Background: Basic Virology Structure: Virion structure, genome, and proteins

1. HIV Structure, Lifecycle, and Replication Background: Basic Virology Structure: Virion structure, genome, and proteins Lifecycle: Infection and Expression skitchen@ucla.edu

2. Viruses Microscopic infectious agents that can infect the cells of a biological organism. Viruses can only replicate themselves by infecting a host cell and are incapable to reproduce on their own. A complete virus particle, known as a virion consists of nucleic acid surrounded by a protective coat of protein called a capsid.

3. Human immunodeficiency virus (HIV) is a retrovirus that causes acquired immunodeficiency syndrome (AIDS). HIV primarily infects vital cells in the human immune system such as helper T cells (CD4+ T cells), macrophages and dendritic cells. HIV infection leads to low levels of CD4+ T cells. http://www.unaids.org/en/

4. The Natural History of HIV Infection

5. The “Enemy”

7. Basic Virology Virus: • Genomic “instructions” (RNA or DNA) • Physical structure (envelope and capsid) • Viral enzymes (reverse transcriptase, accessory gene products) • Parental host cell membrane

10. ~ 9,100 RNA bases in length • Encodes 9 genes

11. HIV Structure Virion Genomic Proteomic

12. HIV Proteins Structural Proteins Gag: Matrix, Capsid, NC Pol: Protease, Reverse Transcriptase, Integrase Env: gp120, gp41 Regulatory Proteins Tat Rev Nef Accessory proteins Vif Vpr Vpu

14. HIV Lifecycle:

15. Viral RNA gp120 p24 RT & other virion prteins HIV Lifecycle:

16. Viral RNA gp120 p24 RT & other virion proteins HIV Lifecycle: Binding CD4 CXCR4 or CCR5

17. Viral RNA gp120 p24 RT & other virion proteins HIV Lifecycle: • Entry Inhibitors: CCR5 antagonist, maraviroc Binding CCR5 CD4 CXCR4

18. Viral RNA gp120 p24 RT & other virion prteins HIV Lifecycle: Fusion & uncoating

19. Viral RNA gp120 p24 RT & other virion proteins HIV Lifecycle: B. Fusion Inhibitors: T20 Fusion & uncoating

20. Viral RNA gp120 p24 RT & other virion prteins Reverse transcription HIV Lifecycle:

21. Viral RNA gp120 p24 RT & other virion proteins Reverse transcription HIV Lifecycle: C. Reverse Transcriptase (RT) Inhibitors: 1. Nucleoside RT inhibitors (NRTIs) 2. Non-Nucleoside RT Inhibitors NNRTIs)

22. Viral RNA gp120 p24 RT & other virion prteins HIV Lifecycle: Nuclear localization & entry

23. Viral RNA gp120 p24 RT & other virion prteins HIV Lifecycle: Integration

24. Viral RNA gp120 p24 RT & other virion proteins HIV Lifecycle: • Integrase Inhibitors: raltegravir Integration

25. Viral RNA gp120 p24 RT & other virion prteins HIV Lifecycle: Integrated provirus

26. Viral RNA gp120 p24 RT & other virion prteins HIV Lifecycle: Integrated provirus

27. Viral RNA gp120 p24 RT & other virion prteins Viral Gene Transcription HIV Lifecycle:

28. Viral RNA gp120 p24 RT & other virion prteins HIV Lifecycle: Translation

29. Viral RNA gp120 p24 RT & other virion prteins HIV Lifecycle: Post-translational processing

30. Viral RNA gp120 p24 RT & other virion prteins HIV Lifecycle: Assembly

31. Viral RNA gp120 p24 RT & other virion prteins HIV Lifecycle: Budding

32. Viral RNA gp120 p24 RT & other virion proteins HIV Lifecycle: Budding Inhibition of Virion Maturation E. Protease Inhibitors: e.g. Lopinavir, Indinavir

33. Viral RNA gp120 p24 RT & other virion prteins HIV Lifecycle: This process averages about 1.2 days

34. Viral RNA gp120 p24 RT & other virion proteins Reverse transcription Infection Fusion & Entry Binding Nuclear localization & entry CD4 Integration CXCR4

35. Viral RNA gp120 p24 RT & other virion prteins Viral Gene Transcription Assembly Post-translational processing Budding Translation Expression

36. Some Take-home points: HIV Structure: • HIV is comprised of viral proteins, host cell membrane • env is the only exposed viral protein (evades immune response) • gag (p24) represents the primary structural component of virion

37. Take-home points: HIV Genome: • RNA genome -- requires HIV reverse transcription to DNA • In a productive infection, genome permanently integrates into host genome • HIV Genome encodes 9 viral genes: 3 structural, 3 regulatory, 3 accessory

38. Discussion Points/Exercises Can you draw a representation of what HIV looks like? Explain, in general lay terms in 1 sentence, how an HIV entry inhibitor, reverse transcriptase inhibitor, integrase inhibitor, and protease inhibitor work based on your knowledge of the HIV lifecycle. Discuss where you think other targets for antiretroviral therapy may be based on its lifecycle.