4.4 Michael Worobey — Spread of HIV in the New World

Michael Worobey: [00:00:00] Thank you very much. I imagine I wasn't the only person who was thinking, I'm pretty sure I've been called stupid by Beatrice Hahn at some point in my career. The chimps have a higher place in the order of things. First, I want to say, as so many people have, what an honor it is to be here with such distinguished people [00:00:30] and thank you, John [Coffin], for the invitation.

I'm going to carry on the story from where Ron [Desrosiers] and Martine [Peeters] and Beatrice left off, and I'm going to concentrate on getting us back to this morning's talks. When people like Mike Gottlieb and Paul Volberding started seeing clusters of these people without functioning immune systems, [00:01:00] that was the kind of end result of all of the things that we've been hearing about.

Of course, we've gone over this in detail, but very briefly, of course, this virus appears seemingly or this syndrome appears seemingly out of nowhere in the early 1980’s and there are various clues and tremendous suffering and [00:01:30] death of the kind that we don't see anymore, at least in this country for most people. (1) The question at that point was: What is this? Where is this from? That's a question that's intrigued me. Unfortunately, I don't have any anecdotes of much interest about what I was doing at this point because I was I think, eight years old. I skinned my knee roller skating, I remember that. [00:02:00]

We've covered some of this early history so I'll just move along and before I get onto, or back to North America, I want to just condense what we've heard with the image of these Russian dolls. What people were seeing in 1981 was kind of a, the inner Russian doll [00:02:30] of this nested process, where now, with the benefit of hindsight, we know this is a lentivirus that affects many orders of mammals. It was a primate lentivirus, it was—The pandemic human virus was earlier a chimpanzee virus. 

So there are these series of bottlenecks that this pathogen passed through, and it was a very derived, [00:03:00] as we say, in the phylogenetics world, a very derived lineage that was infecting these young gay men.

If you look at a map of the world, the virus that was identified in California, in Mike Gottlieb's paper in Los Angeles, was what we now call subtype B, which is one of several sub-types of this chimpanzee [00:03:30] virus. One of multiple chimpanzee viruses that have crossed the species barrier that we call HIV-1 group M, the main group of HIV-1. (2) The distribution and patterns of the subtypes tell us something. The greatest diversity genetically of this virus by far is in Central Africa, in places like Kinshasa (DR Congo) near where these primates [00:04:00] that donated the virus come from. I don't have time to do a really comprehensive history, but I wanted to touch on some key landmarks. 

Beatrice has already mentioned [Bette Korber's] paper that suggested maybe this virus was already on the scene say in 1920 or 1930. (3) [00:04:30] Bette had this one little bit of a fragment from this 1959 sequence that David Ho's group had sequenced earlier as a kind of a safety check. (4) Even if you are someone who doesn't spend all day looking at phylogenetic trees and you're skeptical, you take a bunch of sequences from the 1980’s, '90s and you run these programs and it spits out an answer of [00:05:00] an ancestor in 1920, viruses like this 1959 one give you some reinsurance and I'll add to that in a second. 

Another key paper—kind of a very, very short paper—is this one by [Andrew] Rambaut and colleagues in Nature, and it shows those that if you step back to this area of Central Africa, which is the epicenter of the pandemic of the main group of HIV-1, [00:05:30] the patterns of genetic diversity look a lot different. (5) Other places, you have a epidemics dominated by one subtype, or a couple of subtypes like subtype B in North America. Back in Central Africa, you not only have all of the different sub-types, but you have a whole bunch of sequences that don't really fit. That is the kind of genetic signature of the epicenter, and I'll get back [00:06:00]into that in more detail. 

One of the contributions that our archival sequences have made is to now be able to do comparative genetics on sequences in the past. You take this '59 sequence and this 1960 sequence and you can now step back in time, forget about inferences from modern sequences. (6) You can step back in time to [00:06:30] 1960 and see that there was already a lot of genetic diversity. This evolutionary tree needed several decades of transmission in humans to generate that level of genetic diversity.

