Lec 6 Retroviruses (Final Start Pt 1) Flashcards
Retroviruses
Lentivirus
Spumivirus
REVERSE TRANSCRIPTION
INTEGRATE GENOME into HOST eg. Hep B
RNA viruses
LENTIviruses (slow viruses) TAKE TIME B4 DEVELOPING SYMPTOMS. The complex lentiviruses eg. HIV
Alpha, beta, gamma, epsilon, delta Spuma- viruses
Spumiviruses (SFV) cause infections but NOT CAUSE SYMPTOMS.
Go from species to species… problem for all animals
Another thing: HERV-W uses W (tyrosine) tRNA!
In general
Encode >= 3 genes
Gag encodes gag polyprotein, cleaved by viral protease (PRO) into:
- Nucleocapsid (NC): packages genomic RNA (core)
- Capsid (CA): packages the core (p24 for HIV)
- Matrix (MA): lines the inside of the lipid bilayer envelope, connects the capsid to the envelope (p17 for HIV)
– Pol (polymerase gene) encodes:
Protease (PRO)
• Reverse transcriptase (RT)
• Integrase (IN)
• Both incorporated into the virus particle
– Env (envelope gene) encodes the envelope glycoprotein
Retroviral Virion Features
RT, PRO, IN (encoded by pol) incorporated in the virus particle
Lipid bilayer w/ capsid, 2 copies of RNA genome, envelope which binds to host cell receptor and mediates entry.
Viral RNA capped and contains poly A tail (mRNA)
Proviral DNA have duplicated LTR (long terminal repeat)s which make up 1 molecule which is cleaved to make gag, pol, env. LTRs are the promoters
HIV-1 wrt other retroviruses
Have other protein coding genes… HIV-1 has more than 3 genes and ORF so is called a COMPLEX RETROVIRUSES.
Other genes’ proteins are spliced differently to make different products
Simple life cycle
Viral membrane and cell membrane fuse together, particle enters
Particle stays intact, loosens up, conf. change, reverse transcription occurs in side the virus! cDNA (proviral DNA) is made, transported into nucleus w/ integrate, and integrates AT RANDOM into the genome but some sites are preferred!
BUT it can only integrate where the integrin is loose (transcriptionally active genes!)
Gene expression: splicing to make env, make full length RNA molecules and splice variants to make gag structural protein, then make new genomes.
COMPLEX retroviruses have REGULATORY PROTEINS that help mediate these processes.
Grab RNA, gag pol and buds out of the virus w/o lysing the host cel;. Virus is still immature. Not infectious b/c the polymerase and other proteins are still in polyprotein form, not functional.
When protease cleaves virus particles more, they will become mature particles. The cell can do this w/o dying, cell lives normally.
How is the cell’s life span affected?
**How is the cell’s life span affected? Varies in btw viruses! Lowered by a bit, most of the time.
When HIV express auxiliary (other genes/proteins) they are expressed a lot more, and they regulate polyprotein splicing
tat: transcription activator expresses other genes and these proteins help bypass host defines mechanisms.
Oncogenic retroviruses
Major causes of leukaemia, lymphoma, sometimes sarcomas in many animals and bird.
Human T-cell leukaemia virus (HTLV) –> T cell lymphoma
Cattle Bovine leukemia virus (BLV) –> B cell
Not every retrovirus causes cancer.
Mouse mammary tumor viruses
Highly and weakly oncogenic retroviruses
HIV-1 can indirectly affect tumorgenesis d.t. induced immunodeficiency
Highly oncogenic retroviruses r rapidly acting by activating oncogene
(V-onc)
V-> viral oncogene
C-> cellular oncogene
In many cases the genome has deletions in > 1 essential genes… defective retroviruses can still replicate in presence as long as non-defective ones are still present
V Have same functions as C counterparts: Tyrosine PK’s GTP binding proteins, transcription factors
Reverse Transcriptase Activity!
- tRNA binds to PRIMER BINDING SITE, elongates toward the 5’ end of the RNA! Translated 5’ untranslated region and repeat region.
- RNAse H comes and cleaves the original RNA, the newly replicated material is NOW DNA!
- This 3’5’ DNA is moved to the 3’ end of the RNA and oriented backwards so the 5’ end of the DNA faces the start of the 3’ untranslated region of the RNA.
- Reverse transcriptase synthesizes a complementary DNA by elongating from the start of the untranslated region towards the 5’ end, in 3’5’ direction.
- RNAse H comes in again and separates the complete DNA from the RNA. The first strand has been made!
- An RNA primer comes to the left of the 3’ untranslated region of the DNA, at a POLY PURINE TRACT! Reverse transcriptase synthesizes the 3’ UTR, repeat region and 5’ UTR
- RNAse H comes again and tRNA is cleaved from the 5’ end of the 1st DNA or 2nd DNA’s 3’ end. Now the newly made fragment is moved to the 3’ end of the first synthesized DNA!
* The PRIMER BINDING SITES of the 2 DNA strands align. - RT makes the 3’UTR, repeat and 5’ UTR region for both DNA strands from 3’ to 5’ AND the CODING REGION of the 2nd DNA strand.
Avian leukosis virus
Weak oncogenic virus, causes cancer slowly. Does not even have oncogene, and induce B and T cell leukemias. Cause life long viremia but last for life
When the oncogene is seen near the envelope gene, the virus must steal an envelope from the host to survive, from the cell surface! This includes their receptors to mimic them in the immune system!
Highly oncogenic is faster, has it close from the LTR regions
Insertional tumerogenesis
Mouse Mammaty Tumor Virus
Integration into important regulatory genes
LTR (virus promoter), using LTRs or enhancers.
LTR activates flanking gees
Genome interrupts host genes
Induction by other viral proteins (no oncogene)
HTLV-1 endemic in places. Adult T cell leukaemia/lymphoma
ATL is an aggressive malignant of mature CD4+ T cells
Most patients die, very tough to treat b/c its a complex retroviruses.
Make envelope w/ splice variant. The Tax protein works as transcriptional activator. which cause tumor genesis, which also interacts with cell activities
The accessory proteins (Tax, Rex, p12, p13, p30) play a role in HTLV-I tumor genesis
Tax activities
Disrupt signalling cascades which cause tumor genesis
Interacts with transcription factors and molecules involved in signal transduction pathways
Dysregulation of both viral and cellular genes
increased expression of cytokines and their receptors
increased expression of anti-apoptotic proteins
Many genes dysregulated by Tax play a role in cell cycle control, apoptosis, and DNA repair
ENDOgenous Retroviruses
EXOgenesis Retroviruses (HIV)
EXOgenous: horizontal transmission in-between people! Typical viral infectious agent.
ENDOgenous: vertical transmission via germ line cells to progeny! No need for viral particle, the DNA must contain viral DNA!
Silense in Expression: proviral genome is silent in the host, most of the time. Can get activated in host by:
-induction, irradiation, exposure to mutagenic chemicals, hormola or immunologicl stimuli (LTRs are sensitive)
Part of host genome: contains fully functional viruses and deletion mutants that are not/partially functional. ~10% of your DNA is made of these genes!
Could result in production of visions that are infectious and transmitted!
Some endogenous retrovirus elements actually protect us from exogenous ones! Evolution…
Functional or pathogenic
Remnants of old retroviral infections
Can move around the genome
Cause or exacerbate disease
Antiviral activity: Endogenous retroviral transcripts act as microRNA?
HERV-W envelope (Syncytin) is important in human pregnancy! Stolen from viruses for our placental development! Could be bad if activated!
