HIV/AIDS Research: Its History & Future Meeting
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Beatrice Hahn: Okay, so thank you very much for the invitation to speak tonight. What I will talk to you about tonight is the title that the organizers gave me, “Apes to Humans: Origin of HIV.” What I really will tell you is how remarkably much we know about the details where, when, how and why HIV-1 [00:00:30] emerged. Actually Mike Worobey will speak after me, will cover the why. 

The story really started with our study back in 1999, when we described the origin of HIV-1 in one particular chimpanzee subspecies, that was the first piece in the puzzle. (1) The last piece in the puzzle really was Martine [Peeters’] paper in 2015, where she described the origin of HIV-1 group O [00:01:00] in Western lowland gorillas. (2)

What I'm going to do in the next 20 minutes is to tell you about what happened in the interim time period. But before I go there, I have to start at the beginning and I have to start the Laboratory of Tumor Cell Biology [at the NIH], where I was a postdoc starting in 1982. I met Bob [Gallo] in Munich, in the Nymphenburg Gardens, he hired me, and I don't really know why because I knew nothing. I went to medical school, but I didn't know anything [00:01:30] about medicine and I sure as hell didn't know anything about science. But he hired me anyway and he hired me to molecularly characterize first HTLV-I, and then HIV-1 under the mentorship of Flossie Wong-Staal.

That's what I did, we cloned, we restriction site mapped and later on, we sequenced. It was a super fun time and that shows a picture of part of the laboratory back in 1984, in People [00:02:00] magazine, and what it says here, "Gallo center poses with his research team after a competitive round of volleyball during their weekly Sunday gathering at his home near NIH. First we talk science, says Gallo, then we socialized, our first meeting ended up was drinking until two o'clock in the morning." (3) Now I do remember that—I don't remember the drinking part because by eight o'clock, we were back in the lab.

[laughter]

Not because we were [00:02:30] forced, but it was so much fun. Imagine this was a time when everybody was interested in your next experiment. Like Jim Watson said yesterday, if you work hard, you might as well do something that's important and HIV was important and you might as well do something that's fun, and it was a lot of fun working with these people. Bob, you have a great legacy, many, many of these people have gone on and become quite successful. Mandy Fisher here, like the little one, she's a [00:03:00] Royal Society member, Anna [Aldovini], of course at Harvard, Lee [Ratner] at WashU and this is George [Shaw] and myself.

Paul Volberding wanted to hang out with Molly, we wanted to hang out with each other, [laughter] except we wanted to hang out with each other and hang out in the lab. Now we didn't just pose for People magazine, this actually really did happen. We did go to Bob's house and every nice [00:03:30] Sunday in the summer we would do so, Mary Jane, would host us and everybody was there, and here's Bob in the pool saying, "Hey guys, it's time for a game of water volleyball." Let me tell you, the girls would not partake in this and they were smart because when the match was over, he looked whether he had accidentally killed some of his postdocs in the heat of the competition.

Beatrice H. Hahn (b. 1955) is a virologist at the University of Pennsylvania, formerly at University of Alabama.

 

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Eventually, it was time to say goodbye. [00:04:00] We all sort of “graduated” at the same time. Bob and Flossie threw us a great party, this is a big cake—it's a cell that was budding lentiviruses. I want to point out that the core by that time had become cone-shaped, so we were in the lentivirus field. George and I went to UAB (University of Alabama at Birmingham) because George's, Ph.D. mentor hired us and [00:04:30] at UAB, we did pretty well at the same thing we did in Bob's house. In fact, I remember George, rented a van and we loaded it up to the hilt with probes and reagents and phage and even equipment. We'd probably be put in jail if Bob knew about it, this was permitted—he'd probably be put in jail if NIH would know—but on Monday morning when we started in Birmingham, [00:05:00] we were sequencing and I think three or four months later we published our next Science paper together where we described the genetic diversity of HIV-1 in several Haitian kids over time. (4) So it was a good investment and it paid back to the NIH and to Bob.

In Birmingham, we became interested in the molecular characterization of related primate lentiviruses, as Martine said. We were obviously aware of Martine's [00:05:30] studies when she first discovered SIVcpz in the two pet chimps. (5) However, as she said, everybody and their brother would go off to captive chimps after this first finding and no one could find another virus. Then Martine—again, she has a nose for these things—found the third virus in Noah, that one chimp that was in the zoos. (6) This strain was very, very different from those two strains and [00:06:00] really didn't make sense to us at the time, because this strain differed from these two strains almost as much as two different SIVs differed from each other. So was it really the precursor of HIV-1? We didn't know. 