At a very basic level, I think what happened to allow this primate virus [00:07:00] to successfully emerge in humans was probably quite closely related to changes that happen in Central Africa with the Scramble for Africa (1884–1914). Europe was divvying up the continent, and you had an influx of people and development, and you went from an area, the area where these chimpanzees range that Beatrice was talking about that had very little [00:07:30] dense population centers, very little connection between centers to all of a sudden stitching together, larger populations into a network of steamboats running up rivers, railways. This recent paper by Nuno Faria and Philippe Lemey and colleagues show some very nice work about how railroads were probably key routes that the virus emerged out [00:08:00] of Kinshasa. (7)

In a way, my talk today is a tale of two cities. It's about Kinshasa on the one hand, which was a major landmark where the virus got into the biggest urban center in Central Africa very early on, and then New York City, which I'll get to in a moment. But this is just a quick picture to show that if you go back to the timing of the common ancestor of the virus. It was the same period [00:08:30] that you go from, no big cities to all of these cities being founded and growing over the 20th century.

Now, I want you to look at this. I'm going to—It's five minutes to 10, but I'm going to force you to look at this phylogeny for a second. (8) Because if you can see: This is now HIV-1 group M. Sub-type B is the one that killing these young gay men in Los Angeles in 1981, and it's just one of several sub-types. [00:09:00] The black branches here are lineages that were sampled in Kinshasa in the Democratic Republic of the Congo and if you can see here, they're what we call basal sequences. They're branching off before the rest of the genetic diversity and that is the signature of the source. You see the same pattern in human mitochondrial DNA, where in Africa, you have a great diversity and then outside of Africa, you have [00:09:30] restricted clades of genetic diversity. We see the same thing in HIV and SIV repeatedly. It's these Russian dolls where you have a wider diversity, and then you have a bottleneck as the virus moves into a new species or a new population. 

When John [Coffin] invited me here, he asked me to talk about some of the work I've done specifically on the origin of the North American [00:10:00] epidemic. What I wanted to do with this when I started it was to go back to a sort of a new take on an old question,  about whether the virus that emerged in North America had passed through Haiti in the Caribbean as a stepping stone, or whether the virus had moved into North America and then from there to Haiti. (9) [00:10:30]

There's a pretty clear phylogenetic prediction for each of these scenarios. If the virus moves from Africa into Haiti first, it starts diversifying and the basal lineages within this subtype are going to be in Haiti, and then the subsequent move to the US means that the US is going to be nested [00:11:00] within Haiti. If it's in the US first, it's going to look the opposite way. What I did was I went back to one of the first reports of AIDS in people outside of the MSM community by Arthur Pitchenik, Margaret Fischl was the co-author on the paper too. (10)

This was actually, [00:11:30] compared to some of the other work I've done, incredibly easy. I got the paper from 1983, it had Arthur Pitchenik's mailing address and his phone number and 25 years later, I picked up the phone and phoned the number on the 1983 paper. Immediately, Arthur Pitchenik who I didn't know, picks up the phone and says, "Hello." I said: “I want to answer [00:12:00] this question and if you happen to have samples from some of those patients…?” and Arthur was someone who was seeing AIDS-like symptoms in Haitian immigrants in Miami in the late 1970s early 1980s.

Arthur said, "Yes, well, I sent PBMC samples to Tom Spira at CDC so let's phone him up." Within a few days, we'd located the samples, [00:12:30] and I was able to sequence complete envelope genes from a number of these samples from people who had quite recently moved from Haiti into Miami from 1982, 1983. They are dotted here. What you see is this clear pattern of deeper genetic diversity in Haiti, and restricted [00:13:00] genetic diversity in the USA and all of these other countries. This is consistent with this directional movement where the virus emerges first in Haiti and then subsequently moves to the US. I published this in PNAS in 2007. (11)

Not only does the geographical pattern tell a very strong story, it also tells you some other more subtle points. [00:13:30] It could have been that when we did this work that there was so much movement of the virus from the US to Haiti to wherever else that the whole thing could have been a mixed mess, but it's not.

