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Charles Darwin Origin of the Species

“What limit can be put to this power ( natural selection ), acting during long ages and rigidly scrutinising the whole constitution, structure, and habits of each creature,-favouring the good and rejecting the bad.”. Charles Darwin Origin of the Species. Natural Selection.

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Charles Darwin Origin of the Species

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  1. “What limit can be put to this power (natural selection), acting during long ages and rigidly scrutinising the whole constitution, structure, and habits of each creature,-favouring the good and rejecting the bad.” Charles Darwin Origin of the Species

  2. Natural Selection • All species produce more offspring than can possibly survive and reproduce. • Organisms differ in their ability to survive and reproduce, in part due to differences in genotype. • In every generation, those genotypes that promote survival in the current environment are present in excess at the reproductive age and therefore contribute disproportionately to the offspring of the next generation. • For natural selection to operate there must be heritable variation for traits that are correlated with reproductive success.

  3. Average Rates of Nucleotide Substitution in Different Organisms Substitution Rate Organism/Genome (per site, per year) -9 Plant chloroplast DNA ~ 1 x 10 -9 Mammalian nuclear DNA 3.5 x 10 -9 Plant nuclear DNA ~ 5 x 10 -9 E. coli and Salmonella enterica bacteria ~5 x 10 -8 Drosophila nuclear DNA 1.5 x 10 -8 Mammalian mitochondrial DNA 5.7 x 10 -3 HIV-1 6.6 x 10

  4. The Degeneracy of the Genetic Code Proline (4 synonymous codons) CCT CCC CCA CCG Histidine (2 synonymous codons) CAT CAC CAA - Gln CAG - Gln

  5. Measuring Selection Pressures in Genes • Selection pressures can be measured by comparing the relative rates (ratio) of synonymous (silent) (dS) and nonsynonymous (amino acid changing) (dN) substitutions: Ser Met Leu Gly Gly Seq 1: TCA ATG TTA GGG GGA † * † † * * Seq 2: TCG ATA CTA GGT ATA Ser Ile Leu Gly Ile † Synonymous substitution * Nonsynonymous substitution dN/dS < 1.0 = negative selection (functional constraint - most genes) dN/dS ~ 1.0 = neutral evolution (pseudogenes) dN/dS > 1.0 = positive selection

  6. Genetic Variability of HIV • HIV exhibits extremely high levels of genetic variation: the virus evolves about 1 million times faster than human DNA (HIV-1 = ~10-3 subs/site/year, human DNA = 10-9 subs/site/year) . • This is mainly due to: • Extremely high mutation rate, particularly because the replication enzyme reverse transcriptase that converts RNA to DNA is very error prone • High turnover of virus within infected individual ~1010 viruses produced in each patient each day • Rapid generation time (~2.6 days)

  7. Phylogeny of global HIV-1 isolates + 197 strains from the Congo

  8. Genetic diversity at transmission • Early analyses concentrated on the env gene and revealed a low level of diversity in seroconverters • Ho D., Science, Leigh-Brown A., J. Virol • So the infection was thought to be established by a small “founder” set of clones • But that work did produce evidence of greater diversity in gag, nef and pol than env

  9. Four Sexual Transmitters

  10. UNRELATED SEROCONVERTER Maximum Likelihood phylogenetic tree DONOR RECIPIENT

  11. Evading Cytotoxic T-Lymphocyte Recognition May Enhance Viral Fitness

  12. Evading Cytotoxic T-Lymphocyte Recognition May Enhance Viral Fitness

  13. Selection of escape mutants replication A A1-A101 SELECTION PRESSURE e.g. A6 e.g. A12 Some lead to increased fitness - survive Some mutations lead to reduced fitness - die off

  14. Continued selection of escape mutants replication A6 A6.1-A6.101 SELECTION PRESSURE e.g.A6.4 e.g. A6.9 Some lead to increased fitness - survival Some mutations lead to reduced fitness - extinction

  15. “Extinction has only separated groups: it has by no means made them: for if every form which has ever been were suddenly to reappear…all would blend together by steps as fine as those between the finest existing varieties” Charles Darwin Origin of the Species

  16. Do CTL Select for Escape Variants During Acute Infection? CTL Response Viral Load Weeks Years

  17. 5 CTL Epitopes Accumulate Variation at Different Rates During Acute SIV Infection Consensus QGQYMNTPW ARRHRILDIYL IRFPKTFGW GDYKLVEI KRQQELLRL Inoculum ......... ........... ......... ........ ......... ......... ........... T.Y...... ........ ......... ...H..... ........... T.Y...... ........ ......... ......... E.......... T.Y...... ........ ......... ......N.. E.......T.. T.Y..I... ........ ......... ......N.. E.......M.F T.Y..I... ........ ......... ......N.. E.......K.. T.Y..I... ........ ......... ....I.N.. E.......K.. ..Y..I... .....I.V ...H..... ......N.. E.......K.. T.Y..I... .....I.V ...H.....

