Virology Flashcards
2 theories of how viruses fit into the tree of life?
- RNA world theory: life arose with the viruses
- Reductionist theory: viruses came after cellular life, they are reduced versions of cellular organisms
* mimiviruses and megaviruses may be the missing link
What are Ribozymes?
- RNAs that can catalyze specific reactions (similar to enzymes)
- ribozymes (produced in lab) can catalyze their own synthesis
- natural fans: cleave RNA, viral replication, tRNA biosynthesis
Examples of DNA viruses?
- herpes, smallpox, mimivirus
DNA -> RNA -> protein
Examples of RNA viruses?
- Rhino, influenza, SARS
RNA-> protein
Examples of Retroviruses?
- HIV
RNA -> DNA (through reverse transcriptase) -> RNA -> protein
Pros and cons of a DNA virus
pros: lower mutation rate, more stable (can carry more genes), no dsRNA phase
cons: lower mutation rate, slower replication
Pros and cons of RNA virus
pros: fast replication rate, high mutation rate
cons: high mutation rate, limited sequence space (less stable), dsRNA phase, degrades faster, humans don’t have dsRNA (easy to identify)
What happens frequently in reverse transcriptase?
- 1 mutation per virus, much more common in retrovirus
What are some challenges in developing HIV vaccines?
- high mutation rate
- integration into host genome
- infects immune privileged region of host
- targets immune system
- multiple serotypes
- costs and time involved in development
- vaccine safety concerns
What is the diversity in HIV strains
- 25-30% in circulating HIV strains
- mutation rate is - 1 base change per genome
What effects can a mutation have on a virus?
- not all mutations are advantageous: some hinder the virus, some prevent virus replication, and some are silent ( have no effect)
- Some allow a competitive advantage, and some allow escape from antiviral drugs
antiretroviral drug classes
- reverse transcriptase inhibitors (NRTIs)
- Fusion/entry inhibitors
- Integrase inhibitors
- Protease inhibitors
Difference b/t nucleosides and nucleotides?
- nucleosides: sugar+ base
3 phosphorylation events required for activity
-nucleotide: sugar+base+phosphate, 2 phosphorylation events required for activity
Nucleoside analogs??
prevent adding of next nucleoside on to the chain looks like nucleoside but doesn’t have site to bind to next nucleoside so it is a chain terminator
3TC (Epivir/Iamivudine)
- FDA approved 1995
- reverse transcriptase inhibitor
- nucleoside analog: mimics cytidine -> acts as a chain terminator
DLV (Rescriptor/delavirdine)
- FDA approved 1997
- Reverse transcriptase inhibitor (non-nucleoside)
- binds RT catalytic site, blocking polymerase fxn
Reverse transcriptase mutations?
- only takes 1 or 2 mutations of virus to make reverse transcriptase drugs ineffective
DRV (darunavir/Prezista)
- FDA approved 2006
protease inhibitor: binds the active site preventing the processing of viral protein precursors - compete with the natural substrate
EVG (Elvitegravir)
- FDA approved 2014
- Allosteric integrase inhibitor (prevents functional multimers from forming (dimers of dimers= tetramer)
MVC (Selzentry/maraviroc)
- FDA approved 2007
- entry inhibitor (receptor antagonist)
drug binds receptor (CCR5), preventing HIV from binding - mutant bind receptor in a different conformation
T20 (Fuzeon/entuvirtide)
- FDA approved 2003
- HIV fusion inhibitor
- mimics viral protein to displace it in the fusion complex (binds p41 and prevents formation of the entry pore)
Vacc-4x
therapeutic vaccine
in clinical trials 9phase 2)
peptide vaccine -> dropped viral load but didn’t slow CD4 T cell decline
SB-728T gene therapy
in phase 1/2 trials
modifies a CD4 T cell CCR5 receptor, making it non-functional, prevents HIV entry
- harvest patient T cells, make mutation and replicate, and put back into pt
- this mutation occurs naturally and confers HIV resistance
- expensive and time consuming
Interleukin
IL-7: trial abandoned b/c IL-7 increased the number of CD4+ T cells but that increased viral load too
IL-2: increased number of CD4+ T cells but didn’t significantly decrease clinical events or death, even when combined with antiretrovirals
Chloroquine
- antimalarial
- drops pH in vacuoles
- disrupts Env protein gp120, inhibits maturation
- drops viral load, doesn’t affect T cells so doesn’t stop T cells from decreasing
What can be done to prevent escape mutants?
- combo drugs Atripla (3) Complera (4) Stribild (4) Triumeq (3) Combivir (4)
Difference b/t viral and human evolution
- humans: complicated, multiple polymerases, error prone, and non-error prone sites, at most 1 mistake/ 100 million, proofreading and correcting machinery, and we only have a couple kids in a lifetime
- viruses: often 1 mistake per genome, no proofreading, often whole populations knocked out, billions of genomes made per day
Potential effects of viruses on human evolution
- immune system diversity
- ABO blood system (decreased A allele frequency after smallpox epidemic)
- endogenous retroviruses (1% of genome)
- cell surface mutations (ex: CCR5)
What does it mean that viruses are a part of us?
- they are a part of our regulation of host gene expression
- they take part in placental formation
- reason why there is immunosuppression during pregnancy
- promoters, enhancers and proteins can be coopted by the host for its own purposes (placenta formation)
- can be fixed or mobile, and no human endogenous retroviruses (ERVs) are capable of replication
What are endogenous retroviruses (ERVs) associated with in humans?
- MS
- schizophrenia
- cancer
- autoimmune diseases
- amayotrophic lateral sclerosis (ALS)
Mutation in humans that allow them to be resistant to HIV infection?
-mutation prevents an HIV corrector from being made by the cell, and therefore HIV can’t infect people with this mutation (CCR5 delta 32 mutation) -> positive selection for this mutation
Hypothesis for why mutation has been selected in specific regions (Europe, Asia, North Africa)?
- either plague (bacteria) or smallpox (virus)
How can humans drive viral evolution?
- each infection is a population
- zoonosis: virus mutating to be able to pass from one species to another
- humans as an enviro: immune system and viral recombination
- antiviral drugs: promote resistance and mutations
difference b/t epidemic and pandemic?
- epidemic: greater than expected incidence “outbreak”
ex: SARS, Dengue - pandemic: spread over a large geographical area (b/t continents) ex: HIV, smallpox, H1N1 (seasonal flu not a pandemic)
Why do viruses start epidemics and then pandemics?
- increased virulence (severity of disease or ability to spread)
- intro into novel setting
- changes in host susceptibility to the infectious agent
- changes in host exposure to the infectious agent
Transmission modes of viruses?
- iatrogenic (blood transfusion)
- vertical
- vector borne
- droplet
- fecal-oral
- sexually
Zoonosis?
- disease that can pass from another species to humans or humans to another species
- often diseases are adapted to their host and more deadly when they jump hosts (ex: Ebola)
- Many viruses can pass from animal reservoir to humans, but have difficulties transmitting human to human
- issues: domestication, deforestation, bush meat
BSL-4 viruses
- aerosol viruses
- severe/fatal viruses w/ no vaccines or other txs:
- bolivian and argentine hemorrhagic fevers
- marburg virus
- ebola virus
- lassa virus
- crimean-congo hemorrhagic fever
- small pox
