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

1. The Influence of Cytopathic and Antigenic Simian Immunodeficiency Virus on AIDS Progression(Kimata J.T. et al.) By Emmanuel Jean-Jacques Seminar Presentation 2

2. 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.

3. 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.

4. 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.

5. The Question that is Addressed • Are T cell-tropic, cytophatic variants that evolve from M-tropic infecting viruses more pathogenic?

6. 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

7. 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.

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

9. 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

10. Methods Cont’d • 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

11. Results

12. Analyzing the pathogenicity of viruses that emerged at intermediate and late stage of SIVMne infection

13. Replication and Cytopathic Effects of SIVMne Variants

14. Clinical Status of Macaques Inoculated with the SIVMne Variants

15. CD4+ T-lymphocyte Levels in Blood in SIVMne-Infected Macaques

16. 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.

17. 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.