  18. Epitope Variants Reduce CTL Recognition

  19. SIV Nef variation (yellow blocks) clusters within epitopes defined by MHC Class I (green blocks) C D A

  20. Summary • Antiretrovirus T lymphocytes recognise peptide antigens dictated by, and bound to MHC Class I molecules • Genetic variants of the virus can alter or even abolish immune recognition of infected target cells • Viruses bearing these sequences have a survival advantage • Escape mutants grow out (at different rates) and are positively selected

  21. 26 year old man admitted with aseptic meningitis • Had unprotected anal sex on 20 Sept.1995 • HIV Elisa negative on 10 October 1995 • P24 gag antigen positive • Viral load >10 millions copies per ml • CTL assay 19 October 1995 • Single nef response

  22. HLA B8NEF EPITOPEFLKEKGGL

  23. Intra-Host Evolution of HIV-1 SIHIGPGRAFYTTGE SIPIGPGRAFYTTGQ SIHIGPGGAFYTTGQ SIHIGPGRAFYTTGD SIPIGPGRAFYTTGD GIHIGPGSAFYATGD SIHIGPGRAFYTTGG SIHIGPGRAVYTTGQ GIHIGPGSAFYATGG GIHIGPGRAVYTTEQ RIHIGPGRAVYTTEQ GIHIGPGSAFYATGR RIYIGPGRAVYTTEQ GIHIGPGSAVYATGG RIYIGPGSAVYTTEQ GIHIGPGSAFYATGG RIGIGPGRSVYTAEQ GIHIGPGSAVYATGD GIHIGPGRAFYATGD GIHIGPGRAVYTTGD RIYIGPGRAVYTTDQ Tip of the V3 loop (part of the envelope protein of HIV-1) - diversity in a single patient • The HIV-1 envelope protein is under very strong positive selection to help the virus escape from the human immune response (the V3 loop contains epitopes for neutralising antibodies and cytotoxic T-lymphocytes (CTLs). • V3 loop dN/dS = 13.182 (Nielsen & Yang. Genetics 148, 929. 1998).

  24. Does transmission of CTL escape viruses impact on the global epidemic?

  25. Questions • Child can inherit a HLA Class I molecule which has dictated a response in the mother • The maternal immune response can select escape mutants Are these immune escape viruses detectable in the mother? Can the mother transmit these viruses? Do these escape viruses propagate infection in the child?

  26. Father Mother Child

  27. Father Mother B27 B27 Child

  28. Father Mother B27 B27 Child

  29. KK10 lies within a conserved region of p24 Gag 100% 50% 40% 20% 10% 5% 2% 1.3% P I V Q N L Q G Q M V H Q A I S P R T L N A W V K V V E E K A F S P E V I P M F S A L S E G A N T V G G H Q A A M Q M L K E T I N E E A A E W D R L H P V H A G P I A P G Q M R E P R G S D I A G T T S T L Q E Q I G W M T N N P P I P V G E I Y K R W I I L G L N K I V R M Y S P T S I L D I K Q G P K E P F R D Y V D R F Y K T L R A E Q A S Q E V K N W M T E T L L V Q N A N P D C K T I L K A L G P A A T L E E M M T A C Q G V G G P G H K A R V L 1 4 5 6 7 11 14 25 27 29 41 44 48 53 71 79 83 86 90 92 96 98 107 110 114 120 123 128 148 154 159 167 170 177 183 187 194 199 208 213 216 219 223 230 T P Q D L N T M L KRWIILGLNK

  30. Structure of N terminal domain of p24: Clustered mutations within B27 epitope, necessary for escape helix 7

  31. Amino acid changes in the antigenic peptide at the second position prevent binding to HLA B27 molecules 100 80 KRWIILGLNK variants 60 KRWIILGLNK=R2L6 % Maximum M=R2M6 40 K M =K2M6 K =K2L6 20 TM =T2M6 0 -9 -8 -7 -6 -5 -4 peptide concentration (log molar)

  32. The HLA B27 Gag peptide is not recognized in children of HLA B27-positive mothers WHY? 1925 2000 1600 IFN-g SFC/ million PBMC 1200 800 400 0 0 0 0 043-C 002-C 048-C 049-C B27-ve mother B27+ve mothers

  33. The HLA B27 bearing MOTHERS acquired an escape virus and transmitted it to the CHILDREN No P2 anchor mutation 2000 P2 anchor mutation shared with mother 1600 IFN-g SFC/ million PBMC 1200 800 400 0 0 0 0 043-C 002-C 048-C 049-C B27-ve mother B27+ve mothers

  34. Father Mother B27 B27 B27 KRWIILGLNK- K- - -M- - - -

  35. HIV IN PERTH, AUSTRALIAHypotheses If CTL-driven selection operates on HIV-1 in populations then selected mutations should: • be within or close to CTL epitopes • because of genetic restriction of immune responses, mutations should be linked to particular HLA variants • viral escape mutations would be evident as HLA-associated polymorphisms.

  36. within published epitopesflanking residues putative epitopes =Significant after correction HLA alleles significantly associated with HIV-RT polymorphisms Moore et al (2002) Science 296, 1439

  37. Natural selection by AIDSWho wins the race? • HIV-1 10-3 subs/site/year • Human genome (eg HLA) 10-9 subs/site/year

  38. “Nothing in biology makes sense, except in the light of evolution” Theodosius Dobzhansky 1973

  39. Eddie Holmes Paul Klenerman David Watkins Angela McLean Simon Mallal David O’Connor David Price Annette Oxenius Andrew McMichael Charles Bangham Philippa Easterbrook Jonathan Weber Sarah Fidler George Scullard Anele Waters Anne Edwards Philip Goulder The patients of The Chelsea and Westminster Hospital; St Mary’s Hospital; KwaZulu Natal Acknowledgments

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