But then as luck turns, Larry Arthur cleans his freezer, and that was really a remarkable thing because in his freezer was a chimp in different pieces. He called me [00:06:30] up and said, “Are you interested in working up this chimp?” The chimp is antibody positive, but Larry was unable to isolate virus from this chimp and the chimp unfortunately died after giving birth to stillborn twins. He said “The chimp had been in primate centers for a long time, perhaps the chimp was accidentally infected with HIV-1, but more likely probably the chimp had been infected back in Cameroon, where it was wild-caught. Did I want to analyze it?” And of course I did. [00:07:00]

And so when Larry's virus was sequenced by Feng Gao in my lab, this is where it fell in the phylogenetic tree. This was really odd. I looked at this when Feng came with the data, and then I called up my friend, Paul Sharp (b. 1957). I said, "Paul, why are we—” we'd been working on SIVs in various species by that time and every single SIV lineage was tight, and you found multiple viruses from the same lineage, and they were [00:07:30] clustering together. And I said, "Why is this virus so divergent from these others?" He said, "You know, I just saw a paper by the Jane Goodall group, and they say there are different subspecies of chimps. Maybe it has to do with the subspecies where these viruses come from." And I said, "Well, you know, two come from Gabon, this one likely from Cameroon and this one from the DRC." And he said, "Go and check out—what you do need is you need a primary material from [00:08:00] the chimps, you need to sequence part of the mitochondrial genome and then you can determine what the subspecies is." 

I immediately called up Martine, and we hadn't known each other at the time, but she knew Paul. I explained the situation, and Martine said, yes, "I do have primary PBMCs from chimps still in my freezer," and she immediately sent it. Then we amplified the mitochondrial genome and sure enough, these three viruses came from this subspecies which was called the [00:08:30] central chimpanzee, or the Pan troglodytes troglodytes—whereas this virus came from Noah who was wild-caught in the DRC, and that's another subspecies and that's called Pan troglodytes schweinfurthii. There are still two other subspecies, the Western chimp here and the Nigerian-Cameroonian chimp here. We published that it's this subspecies [Pan troglodytes troglodytes] that's the source of the ancestors of HIV-1. (7)

A year later, we had the opportunity to write [00:09:00] a review in Science and we proposed that AIDS was a zoonosis, because by that time the third group of HIV-1 was discovered, and we saw the branching patterns of the chimp viruses with the human viruses and it was clear that there were, at that time at least, three different cross-species transmissions. (8) And we proposed, as Martine had shown you, that bushmeat hunting is a risk behavior, because you get exposed to infected blood or other bodily secretion and from the biology of these viruses, we [00:09:30] knew that that was necessary.

But not everyone was convinced. The reason why people weren't convinced is even after Eric Nerrienet and Martine had identified still three other chimpanzee viruses, they were again identified in captive animals. So all this work was from viruses identified in captive animals, and as you might imagine, a lot of things can happen in captivity. [00:10:00] Really, I think Robin [Weiss] was the one that said, “Is there really a natural reservoir?” and that was a legitimate question.

At that point, the NIH actually organized a meeting in Atlanta where they brought together HIV scientists with primatologists. This is Richard Wrangham who is a renowned primatologist, one of Jane Goodall’s first students, who has run the Kibale Forest chimpanzee group and habituated them, I don't know, for the past 40 years. We met him in [00:10:30] Atlanta and we said, "How could we even go about screening wild chimps?" He said, "The one thing you can't do is you cannot anesthetize them because, first of all, even if one were to go down, there would be five other standing around and you would be killed trying to get blood from that animal, or worse that tranquilized animals would climb up a tree and then fall down and break its neck, so this is a no-no.”

But he said, “You know for our own work, we often collect fecal and [00:11:00] urine samples and if he could figure out a diagnostic way to get to your virus from those samples, then you have a possibility.” So we started to work on non-invasive detection of SIVcpz and really two people were-- or three people were key in that, first of all, Mario Santiago, who was a PhD, student who's now Associate Professor in Colorado, Brandon Keele, who is here and who's very photogenic and shown many times and [00:11:30] Yingying Li.

