ORGB 423 Lecture Notes - Lecture 27: Apobec3G, Apobec, Tripartite Motif Family
12 Jun 2018
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MIMM 466 Viral Pathogenesis
2018-02-28 LEC 27 Cellular Factors Influencing Restriction to Retrovirus Infection
à Shringar Rao
Host cell factors: accomplices or adversaries in HIV infection
• Host cell factors: proteins or components that can help or hinder HIV infection
o “Accomplices”: factors promote viral infection
o “Adversaries”: proteins that are detrimental to HIV
• There is a fine balance between these factors that can predict the outcome of HIV infection
Factors influencing restriction to retrovirus infection
• 1 – Host cell can lack a factor necessary to the virus, which is detrimental to virus infection
o E.g. HIV envelope has GP41 and GP120 proteins, which bind host factors CD4 and CCR5 for cell
entry. If the host cell lacks CD4 or CCR5, it can’t be infected.
• 2 – Host cell can possess restriction factors (RFs) that interfere with viral infection
o RFs inhibit viral replication at any stage of the viral life cycle
o 3 Major RFs: APOBEC, TRIM, Tetherin
APOBECs and Viral Infectivity factor (Vif)
• HIV codes for 9 different genes
• Experiment: Vif-/- HIV was used to infect cells to see what VIF was use dfor
o Some cell types were infected, but in others there was no productive infection
o Found that permissive cell types lacked APOBEC3G
• APOBEC: host apolipoprotein B mRNA editing complex, catalytic polypeptide like
o Causes CàU and thus Gà A hypermutations
o 2 isoforms: one in the liver and one in the intestine
§ Liver: long isoform
§ Intestine: short isoform
o Intestinal isoform: C
à
U hyper mutation leads to insertion of stop codon (CAAàUAA) and
synthesis of a shorter protein
o APOBEC has many family members, of which APOBEC3G and APOBEC3F are known to edit
retroviral cDNA
APOBEC3G during Reverse Transcription
• During synthesis of (-) cDNA, APOBEC causes deamination of cytidine
à
uridine
• This leads to insertion of U in the (-) strand, resulting in GàA hypermutations in the dsDNA
o TGG can be converted to TAA which is a stop codon
• WT virus: VIF targets APOBEC3G to the E3 ligase complex, which promotes poly-ubiquitination and
degradation via the proteosomal pathway
• VIF-/- virus: APOBEC3G is incorporated in the virus, and in the next round of replication APOBEC3G
causes hypermutations in dsDNA and leads to defunct provirus production
o Results in a non-productive infection
TRIMS
• Large family of proteins containing a tripartite motif
• Involved in various cellular processes, including cell proliferation, differentiation, development and apoptosis
• Some have antiviral properties
• Old World monkeys can be infected by SIV but not HIV1, which indicates a cross-species protection by
retroviruses
o Trim5a is a monkey protein responsible for blocking infection by HIV1
• TRIM5a is found in cytoplasmic bodies, where it binds the capsid of an incoming virus and promotes its
degradation via the proteosomal pathway
Document Summary
2018-02-28 lec 27 cellular factors influencing restriction to retrovirus infection. Factors influencing restriction to retrovirus infection: 1 host cell can lack a factor necessary to the virus, which is detrimental to virus infection, e. g. Hiv envelope has gp41 and gp120 proteins, which bind host factors cd4 and ccr5 for cell entry. Intestinal isoform: c u hyper mutation leads to insertion of stop codon (caa uaa) and synthesis of a shorter protein: apobec has many family members, of which apobec3g and apobec3f are known to edit retroviral cdna. Trims: large family of proteins containing a tripartite motif. 32 mutation in ccr5 (co-receptor for hiv-1) is highly beneficial for the host: e. g. certain hla types delay acceleration of aids. Ccr5 and the bubonic plague: y. pestis and hiv-1 share the same entry co-receptor: ccr5, descendants of the plague survivors are partially resistant to hiv1 due to inheritance of 32 ccr5 allele, maraviroc: ccr5 inhibitor.
