1970S HIV-1 Genomes Reveal the Early History of HIV/AIDS in the US
1970s HIV-1 Genomes Reveal the Early History of HIV/AIDS in the US
Michael Worobey
Department Head, Professor Ecology and Evolutionary Biology University of Arizona
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 HIV/AIDS basics Early history
• New syndrome recognized by 1981
• Retroviral agent isolated in 1983 Françoise Barre-Sinoussi • Sexually transmitted, but also via needles, transfusions, birth
• Hit these risk groups hard in the US, but also high prevalence in Haiti, Central Africa
The origin of HIV 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? 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… Key discovery: SIVs are found naturally in African primates
Pan troglodytes
Chlorocebus aethiops
Cercopithecus albogularis
Cercocebus atys
Cercopithecus lhoesti
Colobus guereza Origins of HIV/AIDS
“The River: • In the late 1950s 350/400 chimps A Journey Back to the sacrificed in experiments at Lindi Source of HIV and AIDS” camp near Kisangani, DRC, and by Edward Hooper. allegedly OPV cultured in their kidneys (Hooper 1999).
• This culturing process is suggested to have facilitated the transfer to humans of chimpanzee simian immunodeficiency virus (SIVcpz).
• There’s a precedent: early polio vaccines are known to have been contaminated with the simian virus SV40. Origins of HIV/AIDS Origins of HIV/AIDS 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) Origins of HIV/AIDS Origins of HIV/AIDS Origins of HIV/AIDS Origins of HIV/AIDS Western blot analysis of Kisangani chimpanzee urine samples 6 15 19 21 25 28 36 40 48 51
gp160 gp120
p66
p51 gp41
p31
p24
p17 Origins of HIV/AIDS
HIV/AIDS basics Evolution in the fast lane:
• 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
Phylogenetics interlude • It’s all about ancestors and offspring, All the phylogenetics you lineages branching
need to know, in 5 • The ancestor could be distant great grandmother or a human minutes… immunodeficiency virus
• The ancestral form of some gene (a “marker”) is inherited in two offspring lineages
• Let’s assume that we’re looking at virus from a “patient 0” who then infects two others patient 1
patient 0
patient 2 Phylogenetics interlude • Eventually, a series of branching events, plus mutations along each branch, lead to 4 current HIV infected patients
• Their viruses display genetic diversity that reflects their evolutionary history patient 3
patient 4
patient 0
patient 5
patient 2
patient 6 Phylogenetics interlude
• Unfortunately, we almost never have access to that history
• What we can do, is go out into nature and sample genetic markers
• Then we work backwards to infer the most likely series of events that gave rise to what we observe
Origins of HIV/AIDS Phylogenetic position Expected for source population
Phylogenetic position of Kisangani SIV
Worobey et al. Nature, 2004 When and how did HIV jump into humans and begin its initial spread? 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)
Nature, 1998
• Ambient temperature specimens like blood smears and paraffin- embedded tissue are not so rare HIV DNA/RNA can be recovered from “ancient” paraffin-embedded samples:
Sharp & Hahn 2008, Nature. Kinshasa, ca. 1883-1885
-Collection of the Royal Museum for Central Africa 1896
ca. 1955
Sharp & Hahn 2008, Nature.
Implications
•Extensive genetic diversity in 1959/1960 Kinshasa (early hub)
•Local and global level evidence that HIV-1 lives close to the edge of extinction…
-Many sparks, few fires -Self-sustaining epidemics surprisingly rare -Colonial cities + natural chimpanzee virus = pandemic
The bad news: humans likely created the conditions where R0 > 1...
The good news: if we made it, we can realistically unmake it, even in the absence of a preventive vaccine.
Where did AIDS come from?
• First identified in US MSM in the early 1980s, severe immunosuppression
• Pneumocystis pneumonia, KS
• Other rare opportunistic infections, horrendous suffering and death
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)
Phylogenetic patterns under different scenarios:
African HIV-1 African HIV-1
Subsequent move to US Subsequent move to Haiti
Common ancestor in Haiti Common ancestor in US Results: the Emergence of HIV-1 in the Americas
Posterior probability n = 13 of Haitian origin = 0.999 Posterior probability of Trinidad & Tobago clade = 1.0
n = 96
Posterior probability of “pandemic clade” = 1.0
Gilbert et al. 2007, PNAS The Emergence of HIV-1/AIDS in the Americas: when?
Posterior probability of Haitian origin = 0.998
1969 [1966-72] Conclusions:
It’s not a sampling artifact: the B epidemic is older in Haiti, ~50 years old as of 2017
Timing fits well with large movement of people between Haiti and DR Congo after independence in early 1960s
• Samples from New York City from volunteers in a prospective study of AIDS
• 378 had been part of an earlier cohort in hepatitis B virus studies beginning in 1978
• Previous work: 6.6 % HIV-1+ Beryl Koblin, New York Blood Center
• 6875 patients at the San Francisco City Clinic, enrolled in the late 1970s in studies of HBV
• For this study we tested 2231 of these samples from 1978 and found 83 (3.7%) to be Western blot-positive for HIV-1 antibodies
• “Patient 0” Harold Jaffe Walid Heneine
…and Tim Granade, CDC Tom Watts, University of Arizona
How to amplify HIV-1 from badly degraded samples…
“RNA jackhammering”:
Worobey et al, Nature, 2016
Worobey et al. 2016 Worobey et al. 2016 San Francisco 1978 NYC 1979 NYC 1979
NYC 1979 NYC 1979
NYC 1979 The posterior probability for New York City at the origin of the US MRCA for this data set is 0.9976 Effective number US of infected hosts Through time
Caribbean
Worobey et al. 2016
San Francisco 1978 NYC 1979 NYC 1979 Patient 0
NYC 1979 NYC 1979
NYC 1979 The posterior probability for New York City at the origin of the US MRCA for this data set is 0.9976 Slides Bill Darrow used when he first presented cluster study results at CDC, courtesy of Harold Jaffe Slides Bill Darrow used when he first presented cluster study results at CDC, courtesy of Harold Jaffe Slides Bill Darrow used when he first presented cluster study results at CDC, courtesy of Harold Jaffe “In the middle of that study was a Rich McKay circle with an O next to it . . . . When Cambridge University I went to the CDC, they started talking about Patient Zero. I thought, Ooh, that’s catchy.” - Randy Shilts Counseling and testing
Make circumcision available ARV treatment / TasP
Microbicidal PrEP gel
R0 < 1 Promote partner Harm reduction reduction
Reduce concurrency Promote condom use
Phylogenetic approaches to get ahead of transmission? DISRUPT THE NETWORKS THAT ALLOW A POORLY TRANSMITTED VIRUS TO FLOURISH IN LOCAL OUTBREAKS, AND DO IT NOW.
The bad news: humans likely created the conditions where R0 > 1...
The good news: if we made it, we can realistically unmake it, even in the absence of a preventive vaccine. Thanks.
Philippe Lemey, UC Leuven Cladd Stevens, NY Blood Center Ryan Ruboyianes, U Arizona Dollene Hemmerlein, CDC CROI organizers All patients who donate samples