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Why is HIV Fatal

Why is HIV Fatal. Short-Sighted Evolution Selection thinking (Natural Selection) Host dying is clearly bad Heritable variation among humans Eventually there will be resistance. Why is HIV Fatal. Invade host Replicate rapidly Error prone rev. trans. (genetic variation)

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Why is HIV Fatal

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  1. Why is HIV Fatal • Short-Sighted Evolution • Selection thinking (Natural Selection) • Host dying is clearly bad • Heritable variation among humans • Eventually there will be resistance

  2. Why is HIV Fatal Invade host Replicate rapidly Error prone rev. trans. (genetic variation) Antibodies and killer T- Cells recognize epitopes Thus killing virions

  3. Evolution of HIV populations

  4. Genetic variation in population After 7 years leveled out, why? Virions with novel epitopes survived better. This advantage seemed to disappear after 7 years, The strain able to replicate quickly spread the fastest eventually killing the host. HIV evolves itself right out of existence.

  5. Correlation between Lethality and transmission • Rare strains kill their host more slowly, if at all, than do common strains • Sydney Bloodbank cohort. • 5 recipients and donor followed 18-20yrs • 3 have no symptoms (normal cd4 cnts) • 2 and donor have declining cd4 cnts

  6. Correlation between Lethality and transmission • Coreceptor switching • Uses CXCR4 instead of CCR5 • Takes much longer to replicate using CXCR4 • Missing part of nef • Nef helps gain entry into host cells, boosts replication and helps HIV-infected cells evade hosts immune system

  7. Selection • Remember, all hosts eventually die. • To persist the virus must colonize new hosts • 1st level- genetic variation to survive • 2nd level- differences in host transmission rates • Thus good transmitters more common • HIV-1 and HIV-2

  8. Transmission Rate Hypothesis • Paul Ewald • If transmission of sexually transmitted diseases is frequent, virulent viruses are naturally selected • If transmission is low, less virulent strains are selected for • Cost/Benefit ratio for the virus

  9. Transmission Rate Hypothesis

  10. Transmission Rate Hypothesis • Hypothesis states that when the two assumptions hold: • virulent strains of sexually transmitted pathogens should spread through a population most efficiently when rates of partner change are high, • while benign strains should spread most efficiently when rates of partner change are low

  11. Transmission Rate Hypothesis • If monogamy is widespread then virulence should drop • If promiscuity is prevalent, then virulence should increase (transmission) • Virulent strains are dominant • Sex workers in Africa • Homosexual men in USA/Europe

  12. Why are Some People Resistant to HIV Infection? • Some individuals are repeatedly exposed to HIV without becoming infected • Others become infected but are Long-Term Nonprogressors • Magic Johnson, so far • May be linked to type of coreceptors on CD4 cells • D32 allele of CCR5 • 9% Caucasians have this allele • 0% in Asians and Africans • Will the frequency of this allele increase?

  13. Why are Some People Resistant to HIV Infection?

  14. Could an HIV Vaccine Work? • Our immune system recognizes non-self entities by receptors called epitopes • Epitope is the virus’ signature • Our T cells recognize the epitope and mount a response • A vaccine is a dead or incomplete epitope • When we encounter the real virus, our body is already waiting with antibodies for that virus

  15. Could an HIV Vaccine Work? • To combat HIV, we need to create a vaccine with most or all of the HIV epitopes • Must understand epitope diversity to do this • Must reconstruct evolutionary history of virus • Sample HIV from all over world to construct an evolutionary tree of HIV

  16. Reconstructing Evolutionary History • Attempt to reconstruct a phylogeny • Hypothesis of evolutionary relationships • Tree of evolutionary relationships = cladogram or phylogenetic tree • Assume genetically similar individuals are most closely related to each other • Cladogram of Immune Deficiency Viruses

  17. Reconstructing Evolutionary History • Most closely related to primate SIVs • Feng Gao made a phylogeny of HIV-1, HIV-2, and many SIVs • Horizontal branch lengths indicate amount of evolution along a branch • Vertical lengths not informative • Just for ease of understanding