There were a number of hurdles that we needed to overcome. The first was preservation. When we talked to mucosal immunologists at the time they said, "Forget it. By the time you get the fecal sample, everything's degraded." So we found RNAlater, a high salt solution that preserved the fecal samples in the field and could be transported at ambient temperatures, which was key. We also needed a good diagnostic test and that is usually done with antibodies. And Brandon Keele [00:12:00] figured out how to get antibodies out of RNAlater-preserved fecal samples. That test is highly sensitive, it's 92% sensitive under field conditions and 100% specific, and once you know that the fecal sample is positive, then you just PCR the hell out of it until you find the virus, which is also possible. In fact, Jaap Goudsmit (b. 1951) originally showed that viral RNA can be extracted, reverse transcribed and amplified. And then you can [00:12:30] also look at the host by doing the mitochondrial analysis to determine species and subspecies and you can enumerate individuals by doing microsatellite analysis. 

Meanwhile, another hypothesis was put forward by a journalist, Ed Hooper (b. 1951), who published The River also in 1999. (9) You may recall the story in the late 1950s, Hilary Koprowski (1916–2013) and Stan Plotkin (b. 1932) developed an oral polio vaccine (OPV) and delivered [00:13:00] it to about a million people in the Belgian Congo. They had a camp that's called Camp Lindi that was close to Kisangani where they kept chimpanzees, because this was a live attenuated vaccine and on occasion, they wanted to check that the vaccine was safe. They did that in chimps because chimps were sensitive to that.

So what Hooper purported was that the vaccine was not grown as Hillary and Stan said, in Philadelphia, but clandestinely, in chimpanzee kidney [00:13:30] cells, that then were contaminated with SIVcpz, because the caught chimps would have been infected. I never was particularly convinced by this hypothesis and to paraphrase John Moore, who reviewed this book with the title “Up The River Without A Paddle.” (10) I couldn't have agreed more because, first of all, the vaccine was not produced in chimpanzees cells in Kisangani, Hillary and Stan said so but, of course, [00:14:00] people would say they lied, they have something to hide.

#discovery and naming of HIV/HTLV-III/LAV/ARV

But as far as we were concerned, it was implicating the wrong SIVcpz strain—the Eastern SIVcpz—in the wrong chimpanzee subspecies, at the wrong time, and the timing was done by my colleague Bette Korber, who in 2000 published a very nice paper, she timed the ancestor of the HIV-1pandemic and she timed it to 1915 to 1941. (11) And then Mike Worobey [00:14:30] refined this and still another a paper more recently refined it further, but her initial estimates were right on the money, 1920. Which meant that SIVcpz was in people 20 to 30 years before the polio vaccine was even given. 

But the proponents of this hypothesis didn't believe in phylogenetic inference and one of the people who was convinced that who who was right was Bill Hamilton (1936–2000). [00:15:00] Bill Hamilton was a renowned evolutionary biologist and he was a scientist. He said, “This is Kisangani, this is the Congo River, if indeed chimps around Kisangani did contribute to provide their SIVcpz for this purported polio vaccine scenario, then chimps in this area should be infected with SIVcpz and the SIVcpz from this area should look like HIV-1.”

He said, “I'm going to go there [00:15:30] and I'm going to collect non-invasively, fecal and urine samples,” because someone must have told him that we started to work on this.” And in fact, Mike Worobey was his student: he took his student with him, and Mike, before they went on this trip, called me up on the phone, and said, “Do you have any advice how we should collect this material and how we should store it and how we should keep it?” I told him what we knew at the time I said, “Put everything in RNAlater and you're going to be good”, and that is what they did.

Indeed, they want to Kisangani [00:16:00] and they did collect chimpanzee urine and fecal samples, and the results from this first screen were supposed to be discussed at a Royal Society Discussion Meeting, on “The Origins of HIV and the AIDS Epidemic.” But this was an ill-fated mission because Mike got sick and almost lost his arm and Bill Hamilton contracted malaria, Plasmodium and when he returned, he collapsed in the office of his physician, had a massive a catastrophic internal bleed, went into [00:16:30] a coma, and died several weeks later.

