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

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.

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/

The Natural History of HIV Infection

The “Enemy”

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

~ 9,100 RNA bases in length Encodes 9 genes

HIV Structure Virion Genomic Proteomic

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

HIV Lifecycle:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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.