Virtually, all of the sequences in the US actually come from a single migration event. It doesn't mean that the virus didn't move country to country more often than [00:14:00] that but it means that the one that was successful and really took off traces back to a single genetic bottleneck. 

When you do this kind of work—and this gets back to the historian’s (Monica Green's) question about how do you do these estimates? If you have virus sequences taken at different time points, you can do a nifty thing that it's called using a molecular clock, and it's pretty simple [00:14:30] conceptually. Let's say, you have a saguaro cactus in your back yard, and you want to know how old that cactus is. If you just stare at it for a long time it's hard to tell but if you happen to have a photo let's say from 1999 and another one from 10 years later, now, you have a way of calibrating how quickly this thing grows. Even if your only photos come from [00:15:00] relatively recently, you can then extrapolate, make the assumption that the thing has been growing at about that same rate, and start to make some reasonable guesses about when that thing sprouted. We do the same thing with the viruses. 

When you do that with these subtype B sequences, you get a pretty early date. This has become much more widely accepted now but when I initially submitted [00:15:30] this paper to Science, got a couple of good reviews but one person, who the editor told me was a very eminent AIDS researcher, just kind of knew that that wasn't possible. That the virus could not have been in the Western hemisphere since 1966, couldn't possibly be true. The paper was rejected, but was accepted [00:16:00] in PNAS, and that's where things stood nine years ago.

Let me just pause and do a couple of mid-point conclusions here. One, is that if that dating is correct that means the epidemic outside of Africa is [00:16:30] already about 50 years old and that timing actually fits well historically with a fairly large movement of people from Haiti to the Democratic Republic of the Congo when that country became independent from the Belgians. The Belgians had been quite careful to not train local people to high levels in various professions, so there's a vacuum of professional people. A lot of Haitian people who were well [00:17:00] educated and held professional jobs moved in to help. It's possible that one of those people then brought the virus back to the Western hemisphere. 

It also means that subtype B genetic diversity in Haiti is more extensive than the US. For example, if you wanted to make a vaccine based on subtype B and use it everywhere where subtype B circulates, that's something you might want to know. It's exactly the same concept [00:17:30] that suggests you might not want to just use a subtype B vaccine in Kinshasa because the genetic diversity is greater. Same idea, may not be the case that the genetic diversity in both places is the same.

When I published this, it created quite a lot of controversy including being called out by Wyclef Jean, which the younger people in the audience might find [00:18:00] more interesting than the rest, but basically I was dissed by a famous rapper. (12) But it was a serious thing and I was actually mortified that what I think is important about this amongst other things, amongst this idea of connecting genetic diversity to some of the interventions that you might want to do is also that this virus had several [00:18:30] more years to spread unchecked in this country than it did in say the US. Part of the stigmatization of Haiti over the years has involved the high prevalence of the virus there. To me, this is part of an explanation of that, that this country has been dealing with HIV for longer than other places. This actually ended up in Newsweek with [00:19:00] the ambassador from Haiti making this statement, "How do we know that a homosexual infected in America didn't bring HIV to Haiti instead?" (13) To that, I would say, I think the proper response to this, of course, is that a virus that was spreading long before anyone knew anything about it is not something that you want to be pointing the finger at any group about. [00:19:30] 

Now, let me turn to a sort of update. This is work now that is going to come out in about a week and a half. (14) To really finish this off, I thought what we really need to do if—you're skeptical about this geographical origin that I've talked about—what you really want to do is you want to look [00:20:00] in early US sequences, early US HIV, and see if you can find lineages that are even more basal even closer to the root. That's the way you try to test this hypothesis. I don't have a lot of time, so let me just hit the key points here. Looked at a whole bunch of samples, colleagues at the CDC including Harold Jaffe and Walid Heneine [00:20:30] helped screen thousands of samples that came from MSM volunteers in HBV (hepatitis B virus) research from the 1970s. Already in the 1970s, you had 6.6% prevalence in this high-risk cohort in New York City, 3.7% in San Francisco.