We still had a Royal Society Discussion Meeting [in London, September 2000] because it was, I guess, already organized, Robin [Weiss] and Simon Wain-Hobson inherited running it and after some quibbles over who should speak and who should not speak, we actually did have our discussion meeting. Now I have to say remembering back to that meeting, it reminded me of the current presidential debate. [00:17:00] [laughter] It was very contentious at times hostile. People were accused of lying all the time and scientific facts just didn't matter, whatsoever. So we discussed it and then the OPV disciples weren't convinced otherwise and we, on the other side, certainly also weren't convinced. (12)

But when I returned back to Birmingham, I knew that the only way that we could debunk this ultimately [00:17:30] was to simply find out what wild chimps were infected, with what viruses, where. What I presented at the Royal Society meeting was actually this Western blot which was from urine samples from Gombe National Park (Tanzania). (13) In fact, we had started first establishing the methods with non-infected captive chimps and then moving to the habituated areas in the Taï forest [00:18:00] with Richard Wrangham in Kibale National Park (Uganda). Richard really introduced me to his colleagues and said we were okay, because in those days, HIV scientists and primatologists working in chimps, they did not talk to each other. But Richard said we were fine and so Jane [Goodall] let us study her chimps and we got this urine with some blood and we had the first positive. I remember it was a Friday afternoon at 4:00 when Brandon [Keele] [00:18:30] and Mario [Santiago] and some other people came into my office and showed me this. When I then emailed the person who had provided the samples, it turned out that these two positives came from the same chimp, so I knew they were infected. 

But what I didn't know at the time is what kind of virus they would have, because it took several months later for Mario to actually amplify the first strain from the Gombe chimps and to show that as we would have predicted, it was a schweinfurthii virus in a schweinfurthii chimp. [00:19:00]

Meanwhile, Mike Worobey didn't want to sit on his hands, and since Bill Hamilton had died and no one had claimed the samples, he said, “Why don't you analyze them?” Ultimately, these samples ended up on my bench. Interestingly enough, we found two urine samples in this first batch that we called “indeterminate.” Indeterminate meant we had one strong band but only one band. In Western blots for HIV, you don't call that positive. In retrospect, [00:19:30] it was positive because sometimes that's how chimpanzee fecal Western blots look like.

#molecular clock

Mike was intrigued by that and in 2003, he took his own money and went back to Kisangani and sampled more fecal and urine samples in the area. This time we hit the gold, one of the samples was positive. And when Mario Santiago amplified it now together with a number of additional Gombe viruses that he had characterized it, again, fell exactly where it was supposed to fall [00:20:00] within the lineage of the schweinfurthii chimpanzee viruses.

One good thing that emanated from this fateful trip was we got to meet Bosco (Jean-Bosco N. Ndjango). I've never talked to Bosco because he speaks French, and I've never met him, but he has worked with us for almost 20 years. He was the one who helped Bill Hamilton the first time around to actually find the chimps—Martine explained to you [00:20:30] that this is not an easy task. He then also helped Mike in the second expedition and then Mike couldn't continue to employ him, so we contracted with him. He said he needed a motorcycle, so we bought him a motorcycle. First I swallowed a little bit, but then I said, well, we want him to sample in the DRC, so he needs to get around. In the meantime, I have replaced this motorcycle and he still is collecting for us and in fact, he has co-authored [00:21:00] 12 papers with us.

In the meantime, Martine geared up in Cameroon, this is her team and they went out as she described to you to collect fecal samples from various populations in Cameroon, and Martine's samples were fantastic. This is a fecal Western blot from Brandon Keele and you see the pattern. This is a positive human plasma, this is a negative human plasma and you see the pattern that you get [00:21:30] from fecal samples. Some of them are indistinguishable from the human pattern and some just give you a p24. And then with the microsatellite analysis, Brandon was able to identify the number of infected individuals. Then he amplified pieces of the genome and even the entire genome of some of them and he found that there was one group of chimpanzee viruses that was very closely related to the M group and this chimpanzee [00:22:00] virus came from one particular region in Cameroon, the south eastern corner and they only came from that area.

Obviously that was the smoking gun for the source of the pandemic version of HIV-1. You see, one of these samples here is called LB7, originally it was called LBK7 and when the guys showed me the first phylogenetic trees, I said, "Why do you call this LBK7, we usually have a two letter code that identifies [00:22:30] our field sites", and they said for, "Lucky Brandon Keele." Because he did then publish the origin of the pandemic and also the origin of the N Group here in the Dja forest (southern Cameroon). (14) Again, it should be emphasized that these viruses are only found here, there's a phylogeographic clustering because the chimps don't move around. There are lots of more divergent chimp virus lineages, but they are elsewhere, they were never found here and vice [00:23:00] versa, these viruses were never found elsewhere. 

