Review of Class Format and Syllabus Dr Sara
Review of Class Format and Syllabus Dr. Sara Ruane 407 Boyden Hall sara. ruane@rutgers. edu www. sararuane. wordpress. com
Evolution Lectures 1 & 2: (Chapter 1 of Herron & Freeman) Why study Evolution? & A Case Study: HIV Evolution video clips accompany https: //www. youtube. com/watch? v=34 Ge. Ua 7 Rzv. Y https: //www. youtube. com/watch? v=Kvknt. XYn. KW 0 https: //www. youtube. com/watch? v=guh 837 QJIi. A (minute ~43)
Why Study Evolution? “Light will be thrown on the origin of man and history” -Darwin “Nothing in biology makes sense except in the light of evolution” -Dobzhansky
Why Study Evolution? Understanding evolution can be life and death matters Evolution matters outside of the class and lab!
Why Study Evolution? A Case Study: HIV Evolution AIDS recognized 1981, HIV identified Always fatal (at time) Transmitted from someone who has it via body fluids directly
Figure 1 -1 Geographic distribution of HIV infections (in 2012)
Why Study Evolution? A Case Study: HIV Evolution Antivirals lowers risk of infection -stop/halt/slow development of virus Change human behaviors?
Figure 1 -3 b
What is HIV? Virus-an intracellular parasite incapable of reproducing its own HIV enters cell, enzyme reverse transcriptase liberates single-stranded RNA genome, & copies it into a complementary DNA molecule to replicate itself. Uses the host cell resources/machinery for replication, killing host cell in process (T-cells)
HIV specifically using T-cell hosts, part of the immune system Uses resources of the host cell for entire process (hard to design drugs that don’t harm host cells!) https: //www. youtube. com/watch? v =_x 13 XDNr 39 o Video on how HIV attacks our immune system
How does HIV cause AIDS? Depletes supply of T-cells, infects new active T-cells, eventually few T-cells Allows other pathogens to enter the weakened immune system, body can’t fight them off
Figure 1 -9
How can HIV be stopped? Keep it from replicating! Goal: inhibit the HIV life cycle First drug: AZT, inhibits the reverse transcriptase that is part of virus replication
Figure 1 -10 Rev. transcriptase enzyme gets nucleotides from host cell, builds a DNA strand to complement the virus’s RNA strand AZT mimics the host nucleotides, but doesn’t have right attachment site for virus to continue the replication (halted), no replication of virus
Problems with AZT Worked in tests (side effects for host cells) Patient cells or virus could change Tests showed not patient cells So HIV virions must change?
How can HIV be stopped? Resistance to AZT occurs quickly! Populations of virions change over time
How does AZT resistance happen? During successful HIV replications, errors may occur. Randomly, these errors may make the virus better at recognizing the AZT nucleotides and remove/not use them during replication. Continues replication in presence of drug.
HIV Evolution (by Natural Selection) • Replication errors = random mutations in the rev. transcriptase gene. Virions carrying mutant rev. transcriptase gene produce versions of the rev. transcriptase enzyme that vary in resistance to AZT • The mutant virions pass mutant rev. transcriptase genes to their offspring, in other words, AZT resistance is heritable • During treatment with AZT, some virions are better able to survive and reproduce than others • The virions that persist in presence of AZT are the mutant form (mutant form = better survival)
Back Mutations • AZT resistant populations do not reproduce efficiently when AZT treatment is halted • Back-mutations restore AZT resistant rev. trans. To the normal rev. trans when AZT is not present. The original configuration is then favored.