My longtime lab manager Tom Watts, [00:21:00] worked for many years on methods to try to recover sequences from highly degraded samples. These samples are sera positive, but if you try to do PCR amplification on them to get HIV, you don't get anything. He developed something that we call RNA jackhammering. To cut a long story short, it works, and you can take something that has unquantifiable RNA, [00:21:30] and get not just sequence, but complete genome. We have eight of the nine oldest complete genomes and they show us this orange—yellowish-orange sequences are all from Haiti and other Caribbean countries.

Even though these complete genomes come from the earliest time point, there're still nested within this US clade. The New York ones—I think I have a better close up here. Let me just go to here. [00:22:00] The ones from New York from the 1970s are extremely diverse. The ones from San Francisco in 1978 are very, very similar to one another. If you think back to the Russian dolls, these Californian cases are the tiniest doll inside. They are the most nested of the nested dolls. What that's telling us in these circles [00:22:30] here, there's a lot of statistics that go into those. Essentially, what you're looking at is a very, very strong probability that New York City was the key hub for the dispersal of subtype B not just in the US but to other countries around the world.

You can work out the population dynamics of hosts over time. [00:23:00] From an African virus the progenitor or the virus that jumps into the Caribbean, there's a period where it starts growing. This is roughly the number of hosts infected. In the Caribbean, you have an earlier origin—less steep, less rapid growth, and then an earlier plateau. In the US, it gets there later, but it then explodes very [00:23:30] quickly to the point where by the time people like Jim Curran were working on the epidemiology of this, indeed there must have been hundreds of thousands of people infected by the time those first cases were noticed. 

Now, back to this cluster diagram to round things out. Jim put up this cluster diagram, Harold is a co-author on the paper, [00:24:00] and that famous patient zero who's taken on mythological status. (15) The other thing we do in the paper is with a co-author who's a historian who has worked out in forensic detail how this idea of so-called patient zero playing some special role happened.  [00:24:30] Before the paper was published, this patient who was this French Canadian air steward. He was the one who was from “Outside of California.” He was initially patient O, but the co-authors when reading this started calling him patient zero before the paper was published. By the time the paper was published, he actually did become “patient zero.” [00:25:00]

Randy Shilts (1951–1994) then wrote a famous book And the Band Played On. (16) Patient Zero played a pretty prominent role but it was in the promotion of the book, the publisher, and this is Rich McKay’s work, really tried to sell the book on that basis of this false idea that patient zero was a Typhoid Mary Mallon of HIV, which he never was. (17) If you go back to the paper, [00:25:30] that's just not what he was represented at all. (15)

This cluster study, when they did this paper, they noted that these contacts suggested an incubation time of 10.5 months. Jim, [00:26:00] I actually disagree with the interpretation you offered earlier that this cluster study represents an astronomically improbable collection of individuals who progress to AIDS within a year or two of being infected. Instead, almost certainly what this represents is a kind of echo of individuals probably most of whom were infected with the virus [00:26:30] sometime after about 1970, when we did jump into the US.

Then only after the virus was in all of these individuals did Bill Darrow, and Dr. [David] Auerbach and the others interviewed them—and they only thought to ask them about their sexual history over the last couple of years. I think [00:27:00] in the interest of time, I'd better leave it at that and just quickly race through some acknowledgments including my funding. I just wanted to end on a picture of Bill Hamilton, one of the last photos taken before he died trying to work out some of this origin of this virus that we're all interested in. Thank you very much.

[applause] 

Ruth Ruprecht (Moderator): [00:27:30] Thank you very much, Mike, for a great talk. Questions?

