env (viral gene)

• envelope glycoprotein
• gp120
• gp41

pol

• reverse transcriptase
• proviral DNA synthesis for integration

int

• integrase
• promote integration of proviral DNA into ost chromosome

tat

• P14--transcriptional regulator
• controls transactivation of proviral genes
• maintains HIV provirus in infected cell

nef

• alter cell activation signals
• promote replication
• help progression to AIDS

rev

• promotion of export HIV RNA to cytoplasm

gag

core & capsid proteins (p24)

Virion Structure

• Envelope
  • lipid bilayer w/TM (GP41) & SU (GP120)
• Capsid
  • icosahedrol
• Nucleoprotein core
  • 2 identical ssRNA copies of genome
  • 50 copies of RT

Retrovirus Life Cycle

begins when HIV encounters CD4 of T cell

Reservoirs of HIV

• monocytes, macrophages
• microglial cells
• dendritic cells
• B lymphocytes

HIV entry

• binding of GP 120 to CCR5 or CXCR4
• exposure of fusion domain of gp41
  • pH independent conformational change in gp41 leading to fusion of cellular & viral membranes

HIV entry summary

1. GP120:CD4 binding
2. conformational change
3. CCR5 recruitment
4. GP41 membrane insertion
5. membrane fusion--> entry into cytoplasm

Reverse Transcription

• reverse transcription of ssRNA to proviral dsDNA
• occurs in cytoplasm

Integration

• transport of pre-integration complex to nucleus
• circularization of dsDNA
• integration occurs random in host genome
• latency

What happens after REACTIVATION?

production of viral mRNA & viral genomic RNA from integrated proviral DNA

Production, Assembly & Release

• transport of viral RNA & mRNA (full length) out of nucleus
• viral proteins produced
• assembly of capsid @ cell membrane
• packaging RNA into capsid
• proteolytic cleavage
• budding & release of mature viral particles

HIV pathogenesis (1)

• Burst of viremia occurs in early acute infxn
• Loss of CD4+ T cells
• Mono-like symp. 10-30 days after exposure & lasts <14 days

HIV pathogenesis (2)

• Infxn progresses to clinical latency
• AIDS may occur in 2-20 yrs
• After activation & during HIV infxn CD4 T cell # declines

Host factors affecting progression of HIV

• genetic differences among people
  • heterozygous CCR5=slow progression

Aids-Related Complex

(ARC)

CD4<500/microL (accompanied w/ Candidiasis)

AIDS

• HIV infected
• CD4<200 microL
• opportunistic infxn & cancer develops

HIV Drug Targets

• CCR inhibitor--blocks binding fusion & uptake
  • Class IV
• Virion release & maturation
  • Class III
• Reverse Transcription & Nuclear Import
  • Class I & II

Class I: Nucleoside reverse transcriptase inhibitors (NRTIs) Drugs

• Zidovudine [AZT]
• Lamivudine [3TC]
• Tenofovir
• Abacavir

Class I: NRTIs MOA

• Target of action: Reverse Transcriptase of HIV-1
• Tri-phosphate drugs activated by host kinase
• competitively inhibit RT @ active site
• DNA chain elongation BLOCKED
  • no free 3' OH

Class I: NRTI Resistance

• mutation of RT
• poor fidelity (no proof reading fxn)
• must be combined w/other anti-HIV drug

Class II:  Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Drugs:

• Efavirenz (long 1/2 life=given once daily)
• Nevirapine (single dose during childbirth)
• RESISTANCE IS COMMON

Class II:  NNRTI MOA

• RT of HIV-1
• Don't require activation
• Tri-phosphate drugs bind to enzyme @ allosteric site
• NON-competitive, steric hindrance
  • inhibition of RT

Class III: Protease Inhibitors

• Ritonavir
• Indinavir
• Saquinavir
• Atazanavir
• Lopinavir

Class III: Protease Inhibitors MOA

• Target of action: viral protease
  • post translational processing
• Binds & blocks HIV protease activity
  • needed to make fxnl proteins

Class III: Protease Inhibitors Resistance

• Due to mutations in prtoease enzyme
• large potential for resistance--always give in combo w/RTI

Class IV: Fusion Inhibitor

• enfuvirtide
• synthetic 36-amino acid peptide binds gp41
• prevents gp 41 from conformation
• used ONLY in treatment experience pts