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March 22 - HIV proteins.docx

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BIOL 3155
K.Andrew White

March 22: Recall: ...the presence of the virus itself helps to activate transcription of the provirus insert?  Regulatory Proteins o Table 29.3  EARLY Gene Expression o Genes encoded in the 2 kb class are expressed first (Early) o CRS (Cis-acting Responsive Sequence) RNA sequence in gag/pol and env ORFs of the provirus. these sequences are DNA sequences, but are only active in the RNA form. 2 are in the  RNA sequences, not protein but present in protein coding regions o CRS causes viral mRNAs that have them to be retained in the nucleus, so the 9kb and 4kb class remain in the nucleus. o Not the 2kb class (2x spliced)  Both CRS’s are removed from 2kb class and b/c of that it will not remain in nucleus, instead it will be transported to cytosol where it will be translated; so tat rev and Nef are translated. nd  Tat – Transactivator of transcription – 2 early protein – translated from 2kb o Tat is a highly basic protein - +ve charge, so it binds to nucleic acids cuz they're negatively charged. It binds to RNA. o Localizes to the nucleus  activates transcription. Tat doesn't work thru transcription initiation, its not like a transcription factor. it doesnt speed up the transcription. o It binds to TAR (Tat-Responsive element – RNA sequence, not protein) in NASCENT viral RNA. so it binds to viral RNA, unlike transcription factors which bind to DNA sequences (enhancers). o Tat recruits Cyclin T and Cyclin-dependent Kinase-9 (cdk9). this is a protein that phosphorylates other proteins, which needs cyclin T to work. o Cdk9 phosphorylates Pol II  enhances Pol-II processivity (full-length RNA). processivity is very important in terms of the activity of the Tat. it's how well the polymerase elongates and continues to transcribe (not the initiation rate; i.e. once the initiation starts, does it go and elongate?) . so this phosphorylation results in making full- length RNAs. o No phosphorylation  there’s going to be a problem o Fig. 29.5 o a) with no tat, altho the element is present, .. misleading tho, cuz not all polymerases actually terminate too early; there's some low level transcription still occuring. this low level is necessary to allow Tat to be made so it can come enhance the elongation. so the net result of when no tat is present is u get transcription, but its very low. the polymerase will stop transcribing early on. o b) when tat is present, tat will interact with the TAR element, and recruit cdk9 and cyclin T, and since cdk9 is close to polymerase, it phosphorylates it which allows the polymerase to trasncribe full-length mRNAs. o note that initiation rate in a and b is the same. it's the processivity that's affected by the presence of tat.  Rev – Regulator of expression of virion proteins (another early gene, 2kb mRNAs) o Mediates nuclear export of LATE mRNAs in the 4kb and 9kb classes (remember that retention sequence keeps them in the nucleus but u dont need them in there the whole time. Rev goes into nucleus and mediates their export) o Rev binds to RRE (Rev response element, RNA sequence) in vRNAs and Eportin1/RanGTP  Rev protein binds to RRE  In env ORF (present in 4kb and 9kb)  RNA elements are placed strategically in terms of their function o Fig. 29.6  Rev – translated from early 2kb Class mRNA, (so we're getting Rev made in the cytosol, but its function will be in the nucleus, so it will be imported to the nucleus).  In nucleus – Rev will bind to RRE (remember RRE is present in those larger species of viral RNA), Exportin 1, and Ran GTP; Rev is acting like a linker b/w cellular proteins and viral RNA to allow it to shuttle along from cytosol to nucleus  why it needs this ...signal, is cuz they have CRS, so without it they would just stay in the nucleus  Counteracts CRS retention  Nef –rdegative effector (early gene - last of 3 viral proteins made from the 2 kb mRNAs) o 3 early gene (2kb mRNAs) o Important determinant of Pathology o What is the evidence for this? o 1) Nef transgenic mouse; its wildtype but has Nef gene. mice with only Nef gene got very sick with AIDS-like symptoms (without being infected by any immodeficieny agent). So it's important for pathogenecity. o 2) delete Nef from SIV. When chimps were infected by this Nef- SIV, they didnt progress into AIDS symptoms. this was exciting for the possibility to be used a live attenuated vaccine. This worked for chimps, but later on, there were side effects and some of the chimps that were vaccinated ended up with AIDS anyway.. o there are 3 activities identified for Nef, but unclear which are responsible for pathology: o i) Decreases surface expression of CD4 and MHC1  bad for immune system to not have the receptors. Part of how nef does this is its associated with the inside of the plasma membrane . It's able to interact with the cytoplasm
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