The origins of AIDS: from patient zero to ground zero.

The HIV/AIDS pandemic has so far caused about 35 million deaths, while 34 million individuals currently live with HIV. 2 Even if this will have no impact on the course of the epidemic, understanding the factors that allowed the successful emergence of HIV-1 is important, first as a moral obligation towards the victims, but also to draw lessons that could ultimately help mankind avoid facing similar threats in the future. Over the last 12 years, much progress has been made in unravelling the complex chain of events that led to the worst pandemic of modern times. The source of HIV-1 group M (‘M’ for main) is the Pan troglodytes troglodytes chimpanzee of central Africa 4 which inhabits southern Cameroon, Gabon, Equatorial Guinea, the Congo–Brazzaville, the southwest of the Central African Republic, the Cabinda enclave of Angola and a small part of the Democratic Republic of Congo north of the Congo river (figure 1). The true ‘Patient Zero’, the one who started the pandemic, must have lived somewhere within this territory. Sequencing evidence suggests that this may indeed have been in southeast Cameroon or the adjacent areas of the Central African Republic and Congo– Brazzaville. But after some local transmission to start with, HIV-1 eventually managed to flourish and diversify further down the Congo River. Through sophisticated molecular clocks, it was estimated that the original cross-species transmission of HIV-1 group M, from chimp to man, occurred during the first three decades of the 20th century. By exclusion of other hypotheses, this initial event probably occurred through the manipulation of chimpanzee meat by a hunter or his wife, who manipulated the ape’s carcass in order to cook it. Three other ‘groups’ of HIV-1 (groups O, N and P) have been identified. They managed to infect a much more limited number of humans (≈10 000 for O, 14 for N, 2 for P, most of them Cameroonians), and are thought to have resulted from different cross-species events, each chain of transmission starting with a single infected person. If four different cross-species events, one for each group, could be recognised decades later, it is likely that other hunters or hunters’ wives got infected prior to the 20th century, resulting in epidemiological dead ends. The hunter infected his wife, both died of AIDS in their village, and that was the end of it. But then, why did HIV-1 group M become so successful in the 20th century, eventually infecting 69 million people worldwide? Some of the epidemiological success of group M, as opposed to the limited spread of groups O, N and P, may have been driven by biological characteristics of the virus. For instance, tetherin, a human protein that normally protects us from zoonotic viruses, is less effective against group M than against the other groups. But this is unlikely to explain the full story, unless one postulates that no hunter had ever been infected earlier than the 20th century with simian ancestors of group M. It seems more plausible that two factors intimately linked to the European colonisation of central Africa facilitated the emergence of HIV-1: urbanisation and healthcare. The French and Belgian colonisers created small cities where, for several reasons, the number of unmarried men far exceeded the number of unmarried women. Naturally, this imbalance led to sex trade, but for a long time prostitution in central Africa, especially in Léopoldville and Brazzaville, was of a low-risk type. Les femmes libres (‘free women’) had three or four regular clients, each visiting the woman once a week and receiving diversified services which included sexual intercourse. This degree of concomitant sexual partnerships was good enough for the virus to persist and slowly expand, but not for an exponential amplification. The exponential amplification of HIV-1 through heterosexual transmission, for instance, what occurred in Nairobi in the mid-1980s, requires high-risk high-volume prostitution, in which women have sex with a thousand different men each year. Early in the process, another factor allowed HIV-1 to expand. Starting in Cameroon and French Equatorial Africa during World War I, quickly imitated by the Belgian Congo, colonial health authorities implemented ambitious programmes aiming to control selected tropical diseases. Initially, sleeping sickness was targeted, but syphilis, yaws and leprosy soon followed. Twice a year, dedicated mobile teams examined the whole population of each and every village. Participation was compulsory. Those found to have one of these diseases were treated locally by nurses who stayed back after the rest of the team had departed. Antimicrobial drugs were not very effective then; to maximise their clinical impacts, many had to be injected intravenously, generally once a week for 3–15 consecutive weeks, depending on the diagnosis. The existence of viruses was just beginning to be hypothesized, and nobody anticipated that bloodborne viruses could be transmitted by injections. Needles and syringes were used repeatedly on any given day with improper, if any, sterilisation. In many communities of southern Cameroon, 50% of some birth cohorts were ultimately infected with the Hepatitis C virus (HCV), indicating the massive iatrogenic spread of at least one bloodborne virus. In one of these towns called Ebolowa, the intravenous treatment of malaria was the principal route of transmission of HCV among elderly people. Around Nola in the Central African Republic, the worst ever focus of sleeping sickness during the colonial era, located within the area where ‘Patient Zero’ probably lived, HCV was transmitted through the treatment of this parasitic disease before 1950, while Human T-cell lymphotropic virus (HTLV-1), another retrovirus with a chimpanzee reservoir, was spread through the injections of pentamidine given twice a year to the whole population for the prevention of trypanosomiasis. Patients treated for sleeping sickness in Nola in the 1940s experienced a staggering excess mortality, potentially compatible with the iatrogenic dissemination of HIV-1. In another part of the continent, an epidemiological study of elderly people in Guinea–Bissau revealed that HIV-2 had been transmitted through the treatment of sleeping sickness but also of tuberculosis (with long courses of intramuscular streptomycin). Thus, in three different countries, different colonial-era tropical diseases therapeutic interventions resulted in the transmission of three different bloodborne viruses. By contrast with the highly lethal HIV-1, these viruses are compatible with a prolonged survival, enabling such associations to be documented retrospectively. Immunisations Correspondence to Dr Jacques Pépin, Department of Microbiology and Infectious Diseases, Université de Sherbrooke, CHUS, 3001, 12ème Avenue Nord, Sherbrooke, Qc J1H 5N4, Canada; [email protected]