Timing the AIDS pandemic and why it made history (Part I)

This week I would like to discuss two Science papers that have marked a milestone in HIV research. In order to place them in the right context, I need to start with a brief historical digression. If you're interested in the history of the discovery of the AIDS disease, I highly recommend watching the movie And the Band Played On. It's very well done and realistically portrays how the medical investigation was conducted. For the purpose of my discussion here, though, I will start from the movement known as AIDS denialism.

From Wikipedia:

"AIDS denialism is the view held by a loosely connected group of people and organizations who deny that the human immunodeficiency virus (HIV) is the cause of acquired immune deficiency syndrome (AIDS). Some denialists reject the existence of HIV, while others accept that HIV exists but say that it is a harmless passenger virus and not the cause of AIDS."

Famous "denialists" include Nobel laureate Kary Mullis, UC Berkley professor Peter Duesberg (the first to isolate a cancer gene), and biologist Lynn Margulis (who discovered the origin of mitochondria through symbiosis). Oh, and I almost forgot Serge Lang, whose math books I revered back in grad school. (In case you didn't know, being a good scientist doesn't mean you get everything right.) There's some really sad stories associated to AIDS denialism, including a woman whose firm beliefs didn't falter not even after her three-year-old daughter died of AIDS complications. In fact, she even founded an organization to discourage HIV-positive pregnant women to take anti-HIV medications. Even sadder is what happened in South Africa: despite the fact that HAART therapy (a potent cocktail of anti-retroviral drugs) became available around the mid-nineties, the advent of the therapy was delayed because the then South Africa president Thabo Mbeki, along with the rest of the African National Congress party, convinced by the denialist movement, believed that AIDS was the result of poverty and malnutrition.

Part of the puzzle was that people didn't really know how the HIV virus had originated. There were various theories, often inconsistent or almost resembling sci-fi movies: these included several variations over the theory that HIV was a bio-warfare virus engineered by the US Government; another theory was that it had spread through the smallpox vaccination; and, finally, the most realistic was that it had spread through the polio vaccine, which had been developed on chimpanzee tissue, and there was a real possibility that the tissue could've been contaminated. Of course, the fact that nobody knew for sure, deepened the roots of AIDS denialism.

Now fast forward to January 2000, when Hahn et al. published a paper in Science [1] proving that HIV had been transmitted to humans from monkeys and had originated from the SIV virus. This is the paper I would like to discuss today. 2000 was the year South Africa's President Thabo Mbeki invited several HIV/AIDS denialists to join his Presidential AIDS Advisory Panel. That same year over 5,000 scientists and physicians signed the Durban Declaration in which they affirmed that AIDS was caused by HIV. Unfortunately, it didn't stop the estimated 300,000 AIDS deaths in South Africa that could have been prevented by introducing HAART therapy.

Hahn et al. analyzed the full-length genomic sequences of distinct primate lentiviruses from monkeys. These fell into five major, approximately equidistant, phylogenetic lineages:

"Evolutionary relationships of primate lentiviruses based on maximum-likelihood phylogenetic analysis of full-length Pol protein sequences. The five major lineages are color-coded. The scale bar indicates 0.1 amino acid replacement per site after correction for multiple hits."

The above figure is a phylogenetic tree, that is, a graphical representation of the genetic distances across the sample. Each leaf in the tree represents a genetic sequence, and sequences that are most similar are clustered together. As you move from the right to the left, you can reconstruct the evolutionary history of each sequence: for example, the two sequences HIV-1/LAI and HIV-1/ELI are roughly a few mutations away, which means they share a common ancestor. That common ancestor at some point originated the sequence HIV-1/U455. Each node represents a "coalescent" event, an event in which one sequence duplicated and a few new mutations were inserted. (What I just gave you is a schematic explanation, things can get more complicated than that, but let's keep things simple for the sake of the argument.) Phylogenetic trees are constructed using maximum-likelihood methods: basically you compute all possible trees and then choose the one that maximizes the probability function associated with it (the most likely tree). Obviously, this is not done by hand but by a computer program that goes through many iterations and hence takes a very long time. Today, supercomputing machines are utilized to speed up the process.

What can we learn from the above tree? First of all, notice that the lineages are color-coded. Each color represents one lineage found in one particular primate species, and the fact that colors tend to aggregate together in host-specific clusters tells us two things: (1) each lineage has been infecting their respective host for a relatively long time; (2) a "jump" from one host to another one represents a divergence in the evolution of the virus.

"HIV infections have also resulted from cross-species transmission events. Five lines of evidence have been used to substantiate the zoonotic origins of these viruses: (i) similarities in viral genome organization, (ii) phylogenetic relatedness, (iii) prevalence in the natural host, (iv) geographic coincidence, and (v) plausible routes of transmission."

Following the above logic, evidence collected from chimpanzees from Cameron led to conclude that the HIV-1 epidemic arose as a consequence of SIVcpz transmission from a particular chimpanzee subspecies, P. t. troglodytes, to humans.

"The seeds of the HIV-1 epidemic appear to have been planted in west equatorial Africa in the region encompassing Gabon, Equatorial Guinea, Cameroon, and the Republic of Congo (Congo-Brazzaville). It is only here that HIV-1 groups M, N, and O cocirculate in human populations and where chimpanzees (P. t. troglodytes) have been found to be infected with genetically closely related viruses."

The most likely transmission route from primates to humans would have been through blood exposure from butchering and consuming raw meat from infected animals. Such cross-species transmission are not unusual (several flu strains are often acquired that way), but they often represent an evolutionary dead-end for the virus as it may not be well-adapted to the new host. That was obviously not the case with HIV-1, whose high variability allowed it to readily adapt and dodge the human immune system.

In next post, I'll discuss the second Science paper that made history in this field.

Hahn, B., Shaw, G. M., De Cock, K. M, Sharp, P. M. (2000). AIDS as a Zoonosis: Scientific and Public Health Implications Science, 287 (5453), 607-614 DOI: 10.1126/science.287.5453.607