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The emergence of pathogenic viruses: an evolutionary approach

The emergence of pathogenic viruses: an evolutionary approach. Michael Worobey Department of Ecology and Evolutionary Biology, University of Arizona August 25, 2008. Questions:. (1) Where did HIV come from? (2) When, where, and how did HIV-1 first emerge from sub-Saharan Africa?

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The emergence of pathogenic viruses: an evolutionary approach

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  1. The emergence of pathogenic viruses: an evolutionary approach Michael Worobey Department of Ecology and Evolutionary Biology, University of Arizona August 25, 2008

  2. Questions: (1) Where did HIV come from? (2) When, where, and how did HIV-1 first emerge from sub-Saharan Africa? (3) When and how did the pandemic AIDS virus jump to humans and begin its spread? (4) What factors mediate the emergence of new flu lineages?

  3. 1: The origin of HIV

  4. HIV/AIDS basics Where did AIDS come from? • First identified in US gay males in the early 1980s, severe immunosuppression • Pneumocystis carinii pneumonia • Other rare opportunistic infections, horrendous suffering and death Randy Shilts As a national correspondent for the San Francisco Chronicle, Shilts was the first newspaper reporter to cover the AIDS epidemic full time. In his book And the Band Played On—AIDS: The First Five Years (1980-1985), he took almost everyone to task on how the first years of the epidemic were handled

  5. HIV/AIDS basics Early history • New syndrome recognized by 1981 • Retroviral agent isolated in 1983 • Sexually transmitted, but also via needles, transfusions, birth • Hit these risk groups hard in the US, but also high prevalence in Haiti, Central Africa Françoise Barre-Sinoussi

  6. HIV/AIDS basics • Viruses are made up of a set of genetic instructions wrapped inside a protective shell • HIV is particularly succinct at around 3000 amino acid residues that hijack the cell’s own machinery • Genome is in the form of RNA, so it also includes a reverse transcriptase (RNA to DNA enzyme) • About 20 % of your genome is made up of similar “selfish DNA” (more than 10X the amount of your 30,000 protein genes)

  7. HIV/AIDS basics

  8. Evolution in the fast lane: HIV/AIDS basics • About 10 billion virions are generated daily in an infected host (2.5 days per cycle) • Each has a compact genome made up of about 10,000 nucleotides • Approximately one mutation is generated for each new genome • Every possible mutation occurs every day

  9. HIV/AIDS basics Current status: Disaster

  10. Origins of HIV/AIDS • The past… • Where did HIV/AIDS come from?

  11. Origins of HIV/AIDS Where did HIV come from? • Divine retribution • Doesn’t matter--it doesn’t cause AIDS • Conspiracy theories - e.g. the CIA did it • Voodoo rituals • Ritualistic use of monkey blood • Contamination of vaccines • Zoonosis (a disease communicable from animals to humans under natural conditions) How can we discriminate between these hypotheses?

  12. Origins of HIV/AIDS Where did HIV come from? • Divine retribution “The poor homosexuals--they have declared war upon nature, and now nature is exacting an awful retribution” -Pat Buchanan "With 80,000 dead of AIDS, our promiscuous homosexuals appear literally hell-bent on Satanism and suicide” -Pat Buchanan "AIDS is not just God's punishment for homosexuals; it is God's punishment for the society that tolerates homosexuals.” -Jerry Falwell “Grown men should not be having sex with prostitutes, unless they are married to them” -Jerry Falwell

  13. Origins of HIV/AIDS Where did HIV come from? • Divine retribution “The poor homosexuals--they have declared war upon nature, and now nature is exacting an awful retribution” -Pat Buchanan "With 80,000 dead of AIDS, our promiscuous homosexuals appear literally hell-bent on Satanism and suicide” -Pat Buchanan "AIDS is not just God's punishment for homosexuals; it is God's punishment for the society that tolerates homosexuals.” -Jerry Falwell “Grown men should not be having sex with prostitutes, unless they are married to them” -Jerry Falwell

  14. Origins of HIV/AIDS Where did HIV come from? • Doesn’t matter--it doesn’t cause AIDS

  15. Origins of HIV/AIDS Where did HIV come from? • Doesn’t matter--it doesn’t cause AIDS

  16. Origins of HIV/AIDS • Divine retribution • Doesn’t matter--it doesn’t cause AIDS • Conspiracy theories - e.g. the CIA did it • Ritualistic use of monkey blood • Zoonosis (a disease communicable from animals to man under natural conditions) • Contamination of vaccines • THE PLAUSIBLE HYPOTHESES ALL HAVE IN COMMON THE INCRIMINATION OF SIMIAN IMMUNODEFICIENCY VIRUSES (SIVcpz) FROM CHIMPANZEES • THE KEY DISCOVERY WAS THE FINDING THAT AFRICAN PRIMATES ARE INFECTED WITH SIMILAR VIRUSES…

  17. HIV/AIDS basics Early history • New syndrome recognized by 1981 • Retroviral agent isolated in 1983 • Sexually transmitted, but also via needles, transfusions, birth • Hit these risk groups hard in the US, but also high prevalence in Haiti, Central Africa Françoise Barre-Sinoussi

  18. Origins of HIV/AIDS Where did HIV come from? • Divine retribution • Doesn’t matter--it doesn’t cause AIDS • Conspiracy theories - e.g. the CIA did it • Voodoo rituals • Ritualistic use of monkey blood • Contamination of vaccines • Zoonosis (a disease communicable from animals to humans under natural conditions) How can we discriminate between these hypotheses?

