HIV Replication Rachel Carriger Biochemistry Fall 2004.
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HIV Replication
Rachel Carriger
Biochemistry Fall 2004
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AIDS
• Acquired Immune Deficiency Syndrome
• First cases reported to CDC in 1981
• HIV-1 and HIV-2 viruses discovered in 1983 by Luc Montagnier
• HIV is classified as a retrovirus
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HIV is a RetrovirusRetrovirus
Characteristics• Complex interactions
with the host cell• Chronic course of disease• Long and variable
incubation periods• Persistant viral
replication• Destruction of
immunological cells
HIV Characteristics• Chronic course of
disease• 5-10 year latency
period• CD4+ T lymphocytes
are the host cells• Replicates rapidly• Neurological
abnormalities
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HIV structure• 72 glycoprotein
complexes on lipid membrane
• Gp120 and gp41 transmembrane protein
• Inside p17 matrix and p24 core antigen protein
• Two copies of RNA• Reverse transcriptase
enzyme• Nucleoprotein p7
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HIV Entry Into CD4+ Host Cell
Gp 120 molecule attaches to CD4 glycoprotein site and chemokine receptor
GP 41 inserts its NH2 head into the membrane of the host cell
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Reverse Transcriptase
• Discovered by David Baltimore and Howard Temin in 1970
• Purpose: to convert single stranded RNA into double stranded DNA
• Heterodimer of p51 and p66 subunits• p66 subunit consists of five subdomains:
fingers, thumb, palm, connector, and RNase H
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Replication
• tRNA primer bound to 3’ terminal end• Binds free nucleotides at a rate of 20 per second
in the 5’ 3’• DNA/RNA hybrid formed• Ribonuclease H subdomain of reverse
transcriptase digests the original strand of RNA and leaves a string of purines to be used as primer for the new DNA strand
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Reverse Transcriptase Conformational Changes
1. Fingers close down on the palm and hold the template strand in place
2. Fingers bend back releasing a pyrophosphate and base
3. Enzyme positioned at the 3’ end of the growing DNA chain so the replication process can continue
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Transcription DNA RNA
• HIV incorporates itself into genome of the host cell
• Transcription factor NF-kB binds to LTR regions of DNA
• Regulatory proteins rev and tat produced first
• New RNA strand exits cell by budding
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Gene Sequence of HIV
• Gag- group antigen, nucleus
• Pol- polymerase, enzyme
• Env- envelope, outer membrane
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Difficult To Find A Cure• Reverse transcriptase has a high mutation
rate – Very tolerant of non standard base pairs– No exonuclease activity to proofread– 1-10 errors per genome per replication cycle
meaning 109 new viruses a day
• Replicates very rapidly• Long latency period• Drugs targeted at reverse transcriptase and
protease
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Protease Inhibitors
• HIV protease (aspartic protease) cleaves polypeptides that the virus makes and needs for maturation
• Protease Inhibitors bind tightly to the HIV protease and keep it from functioning
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Nucleoside Inhibitors
• Analogs of common base pairs used during replication
• Slight modifications in structure stop the whole replication process
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Non-Nucleoside Inhibitors
Binds to reverse transcriptase and alters it’s structure
Nevirapine Delavirdine