Exam 1

Why Study Evolution

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• Fundamental, organizing principle of biology

What is Evolutionary Biology

• Study of how pops change through time

• Study of adaption and diversity

• Evolution= fact explained via principles (evolutionary theory)

Fundamental ?'s

• Where did earths organisms come from?

• How did they become well suited to enviroment

• (primary= natural selection

  • Natural selection= primary method, widely misunderstood

  • Other methods= incest, genetic drift, mutation

Practical Applications of Evolutionary Analysis

• Antibiotic resistence

• Pathogenic virulence/transmission

• History of dieases and sources of infection (host switch)

• HIV, H1N1, ebola, west nile, sars-cov2

Case for Evolutionary thinking: Understanding HIV W/ Implications for COVID

• Evolution of HIV

• Strains of HIV susceptible to treatment (treatable) -> time/natural selection -> strains of HIV resistant to treatment (untreatable)

Case for Evolutionary thinking: Understanding HIV W/ Implications for COVID

• A contemporary issue introducing evolutionary analysis

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• Illustrating ?'s in evolutionary biology

Case for Evolutionary thinking: Understanding HIV W/ Implications for COVID

• Natural history of HIV

• Need obligate host to replicate (alive= evolution) (destroy cells)

• Bodily fluids (need specific cells= CD4, CCR5) (not saliva)

• Decreased life expectancy in countries greatly affected

Case for Evolutionary thinking: Understanding HIV W/ Implications for COVID

• What is HIV??

• Like other viruses, needs host cell to replicate

• Unique= infects and ultimately destroys human cell

• Integrates DNA w/ host DNA and uses host cell machinery to make new viral cells

• Virion->binding->fusing->dna synthesis (no longer RNA)->DNA splicing->transcription->translation->new virion assembly->budding->maturation

Case for Evolutionary thinking: Understanding HIV W/ Implications for COVID

• Important proteins (HIV)

• Integrase (integrates reverse transcription into host DNA), protease (integrate reverse transcription), reverse transcriptase (helps make mRNA to make virus), GP120&41 (2 surface proteins)

Case for Evolutionary thinking: Understanding HIV W/ Implications for COVID

• Important proteins (Host)

• Surface proteins (CD4, co-receptor CCR5)

Case for Evolutionary thinking: Understanding HIV W/ Implications for COVID

• How does HIV cause AIDS

• Targets cells with CD4 receptors and CCR5 co-receptors

  • Macrophage (clean up particles/infected cells), effector helper T cell (mark pathogen/infection), memory helper T cells (from effector)

• The formation of effector t-helper cells

  • Go to naïve helper T cell and code to find pathogen, CD4 receptors, talk to B cells (make antibodies), release cytokines to kill virus, most effector T cells die at end

• Immunity becomes more effective after exposure

  • Response to primary exposure= 10-17 day peak, 2nd exposure= 2-7 day peak (primed)

Case for Evolutionary thinking: Understanding HIV W/ Implications for COVID

• How does HIV cause AIDS

• Summary

• Dendritic cells activate naïve helper T cell to produce effector helper T-cells (virus specific)

• Effectors activate

• Some effector t-cells become memory cells

• Critical role of T-cells

Case for Evolutionary thinking: Understanding HIV W/ Implications for COVID

• How does HIV cause AIDS

• Summary

• Effectors activate

• B cells to produce virus specific antibodies

• Killer T-cells

• Macrophages

Case for Evolutionary thinking: Understanding HIV W/ Implications for COVID

• How does HIV cause AIDS

• Summary

• Critical role of T-cells

• By targeting, HIV can severely limit or destroy the ability of immune system to function

• Helper T-cells crucial to all of the following: b-cells to make antibodies, killer t-cells to destroy infected host cells, macrophages to destroy viruses/infected cells, memory helper t-cells to produce early activation of the immune system for secondary response

Case for Evolutionary thinking: Understanding HIV W/ Implications for COVID

• Secondary effects

• HIV increases infection opportunities by stimulating the immune system to make more CD4/CCR5

• Constant battle b/w HIV and host exhausts system

Case for Evolutionary thinking: Understanding HIV W/ Implications for COVID

• Untreated as 3 phases

• Acute phase (host shows general symptoms of viral infection, viral loads spike)->chronic (host largely asymptomatic, viral lows low)->AIDS (immune system collapse, viral load high, leaves host vulnerable to opportunistic infection)