Understanding Resistance Evolution and Further Treatments • Since HIV evolves so quickly, what we need is to increase the number of mutations a virion needs to survive. We would like to do this so that the number of mutations required becomes prohibitive to survival • Add new pressures…a cocktail of drugs: – – Rev. trans. inhib Protease inhib. Fusion inhib Integrase inhib
Selection Pressure from Killer T-4 Cells • Killer T-4 cells Recognize epitopes (viral proteins displayed on the surface of the infected cell) • HIV evades detection by changing epitopes • HIV produces 10 -100 million virions a day, with an abundance of mutation and changed epitopes • Over 10 years, virion’s gp 120 gene diverged by 8%
Why does divergence asymptote? Immune System Collapse, therefore no selection to make novel epitopes
Host Switching • CCR 5 and CXCR 4 are two types of co-receptors found on T 4 cells. CCR 5 replicates quickly and thus are infected first • As infection increases, HIV will switch to CXCR 4 (b/c they begin to divide more rapidly to take over for the decreasing CCR 5) • This ultimately hastens the death of the host. Why would this happen?
Evolution is Not Goal Oriented • HIV population in a single host evolves itself out of existence by killing that host…unless it spreads • Those that attack both CCR 5 and CXCR 4 are probably good at replication and infection • This helps them overcome another level of selection…strains that reproduce more are found in higher quantities, are thus able to become transmitted to other hosts more efficiently!!! • Therefore their lineage does not die
Benign Forms of Aids and Low Transmission • Sydney Bloodbank: special strain of aids only infects CXCR 4. Not as deadly b/c it does not reproduce efficiently • Lack of portion of Nef protein does not allow the virus to gain entry into cell, boost viral replication, and thus less immune response from host • HIV-2 poor transmission among hosts and not as deadly • Why are these strains so rare in nature? Inability to reproduce efficiently limits the concentration of virions in hosts blood, thus poor transmission.
Review of the two levels of selection in nature against AIDS • Variation in levels of ability for virus to survive and reproduce in host • Variation in ability to become transmitted from host to host • These two types of selection are obviously tied. Think of an example where being good at the first limits being good at the second?
Selection Against Host and Response • Some humans have unusual coreceptors on the surfaces of their cells • Deletion in CCR gene, bars virion from entrance • In parts of Europe >14% of population has this gene. Why? • Natural selection? Drift? …small populations…Vikings?
HIV Origin and Reconstruction of Evolutionary History • Phylogeny (tree)…diagrams evolutionary relationships…it’s a hypothesis • How to read a tree: – Node = branching point for common ancestors – Branches (internodes)…line of evolution leading to descendants – Branch length may indicate genetic distance or time (in some instances) – Monophyly, paraphyly, and polyphyly (later lecture!)
1. 2. 3. 4. HIV-1 and HIV-2 - Not related HIV-2 in humans related to Sooty Mangabey SIVcpz was transmitted to humans by chimps
Transmitted from chimps 3 times
When Did HIV Move from Chimps to Humans?
Legal Cases Involving Aids Evolution • 1998 -Lafayette, LA, Woman claimed physician injected her with HIV infected patient • In Florida a woman claimed to have obtained HIV from dentist • Able to use genetic divergence to trace back virus to infector and prosecute
Man Cured of AIDS-Berlin Patient • Had both AIDS and blood cancer • Some HIV virions dormant at any given time…so not affected by drugs during dormancy • Had HIV for 10 years, developed cancer at age 40
Was given intense chemo/destroyed immune cells Stem cell donor match from donor with resistance mutation to HIV (CCR 5 delta 32. )…all his own immune cells killed by chemo treatment Immune system repopulated by resistant T cells (also killed off many original T cells, which may have had dormant virions in them) Had to stop taking HIV drugs during cancer treatment…no detectable levels of HIV found in any tissues (since 2007)
Not clear… The resistant T cells (delta 32 mutation) are only resistant to CCXR 5 pathway… Mutated HIV that uses CCXR 4 should still be able to replicate and attack Most patients with long term HIV have both types in their system…including the Berlin man Unclear why/how CCXR 4 pathway using virions did not replicate or were eliminated
Why study Evolution? & A Case Study: HIV Evolution video clips accompany https: //www. youtube. com/watch? v=34 Ge. Ua 7 Rzv. Y https: //www. youtube. com/watch? v=Kvknt. XYn. KW 0
- Slides: 42