The Origins of AIDS

by Pepin

  To some extent, this decreasing proportion in the overall burden of HIV-1 infections was mistaken and reflected changes in the quality of diagnostic assays used to sort out group O from group M. But it is also possible that, over the last two decades, HIV-1 group O proved less transmissible than HIV-1 group M, as suggested by its lack of success in spreading outside its central African epicentre. Among more than 10,000 new cases of HIV infection diagnosed in France between 2003 and 2006, only twelve corresponded to HIV-1 group O (nine among Cameroonian migrants, one in a Chadian and two in French nationals). In the laboratory, HIV-1 group O is less ‘fit’ than group M: it replicates less efficiently in cultures with lymphocytes, which may explain its lower transmissibility.8–10

  Using the same approaches as for HIV-1 group M, the past dynamics of HIV-1 group O were reconstructed. Remarkably, the most recent common ancestor of all group O isolates was dated around 1920, much the same as for group M but with a wide confidence interval (1890–1940). It is thought that all cases of group O infections resulted from a single cross-species transmission, following which the growth of the infected population was slower than for group M, doubling about every six years. By the late 1990s, of the half million Cameroonians who were HIV-infected, about 7,500 were infected with group O. As could be expected from this limited number of infected individuals, HIV-1 group O displays less genetic diversity than group M, with only three or four subtypes identified so far.11–13

  HIV-1 group N (‘N’ for non-M non-O, or new), which was isolated for the first time in 1995 from a Cameroonian with AIDS, had even less success in spreading among humans. Up to now, only thirteen cases have been documented, all in Cameroonians. This may be an underestimate since it is not easy to sort out group N from group M through serologic tests. Two such cases occurred within a couple, indicating some heterosexual transmission. Nucleotide sequences of group N are similar to those obtained from SIVcpz-infected P.t. troglodytes chimps from the same area of southern Cameroon. Group N isolates represent a single lineage with low diversity, perhaps because its introduction in human populations was more recent than groups M and O. The most recent common ancestor of group N HIV-1 isolates has been dated around 1963 (confidence interval: 1948–77).14–17

  In phylogenetic trees, both groups M and N lie within the radiation of SIVcpz isolates obtained from the P.t. troglodytes chimpanzee (Figures 1, 2 and 3) and clearly originated from this same simian host. In contrast, the exact source of group O, the outlier, remained uncertain for some time. The virus most closely related to group O is the recently described virus of gorillas, SIVgor. It seems likely that gorillas, like their human cousins, were infected from chimpanzees. Given the geographic distribution of groups O and N, there is little doubt that their cross-species transmission event, from ape to man, occurred in Cameroon.18,19

  Recently, a new group of HIV-1, group P, has been identified following the isolation of a peculiar strain from (again) a Cameroonian living in France. Phylogenetic analyses showed that HIV-1 group P is closest to SIVgor, and actually closer to SIVgor than HIV-1 group O is. The patient herself recalled no exposure to apes and presumably acquired the infection sexually from an infected man. At some point an initial transmission occurred from gorillas to humans, followed by limited inter-human spread. As with group O, the true source of the virus might be the chimpanzee, which could have infected humans and gorillas independently, or infected gorillas which later infected humans. A second case of group P infection has been identified by a diagnostics company in a patient hospitalised in Yaoundé.20

  These findings about HIV-1 groups O, N and P have at least two implications. First, it shows that other SIVcpz isolates crossed the species barrier in the same geographic region where HIV-1 group M emerged in human populations. In the case of HIV-1 group O this seemed to have happened at roughly the same time as for group M, around 1920, while with group N it was more recent. This supports the idea that cross-species transmissions from chimps to man might have gone on for hundreds of years without triggering a recognisable pandemic and leading only to epidemiological dead ends. One case in point is the HIV-1 group O-infected Norwegian sailor who, in the 1960s, transmitted the virus to his wife who herself infected their child, without any further cases outside this nuclear family. Second, it suggests that one of the reasons behind the dramatic spread of HIV-1 group M might be intrinsic to this specific strain: compared to group O and to HIV-2, HIV-1 group M is better at infecting lymphocytes, which increases its capacity to be transmitted sexually or otherwise from one human to another.

  HIV-2 and Guiné Portuguesa

  Just a few years after their discovery of HIV-1 as the aetiological agent of AIDS, a different virus, soon to be named HIV-2, was isolated by the same researchers at the Institut Pasteur from two AIDS patients, one from Guinea-Bissau and the other from Cape Verde. These observations were extended to a larger group of thirty patients recruited in Lisbon with varying degrees of immunosuppression (seventeen with full-blown AIDS), all but two of whom originated from Guinea-Bissau or Cape Verde. This virus had only 30–40% homology with HIV-1 for most of its genes, hence its designation as a different virus rather than just another group of HIV-1. HIV-2 is not just a medical curiosity but illuminates part of the history of HIV-1, because whatever factors were instrumental in the emergence of HIV-1 in central Africa must have existed as well in West Africa, a few thousand kilometres away.21–22