Case for Evolutionary thinking: Understanding HIV W/ Implications for COVID

• Untreated progresses to AIDS

• T-cell count falls to below 200

• Immune system fails to work

• Opportunistic diseases

Case for Evolutionary thinking: Understanding HIV W/ Implications for COVID

• HIV therapy

  • Reverse transcription, integrase, protease

  • Reverse transcription:

• AZT= azidothymidine- a thymidine (thymine) mimic

  • Stops building of DNA, resistance= problem (HIV not person), favor

  • Evolves by natural selection

    • Random mutation generates variation in HIV variation

    • 1 mutation confers resistance to AZT which is inherited by daughter cells

    • w/ AZT, survive and reproduce, better than other forms

    • Become majority

Case for Evolutionary thinking: Understanding HIV W/ Implications for COVID

• HIV evolution and treatment

• AZT

• Protease inhibitors= prevents formation of mature virus

• Fusion inhibitors= interferes gp120/41 to prevent entry to host cell 

• Integrase inhibitors= interferes integration of HIV into host DNA

• Coreceptors inhibitors= interferes attachment to CCR5 coreceptor

Case for Evolutionary thinking: Understanding HIV W/ Implications for COVID

• HIV evolution and treatment

• HAART= cocktail therapy

• Highly active antiretroviral therapy

• 3 different (2 reverse transcriptase inhibitor, protease inhibitor typically)

• Why more effective= decreases resistance chances

  • Increases # of simultaneous mutations needed to result in evolution of resistance

  • Human immune system fights by maturing T-Cells

  • Best at evading- live

  • Pop. That can evade eventually kills host

Case for Evolutionary thinking: Understanding HIV W/ Implications for COVID

• HIV predicting the future

  • What ancestor can we learn from HIV ancestor= SIV

• African green monkey= 50% of adults who are natural host are infected, natural host tolerate w/o symptoms

• Macoque developed aids when infected

• Suggest natural hosts of SIV have evolved resistance/tolerance

Case for Evolutionary thinking: Understanding HIV W/ Implications for COVID

• HIV predicting the future

• What might we expect to happen to maintain persistence of HIV

• Less virulent forms, evolution of begin form/tolerance, non-lethal strain

• Beign strains exist (HIV2= independent derived from, HIV= no common ancestor, HIV2=less deadly)

• Virulence= viral load and intensity of symptoms (increases rate of transmission, viral load= virulence) (virulence to transmit to success)

• HIV1= transmission rates higher

  • Babies to mom is 20-30X higher

  • Sexual contact is 5-10X higher

  • Likely not evolving to be less virulent (longer in place=evolve more)

Case for Evolutionary thinking: Understanding HIV W/ Implications for COVID

• HIV predicting the future

• Variant of allele that codes for CCR5 coreceptor (32 allele) occurs naturally in human pops resulting in loss of CCR5 coreceptor on T-cells

• Humans homozygous for 32: resistant to HIV infections (western europe)

• Exposable favors 32 (selection favors), variant that favors- not africa

Case for Evolutionary thinking: Understanding HIV W/ Implications for COVID

• HIV predicting the future

• Other natural sources of resistance (humans)

• Variation in CD4 receptors receptor alleles in kenya= partial resistance

• Resistant allele occurs at frequency of 15%

Case for Evolutionary thinking: Understanding HIV W/ Implications for COVID

• HIV predicting the future

• HIV resistance evolution

• Too soon to tell

• Highest frequency of 32 allele found in regions of lowest prevalence (low presence)

• Relationship b/w HIV and humans too young to have resulted in significant evolutionary change in host

Case for Evolutionary thinking: Understanding HIV W/ Implications for COVID

• HIV predicting the future

• Origins of HIV= phylogency (phylogenetic analysis)

  • 
    

• HIV1 and 2 not closely related= 2 viruses

  • HIV1= SIV-cpz (SIV-cpz= jumped from host/intermediate host 4X, 4 lineages of HIV1)

  • HIV2= SIV-sm

  • Host jump (animals= bush meat hunting/butchering)

 

What is HIV

• Like other viruses, needs host cell to replicate

• Unique= infects and ultimately destroys human cell

• Integrates DNA w/ host DNA and uses host cell machinery to make new viral cells

• Virion->binding->fusing->dna synthesis (no longer RNA)->DNA splicing->transcription->translation->new virion assembly->budding->maturation

What are the important parts of HIV that are essential to understand the HIV-host interactions?

