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Every chicken you eat is contaminated with these viruses
Avian leukosis virus
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Why are retrovirsuses difficult to eliminate?
They are ubiquitous and they integrate into the host chromosome.
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Occupy as much as 7% of the human genome
Human endogenous retroviruses (HERVs)
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HERVs:
Transmitted horizontally or vertically?
Vertically
*But produce few, if any, infectious particles
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Family: Retroviridae
Subfamily: Orthoviridae
- 4 genera of oncogenic retroviruses
- Alpha (Rous Sarcoma virus)
- Beta (Mouse Mammary Tumor Virus)
- Gamma (Feline Leukemia Virus)
- Delta (HTLV)
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Family: Retroviridae
Subfamily: Orthoretrovirinae
Genus:???? - (encompasses HIV-1, HIV-2, SIV)
Lentivirus
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Family: Retroviridae
Subfamily 1: ???
Subfamily 2: ???
- Orthoretrovirinae
- Spumaretrovirinae
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Family: Retroviridae
Subfamily: Spumaretrovirinae
Genus:
Spumavirus (Foamy viruses)
*Spumaretrovirinae do not typically cause human disease
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Only human virus derived from animals we've ever successfully linked to a tumor
HTLV-1
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Retrovirus (HIV-1) Structure:
Genome
Genome: ssRNA, diploid + tRNA
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Retrovirus (HIV-1) Structure:
Proteins
- 1) GAG (Group-specific AntiGen): MAtrix, CApsid, NucleoCapsid
- 2) POL (RNA-Dependent DNA POLymerase): PRotease, RevTranscriptase, INTegrase
- 3) ENV (ENVelope proteins): SUrface (gp120) and TransMembrane (gp41)
- 4) Regulatory Proteins: TAT, REV, NEF, VIF, VPU, and VPR
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HIV-1 Protein:
GAG encodes
Matrix, Capsid, Nucleocapsid
(aka these are the structural proteins)
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HIV-1 Proteins:
POL encodes
Protease, Reverse Transcriptase, Integrase
*POL proteins are the ones that enter the host chromosome
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HIV-1 Proteins:
ENV encodes
Surface (gp 120), Transmembrane (gp41)
*Both of these proteins play a part in virus entry
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HIV-1 Proteins:
Name 6 Regulatory Proteins
TAT, REV, NEF, VIF, VPU, and VPR
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HIV-1 protein that encodes the structural proteins
GAG
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Type of Polymerase encoded for by POL
RNA-dependent DNA Polymerase
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POL is accessed by
frameshifting
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ENV mRNA formation involves
splicing
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Generates final viral protein products
Proteolytic cleavage
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Some oncogenic retroviruses (replication incompetent) have lost replicative genes and replaced these with
viral oncogenes (vONCs)
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Retrocompetent Cell: MC29
- Oncogene= myc
- Replication incompetent virus, must replicate with another virus that has a GAG and POL gene
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HIV-1 Attachment and Entry:
Viral protein that mediates attachment
gp120
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HIV-1 Attachment and Entry:
Viral protein that mediates fusion
gp41
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HIV-1 Attachment and Entry:
HIV-1 "co-receptors" or "ultimate receptors"
CCR5, CXCR4
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HIV-1 Attachment and Entry:
Bind virus and facilitate interaction with CD4 and CCRs
- DC-SIGN (dendritic cells/ macrophages)
- a4B7 integrin (GALT CD4+ T cells)
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Primary cell target of HIV-1 virus
CD4 TH cells
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Cells lacking this receptor cannot be infected with HIV-1
CCR5
(Cells lacking CD4 receptors can still be infected, although this is not normal)
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HIV-1 CCRs are
chemokine receptors
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Chemokines (RANTES, MIP-1alpha, MIP-1beta) are thought to block HIV replication by
binding to their receptors (CCRs) and blocking entry
(In some individuals, high expression of CCL3L1 blocks virus entry)
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10% of caucasians are heterozygous for a deletion within the CCR5 gene, and 1% lack it completely. Why is this significant?