  19. Cercopithecus albogularis Chlorocebus aethiops Pan troglodytes Cercopithecus lhoesti Colobus guereza Key discovery: SIVs are found naturally in African primates Cercocebus atys

  20. Origins of HIV/AIDS • Divine retribution • Doesn’t matter--it doesn’t cause AIDS • Conspiracy theories - e.g. the CIA did it • Ritualistic use of monkey blood • Zoonosis (a disease communicable from animals to man under natural conditions) • Contamination of vaccines • THE PLAUSIBLE HYPOTHESES ALL HAVE IN COMMON THE INCRIMINATION OF SIMIAN IMMUNODEFICIENCY VIRUSES (SIVcpz) FROM CHIMPANZEES • THE KEY DISCOVERY WAS THE FINDING THAT AFRICAN PRIMATES ARE INFECTED WITH SIMILAR VIRUSES…

  21. Origins of HIV/AIDS

  22. Origins of HIV/AIDS A direct test: non-invasive sampling of SIVcpz from the supposed “source” (and a big blank space on the map of SIVcpz distribution)

  23. Origins of HIV/AIDS

  24. Origins of HIV/AIDS Phylogenetic position Expected for source population Phylogenetic position of Kisangani SIV Worobey et al. 2004

  25. Extensive non-invasive sampling continues: • >1500 samples collected from across DRC • 212 SIVcpz Ab positive • 22 SIVcpz RNA positive Worobey, Hahn, Li, Ndjango, unpublished results

  26. 2: The Worldwide Emergence of HIV-1

  27. HIV-1 group M Diversity • B RF • B LAI Subtypes A-K 30% amino acid divergence in Env between subtypes Utility: Tracing the global pandemic Documenting recombination • D 94UG114 • D ELI subtypes • A 92UG037 • A U455 • G SE6165 • G 92NG083 • J SE9280 • J SE9173 • C ETH2220 • C 92BR025 • H VI991 • H 90CF056 • K MP535 • K EQTB11 • F1 VI850 • F1 93BR020 • F2 MP255 • F2 MP257 • SIVcpz/US • SIVcpz/Cam5 • N YBF30 • N YBF106 • SIVcpz/Gab1 • O ANT70 • O MVP1580 • SIVcpz/Ant

  28. Molecular Epidemiology of HIV-1 group M

  29. Revisiting an old hypothesis…

  30. Questions: Did HIV-1 move from Haiti to US, or US to Haiti? When and how did these events take place?

  31. Approach: • Archival Haitian-linked samples, Pitchenik et al, AIM, 1983 • Some of the earliest known AIDS patients in the US (Haitian immigrants to the US 1970s/80s) • Full-length env alignment of published B and D subtype sequences (117 B plus 5 D) • Bayesian MCMC approach, MrBayes and BEAST

  32. Phylogenetic patterns under different scenarios: US first Haiti first Simultaneous Unknowable

  33. Results: the Emergence of HIV-1 in the Americas Posterior probability of Haitian origin = 0.999 n = 13 Posterior probability of Trinidad & Tobago clade = 1.0 n = 96 Posterior probability of “pandemic clade” = 1.0 Gilbert et al. 2007, PNAS

  34. Synonymous, dS = 10 x 10-3/site/year Nonsynonymous, dN = 2-5 x 10-3/site/year Mutation rate : 3.4 x 10-5 /site/replication Replications : about 300/year 300 x 3.4 x 10-5 = 10.2 x 10-3 d t Rate = Estimating rates of viral evolution Average: 5 x 10-3/site/year divergence rate: 1% /site/year Using the “molecular clock” Calibrate the clock Correct for multiple hits Account for methodological bias

  35. The Emergence of HIV-1/AIDS in the Americas: when? Posterior probability of Haitian origin = 0.998 1969 [1966-72]

  36. Conclusions: It’s not a sampling artifact: the B epidemic is older in Haiti, >40 years Timing fits well with large movement of people between Haiti and DR Congo after independence in early 1960s One such individual may have been the first to bring HIV out of sub-Saharan Africa

  37. Conclusions • Strong support for a single-patient introduction of “pandemic clade” from Haiti • In or around 1969 (long cryptic period in US) • Ecological, not evolutionary factors determined “success” • Do non-pandemic clade viruses have distinct immunological properties? (Mascola et al, JID, 1994) • Why so few successful epidemic introductions after the pandemic clade in or around 1969?

  38. 3: When and how did HIV jump into humans and begin its initial spread?

  39. Molecular archeology of HIV: motivation • archival sequences can provide direct tests of evolutionary hypotheses • 1918 Spanish Flu virus has been resurrected and used to investigate emergence, pathogenesis and other questions. • For HIV relevant frozen samples are rare and already screened (one from 1959, then 1976)

  40. Nature, 1998

  41. Science, 2000

  42. Ambient temperature specimens like blood smears and paraffin-embedded tissue are not so rare

  43. Between 5 and 10 microtome sections, 5-10 m in thickness • or an approximately equivalent amount of tissue shaved from each block with a disposable scalpel blade • Digestion/extraction optimzed for RNA recovery • Primers designed for short fragments with primers in M-group or subtype A conserved regions

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