• Integrase (integrates reverse transcription into host DNA), protease (integrate reverse transcription), reverse transcriptase (helps make mRNA to make virus), GP120&41 (2 surface proteins)

How does it cause disease?

• Targets cells with CD4 receptors and CCR5 co-receptors

  • Macrophage (clean up particles/infected cells), effector helper T cell (mark pathogen/infection), memory helper T cells (from effector)

• The formation of effector t-helper cells

  • Go to naïve helper T cell and code to find pathogen, CD4 receptors, talk to B cells (make antibodies), release cytokines to kill virus, most effector T cells die at end

• Immunity becomes more effective after exposure

  • Response to primary exposure= 10-17 day peak, 2nd exposure= 2-7 day peak (primed)

How does it cause disease?

Summary

• Dendritic cells activate naïve helper T cell to produce effector helper T-cells (virus specific)

• Effectors activate

  • B cells to produce virus specific antibodies

  • Killer T-cells

  • Macrophages

• Some effector t-cells become memory cells

• Critical role of T-cells

  • By targeting, HIV can severely limit or destroy the ability of immune system to function

  • Helper T-cells crucial to all of the following: b-cells to make antibodies, killer t-cells to destroy infected host cells, macrophages to destroy viruses/infected cells, memory helper t-cells to produce early activation of the immune system for secondary response

How does it cause disease?

• Secondary effects

• HIV increases infection opportunities by stimulating the immune system to make more CD4/CCR5

• Constant battle b/w HIV and host exhausts system

How does it cause disease?

• Untreated as 3 phases

• 
  

• Acute phase (host shows general symptoms of viral infection, viral loads spike)->chronic (host largely asymptomatic, viral lows low)->AIDS (immune system collapse, viral load high, leaves host vulnerable to opportunistic infection)

• 
  

How does it cause disease?

• Untreated progresses to AIDS

• T-cell count falls to below 200

• Immune system fails to work

• Opportunistic diseases

What are the targets of HIV therapy and how do they work?

Reverse transcription: AZT=

• azidothymidine- a thymidine (thymine) mimic

  • Stops building of DNA, resistance= problem (HIV not person), favor

  • Evolves by natural selection

    • Random mutation generates variation in HIV variation

    • 1 mutation confers resistance to AZT which is inherited by daughter cells

    • w/ AZT, survive and reproduce, better than other forms

    • Become majority

What are the targets of HIV therapy and how do they work?

• Protease inhibitors= prevents formation of mature virus

• Fusion inhibitors= interferes gp120/41 to prevent entry to host cell 

• Integrase inhibitors= interferes integration of HIV into host DNA

• Coreceptors inhibitors= interferes attachment to CCR5 coreceptor

What are the targets of HIV therapy and how do they work?

• cocktail therapy

• Highly active antiretroviral therapy

• 3 different (2 reverse transcriptase inhibitor, protease inhibitor typically)

• Why more effective= decreases resistance chances

  • Increases # of simultaneous mutations needed to result in evolution of resistance

  • Human immune system fights by maturing T-Cells

  • Best at evading- live

  • Pop. That can evade eventually kills host

How does evolution by natural selection impact HIV therapies?

• 
  

  • Random mutation generates variation in HIV variation

  • 1 mutation confers resistance to AZT which is inherited by daughter cells

  • w/ AZT, survive and reproduce, better than other forms

  • Become majority

What are the two primary selections pressures that impact HIV evolution? What are the outcomes of the two primary selection pressures on HIV?

• Highly active antiretroviral therapy: can resist immunity (therapies can cause immunity)

• Host immune system= can delay eventual death with treatments to fight specific strains/processes

• 
  

What can we say about the continued persistence/evolution of HIV in human? Discuss the following:

The evolution of a benign strain.

The delta-32 allele

• Less virulent forms, evolution of begin form/tolerance, non-lethal strain

• Beign strains exist (HIV2= independent derived from, HIV= no common ancestor, HIV2=less deadly)

• Virulence= viral load and intensity of symptoms (increases rate of transmission, viral load= virulence) (virulence to transmit to success)

• Variant of allele that codes for CCR5 coreceptor (32 allele) occurs naturally in human pops resulting in loss of CCR5 coreceptor on T-cells

  • Humans homozygous for 32: resistant to HIV infections (western europe)

  • Exposable favors 32 (selection favors), variant that favors- not africa

How does phylogenetic analysis allow us to understand:

a. The origin(s) of HIV

b. Sources of infection

• HIV1 and 2 not closely related= 2 viruses

  • HIV1= SIV-cpz (SIV-cpz= jumped from host/intermediate host 4X, 4 lineages of HIV1)

  • HIV2= SIV-sm

  • Host jump (animals= bush meat hunting/butchering)

What is the evidence that SARS-CoV2 is evolving? Explain how the evidence supports the evolution of SARS-CoV2.