  18. Reconstructing Evolutionary History • HIV-1 appears to have arisen from chimpanzees • HIV-2 arose from sooty mangabeys • Two viruses independently entered humans • Probably from eating those two species • Chimpanzees in east Africa • Monkeys in west Africa • Examine HIV-1 tree more closely

  19. Reconstructing Evolutionary History • HIV-1 entered humans from chimpanzees multiple times • Important to study SIVcpz because it is so closely related to HIV-1 • Is not lethal to chimps • Branch lengths along all lineages are high • Indicates very fast evolution

  20. Bushmeat

  21. How does knowledge of phylogeny of HIV help the fight against it? • Search for vaccine may be futile • HIV epitopes evolve too fast to have enough in vaccine for it to work • Resistant alleles like D32 should increase in human population • New drugs will slow down onset of AIDS • Combination therapies

  22. When did HIV evolve? Can we date the common ancestor of HIV-1 strains of group M

  23. 1931 (1915 – 1941) When did HIV evolve?

  24. Chapter 2: Evidence for Evolution

  25. CHARLESDARWIN(1809-1882)

  26. Two Basic Tenets (in Origin…) • All organisms descended with modification from common ancestors • Chief agent of modification is natural selection on variation. This was the first tree of life with branches, the first with a precise mechanism, and the first to emphasize variation as elemental

  27. Charles Darwin • English naturalist • Participated in Voyage of the Beagle around South America • Did not invent the theory of evolution • Discovered the mechanism of how evolution works • Theory of Natural Selection

  28. Darwin’s Era • Theory of Special Creation • Each organism created by God independently • Species were immutable • Never changed • The earth is very young • Archbishop James Ussher • Earth was created by God on 26 October 4004 BC at 9:00 am

  29. Darwin’s Era • Everyone had believed in special creation • By Darwin’s time there were cracks in the theory • Many biologists, paleontologists, and, especially, geologists had found conflicting evidence • Most scientists believed species changed somewhat • No one knew how they changed

  30. Evidence of change through time • Central tenet of the Theory of Special Creation is that species, once created, are immutable. • Microevolution • Evolutionary changes on the small scale, such as gene frequencies within a population • Macroevolution • Evolution on the grand scale; events above the species.

  31. Change Through Time • Direct observations of change of a species • Soapberry bug evolved a shorter beak within 20 years of switching host plants

  32. Change Through Time • Evidence from living species • Vestigial structures • Can be identified at structural, developmental, and genetic levels

  33. Vestigial Organs • A functionless or rudimentary version of a body part that has an important function in other, closely related species

  34. Vestigial Organs Hair follicles Tail bone

  35. Vestigial structures • Rudimentary or functionless structure • Blind salamanders with eye sockets • Human appendix and tail bone • Snakes and whales with hind legs • Pseudogenes

  36. Cave Salamanders... Multiple lineages have lost eyes, yet vestigial eyes are present in all cave forms

  37. Change Through Time • Evidence from fossil record • Fossils are unlike species living today • Used to think that if we looked hard enough we would find those fossilized species alive somewhere • Extinction eventually became recognized as fact • Special creationists asserted that extinct species were killed by biblical flood

  38. Change Through Time • Evidence from fossil record • Law of Succession shows extinct species are ancestors of living species • Did not die in flood leaving no descendants Pygmy Armadillo Fossil Glyptodont

  39. Irish Elk Cuvier showed evidence that, in fact, this species was not closely related to other living species (American Elk, Moose, or Deer) but rather it was a distinct and EXTINCT species!

  40. Change Through time • Transitional forms • Darwin was concerned that no transitional forms had been found • In 1860 the first Archaeopteryx was found • Environmental change • Marine organism fossils found in deep deserts and on high mountains

  41. Transitional forms • Archaeopteryx (140-150) • Confusciousornis (modern-looking bird) • Sinosauropteryx • Primitive feathers • Dromaeosaurid • Primitive feathers • Modern feathers

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