Susan Zolla-Pazner: In the studies that Phillipe Nyambi did, in which he looked at hundreds of specimens from Cameroon, he never found any clade B viruses. (18) What do you know about clade B in Africa or how that particular clade turned out to be the founder in the US? [00:28:00]

Michael: I'm going to zip back to a slide earlier in the talk. There is one sequence here in black, and that is from Central African country I think Gabon. That would represent a back migration. And [00:28:30] there's nothing particularly mysterious. You have all of these different lineages in black that circulate in Kinshasa. At some point, the virus is drawn from that distribution. You just could have taken any one of these sequences from Central Africa at random and popped it into a new part of the world where it then evolves and that's what gives this subtype pattern. It's just artifact of a founder event. [00:29:00] That virus clearly was a subtype D virus. Once it was isolated and amplified in a different place, we gave it a new subtype name. Jim?

Jim Curran: Michael, this is terrific and I agree with 90% of the things you said. In particular, I think that the issues related to Haiti or this is very [00:29:30] informative and improves the concept. There was a doctor I think Bernard Liautaud who was a dermatologist from Haiti who made a report on Kaposi’s sarcoma in the late 1970s as being epidemic in Port-au-Prince. (18, 19, 20) There is quite a bit of evidence that the disease was only going on in Port-au-Prince, not in the rural areas, which is different from any other areas of developing world.

Now, back to the cluster. [00:30:00] We're talking analysis in speculation about apples and oranges. To me, your apples, which are highly scientific and logical, relate to the genetic sequences of viruses, which have been sampled at one point in time and relate to one thing. What I was saying is that in—We know that there's a distribution of what we'll call [00:30:30] incubation periods, the time from infection to illness and the distribution related to some people getting sick within a year, and other people remaining healthy for 15 years with what looked to be like a mean of about 10 years in adults in the United States at a point in time when the natural history was actually studied.

Now, the question is how can you find certain epidemiologic patterns and what is the likelihood of [00:31:00] finding such patterns? One example would be we had very few cases that were found related to transfusions or cases that were found related to exposures to an infected dentist and it took—a dentist who had transmitted the virus to four people who all developed illness within 15 months. It was that coincidence of, in that case, short incubation periods.

[00:31:30] What we did with the cluster investigation is, Bill Darrow and Dave Auerbach went around the country and they interviewed personally 90 of the first 220 gay men who have been diagnosed in the United States and 40 of those 90 reported direct sexual contact with one of the other ones. Now, IRBs aside—this was done in the context of a public health emergency investigation, right? They showed pictures actually, and talked to people about these other [00:32:00] people.

So the question is, how might one I've ever found somebody that you had sex with? And it didn't matter what the time period was unless they were all short—many of them were shorter incubation period cases. Also, if you think that as you and I both agree that there were hundreds of thousands of people infected by them, how come they're only—who would be the first 200 cases that would be diagnosed? Logically, a lot of them would be in the short end of that tail of incubation periods. [00:32:30]

So that the 250,000 people that were infected would have a mean incubation period of 10 years. Whenever they got infected—there would have been a large numbers by then and you wouldn't expect half of them to have sexual contact with each other. So that’s—I don't know how long incubation period was. I'm just supposing that it would be impossible if it had been on an average distribution of what we knew to be the incubation period from the natural history studies.

Michael: [00:33:00] Yes. I agree with that.

Jim: We are not talking about the same thing.

Michael: I agree with a lot of that, and I think we could probably agree on the statement that we don't know how many of those 40 cases in that cluster actually got the virus from the direct link that was recorded in the cluster. Let me just give you one critical example. This [00:33:30] whole idea of patient zero did have its genesis in that patient being at the center of the cluster and the thought was that he was the link between the East Coast and the West coast. Between New York and California.

Jim: I don't think we ever said that.

Michael: Oh, okay.

Jim: Randy Shilts did, and he wrote an article on California magazine and he [00:34:00] called this person patient zero and he propagated this. We implied that he was the initial part of the investigation that started with Dr. Auerbach in Los Angeles and also the isolates that were initially isolated in the United States weren't from Dr. Gottlieb's patients, of course, they were from [cosstalk]

Michael: I think Harold [Jaffe] disagrees with you.

