Pathogenesis of HIV disease and markers of progression

1. Pathogenesis of HIV disease and markers of progression Anjie Zhen, PhD 8.6.2013

2. Summary • Overview of HIV life cycle • Overview human immune responses • HIV pathogenesis • Acquisition of HIV • Acute infection • Chronic infection and markers of progression • AIDS

3. 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

4. Overview of adaptive immunity

5. Clearance of viral infection

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. HIV disease progression –Acute infection

8. HIV disease progression -- Clinical Latency • During this period of the disease, the immune systems remains competent at handling most infections with opportunistic microbes • Few or no clinical manifestation. • Steady destruction of CD4+ T cells and steady decline of circulating blood CD4+ T cells

9. Mechanism of CD4 T cell depletion in HIV infection

10. Mechanism of CD4 T cell depletion in HIV infection • Infection and killing of infected cells only explain part of the T cells loss • Chronic immune activation and disrupted T cell homeostasis

11. HIV Specific T Cell Responses HIV Infected Cells Killing of HIV Infected Cells HIV-Specific T Cell Mature T-Cells Incomplete Clearance of HIV Infected Cells and Exhaustion Stem Cell Expansion of HIV-Specific Cells RT RT RT RT RT RT RT RT RT RT RT RT RT RT Thymus Periphery

12. HIV disease progression -- AIDS • Acquired Immune Deficiency Syndrome: • Catastrophic breakdown of host defenses, marked increase in viremia and clinical disease. • CD4+ cell count less than or equal to 200 per microliter • Clinical Features: • Opportunistic infection • Neoplasms • CNS involvement

13. Markers of HIV disease progression • CD4 T cell counts • Viral load • Markers of immune activation

14. Markers of disease progression: CD4 cell count • Major Factor to initiate therapy • CD4<350: strongly recommended (Data from randomized trials) • <350<CD4<500: strongly recommended (Data from well designed non-redomized trials or observational cohort studies) • Cd4>500: moderately recommended • Prophylaxis against opportunistic infection is based on CD4 counts The Lancet Volume 360, Issue 9327 2002 119 - 129

15. Markers of disease progression: Viral load • The HIV-1 viral load measurement indicates the number of copies of HIV-1 RNA per milliliter of plasma. • Viral load is an accurate reflection of the burden of infection and the magnitude of viral replication. • It is critical in monitoring virologic response to ART. The Lancet Volume 360, Issue 9327 2002 119 - 129

16. Prognosis according to CD4 cell count and viral load in the pre-HAART and HAART eras The Lancet Volume 360, Issue 9327 2002 119 - 129

17. Markers of disease progression: Viral load set point

18. Markers of disease progression: Immune activation markers • Chronic immune activation is a characteristic of HIV disease progression. • Activation markers expressed on cell surface: CD69, CD25, and MHC class II, CD38, etc.

19. Questions • List key stages for HIV disease progression? • While CD4 T cells are progressively depleted during untreated HIV infection, what happens to CD8 T cells? • List one important laboratory marker of HIV disease progression other than CD4 cell count

20. Questions • List key stages for HIV disease progression? • Acute infection, clinical latency, AIDS. • While CD4 T cells are progressively depleted during untreated HIV infection, what happens to CD8 T cells? • In early HIV infection, CD8 T cells tend to increase in number, in response to viral infection. However, at advanced stages of HIV disease, CD8 cells also decline precipitously. • List one important laboratory marker of HIV disease progression other than CD4 cell count • Viral load.

21. Discussion • How will effective anti-retroviral therapy affect our immune responses?