Date post: | 19-Dec-2015 |
Category: |
Documents |
View: | 218 times |
Download: | 3 times |
HIV Replication
Rachel Carriger
Biochemistry Fall 2004
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
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
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
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
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
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
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
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
Gene Sequence of HIV
• Gag- group antigen, nucleus
• Pol- polymerase, enzyme
• Env- envelope, outer membrane
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
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
Nucleoside Inhibitors
• Analogs of common base pairs used during replication
• Slight modifications in structure stop the whole replication process
Non-Nucleoside Inhibitors
Binds to reverse transcriptase and alters it’s structure
Nevirapine Delavirdine