HIV Structure, Viral Lifecycle and Target Cell Interactions

Structure of HIV Virus and Interaction of HIV with Target Cells and Involved Molecules

·Human immunodeficiency viruses 1 and 2 (HIV-1 and HIV-2)

·HIV-1 is more important (most common cause of AIDS)

·Member of the lentivirus family of animal retroviruses

Molecular Features

oTwo identical strands of RNA wrapped within a core of viral proteins p24, surrounded by a matrix of p17 proteins

o Phospholipid bilayer envelope derived from host cell membrane but including virally encoded membrane proteins gp41 and gp120

§ Proteins form a unit

§ gp41 is a transmembrane molecule and noncovalently associated to gp120 subunit, extruding out of the membrane

o Two very important enzymes in core: reverse transcriptase and proteinase

o Long terminal repeats (LTRs) at each end of the genome regulate viral integration into the host genome, viral gene expression and viral replication

o gag sequences encode core structural proteins

o env sequences encode the envelope glycoproteins gp120 and gp41 (required for infection of cell)

o pol sequences encode reverse transcriptase, integrase and viral protease enzymes required for viral replication

o In addition to typical retrovirus genes, HIV-1 has six additional regulatory genes: tat, rev, vif, nef, vpr and vpu genes

§ Tat and Rev

·Regulatory proteins that stimulate transcription of proviral HIV-1 DNA into mRNA

·Promote RNA elongation

·Enhance transcription of HIV RNA from nucleus to cytoplasm

·Essential for translation

§ Nef

·Induces downregulation of CD4 and HLA class I molecules from surface of HIV-1-infected cells (important escape mechanism for virus to evade an attack mediated by CTLs and to avoid recognition by CD4+ cells)

·Interferes with T-cell activation by binding to various proteins that are involved in intracellular signal transduction pathways

§ Vpr

·Essential for viral replication in non-dividing cells (macrophages)

·Stimulates HIV-LTR in addition to a variety of cellular and viral promoters

§ Vpu

·Important for virus “budding” process

·Involved when CD4-gp160 complexes are degraded within the ER and therefore allows recycling of gp160 for the formation of new virions

§ Vif

·Of paramount importance for protection of the replicating virus from the antiviral activity of APOBEC3G

·Intracellular enzyme that specifically de-aminates cytosine to uracil in mRNA or DNA → accumulation of G-to-A mutations that lead to degradation of viral DNA

Interactions (Viral Lifecycle)

o HIV infection is a multistep process of fusion of the virion envelope with the membrane of the target cell

o X4-strains (CXCR4 co-receptor): HIV variants that, due to specific chemokine receptors, preferentially infect T-lymphocytes; T-tropic viruses

o R5-strains (CCR5 co-receptor): HIV variants that preferentially infect macrophages; M-tropic viruses

o R5X4-strains (both receptors): dual-tropic viruses

o If an individual does not express the previously mentioned receptors, he or she is resistant to HIV infection

o Co-receptor binding → conformational change in gp41 that exposes hydrophobic region (fusion peptide) → viral membrane fusion

o After virus enters a cell, enzymes become active and begin the viral reproductive cycle

o Nucleoprotein core becomes disrupted and RNA genome of HIV is transcribed into a dsDNA (reverse transcriptase)

o dsDNA enters nucleus and is integrated into host cell genome via integrase activity

o Provirus – integrated HIV DNA

§ May remain transcriptionally inactive for months or years (latent phase)

o If latency is ended, DNA provirus is regulated by the LTR upstream of viral structural genes → synthesis of mature, infectious viral particles

o Escape from the host cell via budding from the plasma membrane

§ Increase in plasma membrane permeability

§ Influx of lethal amounts of calcium or osmotic lysis

§ Major cause of CD4+ loss

o Other ways CD4+ cells are destroyed:

§ Plasma membrane of HIV-infected T cell fuses with uninfected CD4+ T cell by virtue of gp120-CD4 interaction → multinucleated cells or syncytia → lethal to HIV-infected and uninfected T cells

§ Unintegrated viral DNA in cytoplasm of infected cells or large amounts of nonfunctional viral RNA may be toxic to infected cells

§ Viral production can interfere with cellular protein synthesis and expression and thereby lead to cell death

§ gp120 binding to newly synthesized intracellular CD4 may interfere with normal protein processing in ER and block cell surface expression of CD4

o Other cells than CD4+ T cells that are involved in progression of immunodeficiency: mononuclear phagocytes (macrophages), dendritic cells and follicular dendritic cells