15,000 fecal samples later, this is what we know about the distribution of SIVcpz in wild chimps. (15, 16) Yellow means positive, white means we didn't detect it. Martine sampled all over Cameroon and Gabon. Katie Gonder sampled in northern Cameroon and also Nigeria, Bosco did all of the DRC [00:23:30] and various primatologist collaborators gave us samples from these—these are the regions where most of the habituated groups of chimpanzees are. We found that indeed, SIVcpz is endemic in the central chimp and in the eastern chimp and in fact, this is the lineage that has not been found in humans. And it's interesting because the prevalence across the board is actually twice that of SIVcpz in this [00:24:00] area.

We confirmed that SIVcpz is absent from the other two subspecies, which included the western chimps, which were over 90% of the primate center chimps from. And that explains why no one ever found anything in captivity. This distribution of infection made sense because Paul Sharp, in 2003, with Liz Bailes discovered that the chimpanzee virus, as Martine said, is actually a [00:24:30] recombinant of portions of SIVs that infect monkeys on which chimpanzees prey. (17)

So, like humans, chimpanzees acquire this infection by cross-species transmission and recombination. But unlike humans, they only acquire this one time, it emerged only once and relatively more recently. And in that sense, it's different from humans who acquired the virus four times. 

Interestingly enough Mike Emerman [00:25:00] then subsequently looked at this junction here with the recombination break-point and he realized that the very C terminus of the vif gene was remodeled in this recombination process. He looked at the vif function and its anti-APOBEC activity and while this protects chimps from SIV infection, because they eat monkeys every day and the monkeys are chock full of SIV. It is the APOBEC that [00:25:30] provides protection to the chimps against most of these SIVs. But the remodeling of the C-terminus now made it possible for the SIVcpz vif to counteract chimpanzee APOBEC. So it pre-adapted it to humans and that basically was when HIV-1 was really born.

As Martine said, she did also sample gorillas, when she first told me about that, I said, "It's a total waste of time, you're not going to find anything [00:26:00] because gorillas don't eat other monkeys, they are herbivores", but she did it anyways, which was a good thing because she discovered that indeed they were infected. (18) The overall prevalence was lower, although in some areas where she did sample it was high and it was restricted to Cameroon, western lowland gorillas in Cameroon. As I'll show you in a minute, it was a transmission of an SIVcpz from sympatric chimpanzees and this virus only emerged once [00:26:30]

So this is now what we know, putting this all together in black here: chimpanzee virus sequences in color, the results of cross-species transmissions. We know that HIV-1 group M and N are chimpanzee viruses that got transmitted to humans. We know that the gorilla virus is transmission from a chimpanzee as well, and so the gorilla served as an intermediary host, because then gorillas transmitted both group P and group O which was the most recent [00:27:00] paper by Martine. (19) Here are the species and as I said, there is no evidence, although this is much more prevalent, for this lineage of SIVcpz to have been transmitted to humans. 

In terms of where and when: it all happened in Cameroon, which still is one piece of the puzzle that has not been solved, because chimpanzees certainly are infected with similar SIVcpz’s in northern Gabon and probably in northern [00:27:30] Congo as well. Yet all four groups of HIV-1 come from Cameroon. The M group came from this area and then Mike will tell you how it made its way down to Kinshasa and from there to the rest of the world. The O group, which stayed locally in West Central Africa came up to about 100,000 cases, also from Cameroon, the N group from the Dja Forest, and the group P, from the Bipindi area. 

We didn't stop there, [00:28:00] we went to Gombe with Brandon Keele who took this picture here. We've studied the chimps in Gombe since 2000, so for almost 20 years, and we looked at infection rates and mortality because they record everything and we realized that SIVcpz indeed can cause immunodeficiency and CD4 T-cell depletion in wild living chimpanzees.

This is my daughter: my kids, their rite of [00:28:30] passage is to work in a lab in the summer and the first thing they learn is how to extract DNA from shit samples and then on occasion, they get a perk. She really loved this trip and she's going to be a vet, so this is good. 

