Retroviruses Flashcards
what is the goal of viruses
to replicate and persist through time
what is unique about retrovirus replication
violates central dogma - begins with an RNA genome and must convert to DNA
- DNA can be used to create new viral genome or code for viral proteins
vRNA –> DNA –> vRNA
AND
vRNA –> DNA –> mRNA –> protein
what enzyme is required for viruses to be able to go from RNA to DNA
reverse transcriptase
what is the basic, 4 component genome structure of retroviruses
5’ methyl cap
LTR
gag
pol
env
LTR
3’ polyA tail
LTR
flanking long terminal repeats
contain viral promoter, enhancer, termination, and polyadenylation sites
enhancer: recruits transcription factors
promoter: facilitates binding of TFs
gag
group specific antigen
encodes core structural proteins
pol
polymerase
encodes reverse transcriptase, integrase, protease, and endonuclease
env
envelope
encodes membrane glycoproteins, viral attachment protein, and fusion protein
steps of retrovirus replication
- envelope proteins bind to host cell receptors
- fusion, entry, and uncoating of virus into cytoplasm of host cell
- reverse transcription of vRNA –> dsDNA by reverse transcriptase in the cytoplasm
- DNA translocates to nucleus –> integrates into host cell genome to form a provirus
- host cell begins replicating –> provirus gets transcribed into mRNA
- mRNA copies become one of the three: gag, env, viral genome
- all three components transport to cell membrane and get packaged/assembled to form a new virus
- virion blebs off of the cell membrane surrounded by env surface proteins
steps of gag formation
- mRNA gets exported out of nucleus and into cytoplasm
- translated into gag core structural proteins
- transported to cell membrane
steps of env formation
- mRNA gets exported out of nucleus and to the ER
- translated into env membrane proteins
- transported to cell membrane
steps of viral genome formation
- mRNA gets transported out of the nucleus and into the cytoplasm
- two copies of mRNA get transported together to the cell membrane
provirus
form of the virus that is integrated into the host cell genome
virion
new virus that gets released from the host cell
contains two copies of the + sense ssRNA genome
exogenous retroviruses
horizontally transmitted virus that undergoes normal viral replication
endogenous retroviruses
vertically transmitted virus that becomes permanently integrates into the host cell genome
infects the germline (egg/sperm) –> all cells of that offspring will have virus incorporated into genome –> acquires mutations as it continues to be passed in germline
virus gets recognized as “self” - animal does not generate an immune response
are endogenous viruses able to replicate
most are NOT able to replicate and are “inert” fossils in the DNA
can viruses have both an endogenous and exogenous form
yes - 6 retroviruses have both
most exogenous viruses occur without endogenization but some do get endogenization
how does the presence of an endogenous virus affect the ability of the exogenous form to infect host
can restrict or promote infection with exogenous virus
what is a clinical consideration of retrovirus infections
gets integrated into host cell genome - causes PERSISTENT infections
“infected for life” but not always detected on PCR because not viremic once integrated into genome
what are retroviruses classified based on
nucleotide sequence
pathophysiology
pathophysiology of retroviruses
- acute –> rapidly transforming
- chronic –> slowly transforming
- immunosuppressive
nucleotide sequence of retroviruses
orthoretrovirinae: a, B, y, d, e virsues + lentiviruses
spumaretrovirinae: spumaviruses
what are the main alpha retroviruses
ALV, RSV
affects chickens
tumor producing
what are the main beta retroviruses
JSRV, ENTV
affects sheep, goats
tumor producing
what is the main gamma retrovirus
FeLV
affects cats
tumor producing
what is the main delta retrovirus
BLV
affects cows
tumor producing
what are the main lentiviruses
SRLV, FIV, EIA
affects sheep/goats, cats, horses (respectively)
immunosuppressive
what are the mechanisms of retrovirus oncogenesis
- insertional mutagenesis
- oncogene capture
- oncogenic viral protein
tumor suppressor genes (TSGs)
suppresses/slows down the cell cycle
Rb and p53
proto-oncogenes
signals for the cell cycle to continue
insertional mutagenesis
integration of the retrovirus in the genome:
1. within a TSG: causes TSG dysfunction –> unable to suppress cell cycle
2. near a porto-oncogene promoter: creates powerful promoter (LTR) –> cis-activation of proto-oncogene –> rapid recruitment of host cell machinery –> rapid cell division
causes unregulated, rapid cell division –> tumor formation
cis-activation vs trans-activation
cis: activation of a nearby host gene
trans: activation of a distant host gene
effect of endogenous murine leukemia virus on exogenous infection
endogenous MLV is protective against exogenous MLV infection by increasing transcription of antiretroviral restriction factors that limit the ability of MLV to infect host cells
oncogene capture
retrovirus co-opts proto-oncogenes from the host cells and integrates it into their own viral genome
often LACKS regulatory elements –> allows them to replicate unregulated
are retroviruses that use oncogene capture able to replicate on their own
most are NOT able to replicate - require a helper virus
integration of proto-oncogene into genome causes loss of part of their own genome
exception: RSV - able to conserve viral genome
proto-oncogene
comes from the host cell genome
ex. C-src
oncogene
transcribed version of the proto-oncogene once integrated into viral genome
ex. V-src
oncogenic viral protein
retrovirus directly encodes the oncogenic viral protein via one of two mechanisms:
1. virus has an additional oncogene segment in its genome (ex. BLV)
2. virus encodes oncogenic proteins directly though their env protiein
tax
potent transcriptional activator that promotes production and transcription of viral genome via positive feedback and able to activate other host genes via trans-activation