• Large genome= repair enzymes (lower mutation rate, less different strains)

• Closest= a SARS-COV in bats/pangolin not SARS-COV

• Natural selection, immune system learned to recognize= strains (evolution)

• Omicron= no longer got into lower respiratory, evolution, transmits more quickly/ reproduces fastest

What does the phylogeny of SARS-CoV2 and its relatives tell you about the origins of SARS-CoV2? SARS-CoV? Hint: Are SARS-CoV2 and SARS-CoV each other’s closest relatives?

• Closest= a SARS-COV in bats/pangolin not SARS-COV

• they have a common ancestor but differ in their recent lineages. this makes them practically two different viruses because SARS-CoV2 is more closely related to bats/pangolin while SARS-COV is not closely related to bats/pangolins, means SARS-CoV2 is more zoonotic which affects treatment/how it reacts

What are the chances of developing a vaccine for HIV? Hint: How do vaccines work

• High diversity (within groups-2% difference, b/w groups= 35% difference, 1 and 2=55% difference)

• Fast mutation rate (producing new genetically unique variants)

• Mutiple points of origin (HIV1 possibly 3 separate jumps from SLVCPZ, 2 not closely related to 1)

Case for Evolutionary thinking: Understanding HIV W/ Implications for COVID

• Timing

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• Emergence of HIV in Africa corresponds with the beginning of pop growth in major cities

Case for Evolutionary thinking: Understanding HIV W/ Implications for COVID

• Forensic phylogeny

• Dentist murder (dentist took blood of infected and put it in nurse, use phylogenetic to map strain/connect it to patient (didn't have regional strain)

Case for Evolutionary thinking: Understanding HIV W/ Implications for COVID

• Implications for cure

  • Vaccine development is difficult b/c…

• High diversity (within groups-2% difference, b/w groups= 35% difference, 1 and 2=55% difference)

• Fast mutation rate (producing new genetically unique variants)

• Mutiple points of origin (HIV1 possibly 3 separate jumps from SLVCPZ, 2 not closely related to 1)

Case for Evolutionary thinking: Understanding HIV W/ Implications for COVID

• Implications for cure

• Botswana: eliminated horizontal transmission of HIV in 20 yrs thus eliminated pediatric HIV/AIDS

• Free ART for pregnant women

• Free formula for 12 months

• HIV clinics and staff

• HIV education free

• Exhaustive data

• Policies w/ data driven decisions

SARS COV-2

• Spike proteins bind to cell-surface ACE2 receptors -> virus hijacks hosts cellular machinery to express viral proteins and replicate -> mutation may occur and alter spike, new virus released

• Cause life expectancy to decrease

• Single stranded RNA (directly turned into virus, no reverse transmission

• Large genome= repair enzymes (lower mutation rate, less different strains)

• Closest= a SARS-COV in bats/pangolin not SARS-COV

• Natural selection, immune system learned to recognize= strains (evolution)

• Omicron= no longer got into lower respiratory, evolution, transmits more quickly/ reproduces fastest

SARS COV-2

• Mrna vaccine

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• Piece of spike protein that’s recognizable, injected and is transcribed, degraded once transcribed, have little pieces to build memory for

Dangerous Idea (Darwin)

• Evolution= change in pop over time

• Natural selection= primary mechanisms

  • New traits

  • New species

  • Evidence= domestication

Requirements for natural selection

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• Individuals within pops are variable

• Variations passed from parents to offspring

• More individual are produced than survive= compete

• Some variants are more successful

• Variation generated by random mutation (heritable)

  • Caused by errors in replication (meiosis)

  • Differential survival/repro not random

  • Most favorable= favored, not= eliminated

 

Natural Selection

• 
  

• Produces descent with modification

• Acts on individuals but changes pops

• Favors most fit individuals  (best at survival/repro)

• Results in adaption -> trait that increases fitness of individual when compared to others

• Verified w/ empirical variation