We looked at the mortality rates and Brandon published this in 2009, showing indeed that SIVcpz infection was associated with an increased risk of death. (20) We now have triple the time of observation [00:29:00] and the estimate will be closer to 10 than to 16, but it is clear that SIVcpz has a pathogenic effect on these chimps in the wild. Jake Estes helped us with some of the necropsy samples that we obtained to show that positive chimps indeed have significant lower CD4 T-cell counts and exhibit AIDS like immunopathology.

Going full circle, this is Cotton. Cotton was experimentally infected in 1996, he's one [00:29:30] of I think only six chimps who was ever mucosally infected with an SIVcpz. He got the virus from Noah, that Martine talked to you about, that was the chimp from Antwerp, the very divergent first strain. We studied him because we were interested in potentially looking for cross-reactive neutralizing antibodies because we realized he had a very high viral load for a very long period of time ranging [00:30:00] between 100,000 and a million, and indeed, when we checked, after he was transferred to Chimp Haven, he had a CD4 T cell count of less than 300 and when we talked to the vets and told them this, he said, "As it happens, he has aggressive and persistent soft tissue infections that do not heal despite the fact that they used multiple rounds of antibiotics."

We said, "It's time to treat this chimp and we did with [00:30:30] Truvada (FTC (emtricitabine)+tenofovir) and dolutegravir, and this is what his viral load did, of course the soft tissue infections disappeared, we had a blip and it's a story for another day, there is some differences in pharmacokinetics. But the bottom line is, P. t. verus chimps—this is the Western subspecies that is not naturally infected—is susceptible to SIVcpz infection and can develop immunodeficiency even if it takes 20 years and it can be effectively treated with antiretroviral [00:31:00] therapy. Indeed, there is still a good number of HIV-1 and SIVcpz infected chimps in American primate centers and they should be monitored because they may benefit from treatment like humans.

#funding and grants

The many samples that we collected, we didn't just forget about them. Martine and I are probably the women who turn shit into gold. We did this on multiple fronts. We worked with Ann Pusey and many other [00:31:30] collaborators from the Jane Goodall Institute and used genetic studies, host genetics from the fecal samples, to look at behavior like paternity, and do fathers recognize their offspring, and aggressive behavior et cetera with Mike Emerman and Frank Kirchhoff. We have multiple, multiple papers on restriction factors because we amplified the accessory genes from SIVcpz and SIVgor and they looked functionally to what extent they represented [00:32:00] barriers of cross-species transmission.

Mike will talk in more detail about this tomorrow and with Howard Ochman and others, and Andrew Moeller, we looked at the ape microbiome. The last thing we did and you may recognize the same people again, here is Martine, here's Paul Sharp, and here's George [Shaw], and Eitel Mpoudi-Ngole, we've been working together almost 30 years. Because Martine and collaborators [00:32:30] from France figured out that you can not only detect SIV in fecal samples, you can also detect Plasmodium parasite nucleic acids. We discovered, looking at the many fecal samples, that Plasmodium falciparum, which is the malignant malaria in humans, is also of ape origin and in fact, it was a single cross-species transmission, this time from a gorilla about five to ten thousand years ago. (21, 22)

Similarly, [00:33:00] Plasmodium vivax, which is the most prevalent parasite outside of Africa, is also of African ape origin. There must have been at some time a stock of vivax that infected both chimps, gorillas and humans, until humans developed a protective mutation, the Duffy negative phenotype, which means they had a mutation that prevented expression of the receptor for vivax, which is the Duffy antigen. Cosmopolitan vivax right now [00:33:30] is the result of an escape of this parasite out of Africa before the curtain of Duffy negativity came. This is what we have done with the fecal samples and we will continue to work on apes and their infections.

I've mentioned many collaborators but I haven't mentioned my current lab and our funding. Thank you NIH for allowing us to do these studies for the past 20 years. Weimin [Liu] and [Yingying Li], [00:34:00] involved in the malaria work, as is Sesh [Sundararaman], where is he? Somewhere and also [Dorothy] Elizabeth [Loy] works on malaria, Hannah [Barbian] did the chimp studies, Gerry does all our phylogenetic trees. And when we get a grant, we celebrate, and when we celebrate, we don't have a pool party because I don't have a pool but we go to the zoo. When we get a big grand, we go to a big zoo. This is the Bronx Zoo and we had a fantastic time. Thank you very much.