Jim: Or just read the paper.

Michael: Yes, well, yes.

Jim: I don't think [00:34:30] we said that he was a central case to the world or anything.

Michael: No, no, absolutely. But you did say, propose that he was the link between the coasts and Harold sent me this slide. This slide comes from internal CDC discussions before the cluster study was published and [00:35:00] Harold sent me a series of them. This patient kind of migrates from the periphery to being essential. I mean, you can look at it, right? LA cases on the left [crosstalk]

Jim: There were 40 cases in the cluster.

Michael: Yes, I understand that. At any rate, I do think that that was an assertion in the paper. It's dissected in this paper, that's coming out in May.

Jim: He lives in Montreal in California and he visited New York. [00:35:30] He lived in Montreal in New York and he visited California.

Michael: Aside from that, there he is his sequence on the tree and it's not something that—

Jim: How did you get 1978 sequences? That comes from the cohort? You isolated from the amplify the antibody specimens?

Michael: This is RNA sequence—[00:36:00] viral RNA sequence complete genomes.

Jim: Where do they get those? Maybe they went back for it.

Michael: These are from HBV cohorts in both New York City and San Francisco.

John Coffin: You're well aware what I found it be quite an insightful book by Jacques Pepin called The Origin of AIDS, which—I think he gets a [00:36:30] very large part of the story as we've heard it pretty much right as far as I can tell, at least not being at all familiar with the details. (21) But he does, in one photograph, point to an individual who he claims has a high probability of being the person who brought the virus, brought HIV from Africa to AIDS and founded the local epidemic in Haiti. Then, which of course then moved on to the US. [00:37:00] Do you buy that?

Michael: I don't buy that actually. One thing I didn't mention is in this discussion of evolutionary trees, what we can say is that to get back to the US, the US has definitely nested within Haitian genetic diversity. That doesn't mean a Haitian person brought the virus to the US it could have been an American—

John: Of course.

Michael: There's also another possibility that a lot of blood products used in the US, and this is mentioned in [00:37:30] Pepin's book, came from Haiti from the Hemo Caribbean Company, a commercial company until the mid '70s. When I published that PNAS paper, I got a zillion emails. One of them was from someone who said: I used to work at the airport in Miami, and we got these planeloads, cargo planes, just chock-full of blood in the mid-1970s. [crosstalk]

Jim Curran: There were many cases that many of the [00:38:00] early cases had vacationed in Haiti and had sex in Haiti.

Michael: Oh, yes.

Jim: It doesn't mean how it happened but I mean it—

Michael: Yes, absolutely. There was definitely migration in both directions.

John: I think it probably is quite probable even individuals who brought whatever whoever he was brought the virus into Haiti probably was Haitian.

Michael: I think that's very possible because of that movement of people.

John: People from Haiti going to Africa.

Michael: Yes, but it's worth emphasizing there again, that [00:38:30] it's because Haitians stepped up and actually we're trying to help out in another country. It's a quirk of history. Robin?

Robin Weiss: Mike, that's a great story, and it's such a pity we lost Bill Hamilton, even though he was chasing the wrong theory. I want to come back to your very last remark, because I remember reading, I think it was [00:39:00] Jacques Pepin's book about Haitians being drafted in the UN peacekeeping “forces” during the war of succession of Katanga in the Congo immediately after independence. How much was the economic migration and how much was the UN?

Michael: I'm not aware of that. There were Cubans that definitely fought in Katanga.

Robin: [00:39:30] They have fought along the Caribbean islands.

Michael: A lot of the Haitians who worked in the Congo were teachers that were working under a UN program.

