Immune reconstitution Anjie Zhen, PhD

1. Immune reconstitutionAnjie Zhen, PhD

2. Overview of HIV life cycle • HIV life cycle: • Binding and Fusion • Entry • Reverse transcription • Integration • Viral RNA and protein expression • Assembly and budding • Maturation • HIV target cells: • CD4T cells, • Macrohpages, • Dendritic cells

3. Anti-retroviral therapy • HAART: Highly active anti-retroviral therapy • Usually combine several drugs that target different stages of HIV replication • Classes: • Entry inhibitors (Maraviroc/enfuvirtide) • Nucleoside reverse transcriptase inhibitors (NRTI) and nucleotide reverse transcriptase inhibitors (NtRTI) (tenofovir, deoxythymidine, zidovudine, etc) • Non-nucleoside reverse transcriptase inhibitors (NNRTI) (nevirapine, etc) • Integrase inhibitors (Raltegravir) • Protease inhibitors (Indinavir, Nelfinaviretc)

4. Overview of HIV life cycle X • HIV life cycle: • Binding and Fusion • Entry • Reverse transcription • Integration • Viral RNA and protein expression • Assembly and budding • Maturation • HIV target cells: • CD4T cells, • Macrohpages, • Dendritic cells X X X

5. Effect of HAART in US

6. 4 – 8 weeks HIV disease progression – clinical latency AIDS and Death Acute Asymptomatic (clinical latency) Primary infection HIV viral load CD8+ T cell Neutralizing Antibodies Levels (Separate Scales) CD4+ T cell Years

7. T cell homeostasis

8. Immune reconstitution during HAART • Phase 1: Sudden halt in viral production provokes a rapid increase in CD4 T cells in the first three months • Phase 2: Slow recovery over several years, results mostly from regeneration of naïve CD4 T cells population.

9. Immune reconstitution during HAART • Restoration of pathogen and HIV-specific T lymphocytes

10. HAART effects on immune response • Increase CD4 cell number and function • Increase memory and naïve CD4 and CD8 cells • Decrease markers of cellular activation • Normalize distortion in CD4 repertoire • Reconstitution of antigen-specific CD8 T cell and B cell responses to opportunistic pathogens

11. Viral Latency • The latent viral pool persists in everyone following Highly Active • Anti-Retroviral Therapy (HAART) • Is established soon after infection • T1/2 of replication competent virus is ~44 months therefore • eradication could take up to 60 years.

12. Evidence of Viral Reservoirs Primary Infection Viral Rebound Viral Setpoint Cessation Of HAART Plasma Viral RNA HAART 50 copies Infection

13. Modelfor establishment and maintenance of HIV-1 reservoirs Death Activation: antigen Activated T-cell Quiescent T-cell Activated T-cell and renewed viral replication

14. HIV T cell dynamic on and off HAART

15. Factors influencing immune restoration with antiretroviral therapies Blood, 2011

16. Therapeutic possibilities to improve immune reconstitution

17. Targeting HIV latent reservoir

18. Q&A What is HAART? Can virus be cleared by HAART and why? What are the two phase of immune reconstitution after initiation of anti-retroviral therapy?

19. Q&A What is HAART? HAART stands for Highly Active Antiretroviral Therapy. The usual HAART regiment combines three or more different drugs. Can virus be cleared by HAART and why? HAART regiments can reduce the amount of active virus and in some case can lower the number of virus until it is undetectable by current blood testing techniques. However, usual HAART treatment cannot clear HIV infection due to the fact that virus can establish latent infection in the patient. What are the two phase of immune reconstitution after initiation of anti-retroviral therapy? First a rapid initial rise of CD4 T cell counts in the first few months, primarily due to increase in memory T cells, and followed by a slow, steady increase in naïve T cell counts that can continue for years with sustained suppressive ART.

20. Strategies targeting latent reservoirs How to reactivate latently infected cells? How to improve immune responses to eliminate infected cells?