[applause] [00:34:30] 

Anchor
qa
qa

Ruth Ruprecht (Moderator): Thank you, Beatrice. Questions, Doug.

Douglas Richman: So B, that's a great story. The one thing that I can't put together from looking at all of this is there are these different phylogenetic branches of both the gorilla and the chimpanzee viruses, they [00:35:00] clearly have a common ancestor because of the recombination. You say these groups don't migrate and so on, so what can you tell us about the timing and the distribution and how this virus originated and how it spread to these different groups?

Beatrice: That's what Mike [Worobey] is going to do in the next 30 minutes.

Douglas: Oh, good.

[laughter]

Beatrice: Don't steal his thunder.

Ruth: Other questions.

David Gludish: [00:35:30] My question on a similar note, so the chimpanzee virus that became a gorilla virus, it's pathogenic, you've shown, in chimpanzees. First question is, is it also pathogenic in the gorillas?

Beatrice: As Martine said, this is very difficult to study because we don't have habituated gorilla populations that can be studied on a day-to-day basis that are infected, unfortunately. She's trying to do this noninvasively because [00:36:00] they stay put and she's using microsatellites to do that. It's a heck of a lot more difficult than to do this in a place like Gombe.

David: The second question is, you probably thought at some length about this, anecdotally, what do you think it is about the chimpanzee and the human virus that makes it pathogenic in their natural hosts compared to the SIV, the large bulk of them that don't cause disease?

Beatrice: Two strains of [00:36:30] SIV have been really characterized in great detail, the African green monkey and the sooty mangabey virus. They really are not pathogenic. Guido Silvestri has written books on that. (23, 24) The big difference is, these animals, when they are infected, they don't have the immune hyperactivation that you see in HIV-1. Exactly how that works and why these viruses are pathogenic and the other ones are not is still being worked on. Guido some good leads. They, for example, [00:37:00] spare cells that you should spare and they infect specifically cells that are destined to die anyway. We haven't learned that yet. That is one aspect and there may be other aspects.

#women in science

 

 

 

 

 

#malaria, Plasmodium

 

 

 

 

 

 

 

 

 

Jump to:

Mike Worobey: Since it's a conference about history, I just wanted to correct the record on a couple of small points. I wasn't [Bill Hamilton's] student, we were colleagues in the department of zoology. Bosco, was someone I met on the second trip. The first trip, we were kind of freaked out and kept our heads down and [00:37:30] we were scared of anyone who we talked to that they might try to extort money from us. The second trip, I went to the University of Kisangani and talked to the deans there and they put me in touch with Bosco. It was the most extraordinary thing, a country that had experienced years of civil war, the people at the university wanted to do nothing except help with the research.

Beatrice: Bosco has been fantastic. I can tell you to send fecal samples from Kisangani [00:38:00] is easier than to send blood from Boston.

[laughter]

Ruth : Any more questions?

Monica Green: Yes, hello. I'm one of the historians here and I just want to say for the record so everybody knows this, the work that the Hahn lab has done, both for HIV and for malaria, is turning around everything that we as historians can say about the history of these two diseases. It is absolutely radical, which is [00:38:30]why I want to ask the historical question, which is: the timing of the transfer into humans of HIV-1. Could you just say a few more words about how that determination is made? Because that's still being contested by historians, they want to say it's a variety of other dates.

Beatrice: Mike, will you cover this?

Mike: That I'll cover. Doug’s thing, I might not cover.

Beatrice: You may not?

Mike: Doug’s question, I won't go into too much detail if you want to--

Beatrice: I think there [00:39:00] are now phylogenetic methods that are very sophisticated that allow you to trace back the last common ancestor. In fact, when Bette [Korber] first did this was many fewer sequences than are available now, she had controls in there, because she had sequences from human samples that were dated 1959 and later 1960, and now Mike has a whole collection of samples that came from a couple years later. When she did the estimation, [00:39:30] she did it without those sequences. Then she put those sequences in as a query and said, "My algorithm, when would you tell me that these sequences existed", and the computer spit out exactly the date that they had been collected.

That is how this is controlled. That's why we know it was 1920 plus minus 10 years and that HIV would have already or soon celebrate [00:40:00] its 100's birthday.

