mononuclear
  cells (PBMCs) and unstimulated PBMCs.
• Each virus was exposed to neutralizing antibody
  (NTAB).
• Test for viral load (replication)
• Test for immune response (clinical status)
• Test for CD4 lymphocyte counts

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Results
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Analyzing the pathogenicity of viruses that
emerged at intermediate and late stage of SIVMne
infection
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Replication and Cytopathic Effects of SIVMne
Variants
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Clinical Status of Macaques Inoculated with the
SIVMne Variants
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CD4 T-lymphocyte Levels in Blood in
SIVMne-Infected Macaques
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Conclusion

• We can see that there is a profound difference in
  viral RNA levels between macaques infected with
  the late and the early virus
• These data demonstrated that variant viruses have
  increased abilities to replicate in vivo relative
  to the parent virus from which they evolve.

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Reference

• Kimata J.T., Kuller L., Anderson D.B.,
• Dailey P., and Julie Overbraugh. 1999.
  Emerging cytopathic and antigenic Simian
  immunodeficiency virus variants influence AIDS
  progression. Nature Medicine, vol. 5(5)
  535- 541.