The 1% that lack CCR5 completely show resistance to HIV-1 infxn
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New anti-HIV drug that is a CCR5 antagonist
Selzentry, Maraviroc
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HIV-virus enters the cells as a:
Once in the cell, virus turns into:
- Enters: ssRNA
- Turns into: dsDNA
(The dsDNA integrates into the host chromsome allowing the virus to replicate)
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When HIV-1 enters the cell, it is bound to a?
What region is always present?
- tRNA
- Always present= LTR (Long Terminal Regions)
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Binds to LTR and activates HIV replication
NFkB (So every infxn you get, increases replication and makes your immune system weaker)
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In contrast to other viruses, when HIV is released
It is still maturing due to proteases in the capsule
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HIV Reverse Transcription:
Virion-associated Reverse Transcriptase synthesizes a copy of?
Uses what as a template and what as a primer?
- cDNA
- Template: Genome RNA
- Primer: tRNA
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HIV Reverse Transcription:
Virion RNA is degraded by?
And a second strand of DNA is synthesized by?
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HIV Reverse Transcription:
dsDNA copy of the viral genome is flanked by
LTRs
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Retrovirus Integration:
Although integration is random, HIV-1 preferentially integrates into
active genes
(If HIV does not replicate at an active gene, you will not see it)
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Integrated viral DNA, part of the host chromosome, inactive not making viral proteins, but could be activated if that portion of DNA is activated. This complicates HIV therapy.
Proviral DNA
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HIV-1 Transcription and Genome Synthesis:
Enzyme that synthesizes both genomic (unspliced) and mRNA (both spliced and unspliced) using proviral DNA as the template.
Host Pol II (DNA-dependent RNA Polymerase)
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HIV-1 Transcription and Genome Synthesis:
2 Ways transcription is upregulated
- Binding of transcription factors within LTR
- Action of TAT
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HIV Translation:
Synthesis of capsid and catalytic proteins uses a genome-sized template and involves
- Synthesis of a polyprotein
- Frameshifting/ readthrough
- Proteolytic cleavage
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HIV Translation:
Regulatory and glycoproteins are translated from
spliced mRNAs
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Because both structural and catalytic proteins are generated by cleavage from a larger precursor protein....
blocking protease activity inhibits viral assembly
(A number of protease inhibitors are currently in use and have dramatically lowered the mortality associated with HIV-1 infxns)
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HIV Assembly:
Where does virion assembly take place
In the vicinity of the plasma membrane
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HIV Assembly:
Assembly is determined by?
Driven by?
- Concentration of precursors
- Proteolytic cleavage
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Regulatory Proteins of HIV-1
- TAT- upregulates transcription
- REV- promotes nuclear export of unspliced and partially spliced mRNAs
- VIF- suppresses an innate anti-viral activity found in some T cells
- VPU- Degrades CD4 in ER and promotes virus release
- NEF- downregulates CD4 and MHC class I from the cell surface
- VPR- promotes nuclear translocation of pre-integration complex
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Regulatory Protein of HIV-1: Upregulates transcription
TAT
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Regulatory Protein of HIV-1:
Promotes nuclear export of unspliced and partially spliced mRNAs
REV
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Regulatory Protein of HIV-1:
Suppresses innate anti-viral activity foundin some T cells
VIF
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VIF counteracts the effect of
APOBEC3G (a cytidine deaminase)
*APOBEC3G is likely responsible for hypermutation within HIV-1 DNA (Deaminated viral DNA is degraded by the DNA repair apparatus.) VIF binds APOBE3G and recruits ubiquitin ligase that degrades it.
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HIV-1 Regulatory Protein:
Degrades CD4 in ER and promotes virus release
VPU
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HIV infxn w/ no clinical tx generally progresses to clinical diseases within
8-10 years
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HIV-1 Regulatory Protein: Downregulates CD4 and MHC class I from the cell surface; induces infected macrophages to secrete MIP-1alpha and -1beta which attracts and activate CD4+ cells and leads to their infxn.
NEF
(SIV and HIV NEF deletion mutants are attenuated in vivo)
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HIV-1 Regulatory Protein: Promotes nuclear translocationof pre-integration complex
VPR
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