John Coffin: To return to Doug's question, what is the best estimate from your—from Mike, as to when the chimpanzee virus actually was created if you like? When was the first chimpanzee infected? How long ago?

Beatrice: We don't want to say anything because these time estimates are great on the short scale—

John: Yes, sure.

Beatrice: —but they are sucky when it goes—

John: Yes, you're pointing with a rope, but [00:40:30] give a guess.

Beatrice: I don't know, 5,000 years, 10,000 years.

Mike: Thousands of years probably and I think—[crosstalk]

John: Does that correlate, again to go back to Doug's question, does that correlate with what we think we know or what some people think they know about how the chimpanzees have historically moved around? Because the virus' infection spans a very large distance, thousand miles or something like that probably.

Beatrice: There's two subspecies that are not infected (Pan troglodytes verus, the Western chimpanzee, and Pan troglodytes ellioti, the Nigeria-Cameroon chimpanzee) have separated from the two that are infected much, much earlier [00:41:00] than that. Troglodytes and schweinfurthii I think is separated about 100,000 years ago and then—

Mike: Something like that.

Beatrice: —the other two, millions.

John: So the virus spread, somehow long after the animals, unlike the situation probably with African green monkeys for example where the virus followed species.

Beatrice: Correct, yes.

John: How did the virus actually move around over all these distances, any speculation on that?

Beatrice: The way it moves around in Gombe and surrounding [00:41:30] areas is by migrating females. In the chimp social structure, it's the adolescent female that leaves the nest as an avoidance of inbreeding strategy. We have seen many instances where infected young females go from one community to the next and they bring in the infection. So in an area like the DRC where the forests are still largely intact, at least in some of the DRC, you can see this happening, [00:42:00] the more fragmented a habitat becomes, the more difficult it gets. That's probably the reason why on the very eastern edge of the eastern chimp (P. t. schweinfurthii) habitat, almost all of the sites are negative.

John: They still have to cross some rather major geographic barriers I would imagine in between those rivers and mountains and things.

Beatrice: You know, the Gombe guys tell me what the chimps do and don't do and then we come across something that they totally did not expect. One thing [00:42:30] I can tell you, they're not stupid. [laughter] 

Ruth: It's good for us.

[laughter]

[00:42:40] [END OF AUDIO]

#First and Second Congo Wars (1996–2003)

Citations

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  10. Moore, John P. “Up the River without a Paddle?” Nature 401, no. 6751 (September 1999): 325–26. doi:10.1038/43778.

  11. Korber, Bette, Mark Muldoon, James Theiler, Feng Gao, Rajan Gupta, Alan S. Lapedes, Beatrice H. Hahn, Steven Wolinsky, and Tanmoy Bhattacharya. “Timing the Ancestor of the HIV-1 Pandemic Strains.” Science 288, no. 5472 (June 9, 2000): 1789–96. doi:10.1126/science.288.5472.1789.
  12. The proceedings of the "Origins of HIV and the AIDS epidemic" conference were published in Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences vol. 356, no. 1410, https://royalsocietypublishing.org/toc/rstb1990/2001/356/1410
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  14. Keele, Brandon F., Fran Van Heuverswyn, Yingying Li, Elizabeth Bailes, Jun Takehisa, Mario L. Santiago, Frederic Bibollet-Ruche, et al. “Chimpanzee Reservoirs of Pandemic and Nonpandemic HIV-1.” Science 313, no. 5786 (July 28, 2006): 523–26. doi:10.1126/science.1126531.
  15. Boué, Vanina, Sabrina Locatelli, Floriane Boucher, Ahidjo Ayouba, Christelle Butel, Amandine Esteban, Alain-Prince Okouga, et al. “High Rate of Simian Immunodeficiency Virus (SIV) Infections in Wild Chimpanzees in Northeastern Gabon.” Viruses 7, no. 9 (September 2015): 4997–5015. doi:10.3390/v7092855.
  16. Sharp, Paul M., and Beatrice H. Hahn. “Origins of HIV and the AIDS Pandemic.” Cold Spring Harbor Perspectives in Medicine 1, no. 1 (September 1, 2011): a006841. doi:10.1101/cshperspect.a006841.
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  23. Ansari, Aftab A., and Guido Silvestri. Natural Hosts of SIV: Implication in AIDS. Amsterdam: Academic Press, 2014.
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