Bob Gallo: In the end, I think it's a kind of a barroom talk because, who gives a damn what person brought it. I mean, a person brought it. We're going to spend the night talking about whether it was this guy or that guy, the country may be important. It's interesting historically, but in the end, who gives a damn? That discussion will go on forever. [crosstalk] When you quote Randy Shilts’ book, [00:40:00] I mean, Jesus, he has Jim Goedert as the director of Cold Spring Harbor, when Jim Watson was the director, that's just the nature of his scholarship. The Band Played On is filled with nonsense. We use it as a quote even as a joke.

Michael: Which is actually why it's worth pointing out that there's no reason to think that that particular patient played any special role.

Bob : Oh, good. I misunderstood you. I thought you were saying [crosstalk]

Michael: Yes, no, just the opposite.

Bob : I misunderstood you. [00:40:30] I thought you were saying [unintelligible 00:40:34].

Ron Desrosiers: I propose that we continue this in the bar.

[laughter]

[applause]

Michael: I agree.

Ruth: Thank you all for the great discussion.

[00:40:44] [END OF AUDIO]

Index

• 1.1 James D. Watson — Welcome 
• 1.5 John Coffin — The Origin of Molecular Retrovirology 
• 2.0 Michael Gottlieb — Introduction to Session 2 
• 2.1 Paul Volberding — The First Patients 
• 2.2 James Curran — Deciphering the Epidemiology of AIDS 
• 2.4 Robert Gallo — Discoveries of Human Retrovirus, Their Linkage to Disease as Causative Agents & Preparation for the Future 
• 4.0.2 Ruth Ruprecht — Session 4, Introduction 2 
• 4.1 Ronald Desrosiers — The Origin of SIVmac: Non-human Primate Models for HIV 
• 4.2 Martine Peeters — On the Road to HIV: Primate Lentiviruses 
• 4.3 Beatrice Hahn — Apes to Humans: The Origin of HIV 
• 8.2 David Ho — Unraveling of HIV Dynamics In Vivo 
• Auerbach, David 
• Belgium 
• blood — banks, donors, plasma, screening, transfusions, clotting factors (factor VIII), PBMCs 
• bottleneck — population bottleneck, genetic bottleneck 
• Cameroon 
• Caribbean and West Indies 
• CDC (Centers for Disease Control and Prevention, US) 
• Central Africa (region) 
• chimpanzee (Pan troglodytes) 
• cohort study
• Cold Spring Harbor Laboratory (CSHL) 
• contact tracing 
• control — experimental control, control group, blinded experiment 
• Darrow, William 
• demographic cohort 
• dermatology 
• Dugas, Gaëtan (1952–1984) 
• env 
• epidemiology 
• Fischl, Margaret A. 
• Gabon 
• gay men, gay community 
• Green, Monica H. 
• Haiti 
• Hamilton, William D. (1936–2000) 
• Heneine, Walid 
• hepatitis 
• incubation period 
• IRB (institutional review board) 
• Jaffe, Harold W. 
• Jean, Wyclef (b. 1969) 
• Kaposi's sarcoma (KS) 
• Korber, Bette 
• Liautaud, Bernard 
• Los Angeles 
• McKay, Richard A. 
• Miami 
• mitochondria 
• molecular clock 
• MSM (men who have sex with men)
• Nature (journal) 
• New York 
• Newsweek 
• North America 
• Nyambi, Phillipe 
• PCR (polymerase chain reaction) 
• peer review 
• Pepin, Jacques
• phylogenetics 
• Pitchenik, Arthur E. 
• PNAS (Proceedings of the National Academy of Sciences)
• public health 
• railroad 
• Rambaut, Andrew 
• San Francisco 
• Science (journal) 
• scientific controversy and consensus 
• Scramble for Africa (1884–1914) 
• sequencing 
• Session 7: Prospects for an HIV Vaccine 
• Shilts, Randy (1951–1994) 
• spillover, zoonotic disease, xenotropic virus 
• Spira, Thomas J. 
• Typhoid Mary (Mary Mallon, 1869–1938) 
• Watts, Thomas A.