  The source of HIV-2 was identified as the sooty mangabey (Cercocebus atys atys), a small monkey which inhabits parts of coastal West Africa that correspond closely to the geographical distribution of HIV-2 (Map 7). This conclusion was based on the sequencing of simian viruses called SIVsmm (smm for sooty mangabey monkey), isolated from this primate, which revealed a high degree of similarity with human HIV-2 isolates. SIVsmm does not cause AIDS in its natural sooty mangabey hosts despite replicating at high levels, but causes disease when transferred to other species, especially the macaques, through cage infections. Presumably, when a given SIV has infected a given species of monkey or ape for a long time, individuals who were more susceptible to the pathogenic effect of the virus, regardless of the underlying mechanisms, were preferentially removed from the population by death so that eventually the species became relatively resistant to the ill effects of this specific virus. One wonders whether the recent decrease in HIV-1 prevalence in some countries of East and southern Africa might to some extent reflect a similar process of natural selection in human populations.23–27

  Map 7 Historical range of the sooty mangabey (Cercocebus atys atys) in West Africa.

  SIVsmm and HIV-2 sequences from animals and humans originating from the same geographic areas were found to be most related, which implies local activities as the route of transmission. In Liberia and Sierra Leone, 22% of free-living sooty mangabeys were infected with SIVsmm, compared to only 4% of those kept as household pets, most of which had been removed from their native troops as infants. Among sooty mangabeys in the Taï Forest of Ivory Coast, SIVsmm prevalence was even higher at 59%. Because of hunting and destruction of their habitat, sooty mangabeys are now extinct in Senegal, Guinea-Bissau and parts of Guinea, while substantial populations remain in Sierra Leone, Liberia and Ivory Coast.28–29

  Molecular studies revealed that HIV-2 can be divided into eight groups, defined according to their degree of genetic diversity. Only groups A and B managed to spread between humans while groups C to H represent individual human cases documented in Liberia, Sierra Leone and Ivory Coast. Each group represents at least one distinct cross-species transmission event, from the sooty mangabey to man. In Guinea-Bissau and The Gambia, only HIV-2 group A is found. HIV-2 group B has been detected mostly in and around Ivory Coast. Sierra Leone, the country with the highest diversity of HIV-2 groups among humans, also has the lowest HIV-2 prevalence, at 0.02%. The 1,000-fold higher SIVsmm prevalence among sooty mangabeys in the same country implies that inter-human transmission following an initial cross-species event was generally
ineffective. But cross-species transmission of viruses from sooty mangabeys might have been more common than from chimpanzees, because the former live closer to humans and can be domesticated as pets.29

  Epidemiological studies uncovered that the distribution of HIV-2 was largely limited to West Africa and that its epicentre was Guinea-Bissau, a tiny country that became independent only in 1974 after a protracted liberation war against the Portuguese dictatorship, where HIV-2 managed to infect 9% of adults. A lower prevalence (less than 2.5%) was found in other West African countries: Senegal, The Gambia, Cape Verde, Guinea, Liberia, Sierra Leone, Ivory Coast, Burkina Faso, Ghana, Mali and Nigeria. A few cases were documented in distant countries that had had a colonial link with Portugal: Angola, Mozambique and India.

  In Guinea-Bissau, an initial survey conducted in Bissau in 1987 revealed a HIV-2 prevalence of 8.9% amongst adults but with a marked age gradient, 20% of those aged forty and over being infected. HIV-1 was absent. Even though HIV-2 does cause AIDS, it is less pathogenic than HIV-1, increasing adult mortality by a factor of two to three while HIV-1 increases mortality ten-fold. In other words, HIV-2 is compatible with prolonged survival in a large portion (perhaps even the majority) of infected individuals, who will ultimately die of something else, in contrast with HIV-1 which kills nearly all untreated subjects within fifteen years. The age distribution of HIV-2, so different from that of HIV-1 elsewhere in Africa, was initially thought to reflect this low mortality and the effect of cumulative exposure over a long period of time.30–32

  Subsequently, HIV-2 was shown to result in a lower degree of viraemia than HIV-1 and a lesser genital shedding in semen and cervical secretions. As a consequence, HIV-2 is less transmissible than HIV-1, both sexually and from mother to child. This raised the question of how, if the virus is poorly transmissible, prevalence could have reached such a high level in the first place.33–35

  Serial surveys showed that the infection was so rare among younger people that cumulative exposure could not mathematically explain the high prevalence among the elderly (Table 1). This corresponded rather to what epidemiologists call a ‘cohort effect’: something peculiar happened to the cohort of individuals born before 1962, which did not apply to those born since. Research then focused on older people. Among women aged fifty and over, HIV-2 was associated with having had sex with a white man, possibly a proxy for prostitution. It was hypothesised that this cohort effect was related to changes in sexual activity (higher promiscuity, more commercial sex) during the 1963–74 liberation war, with the same people becoming less promiscuous after the war came to an end.30,36–41

  Table 1 HIV-2 prevalence in Guinea-Bissau by age, 1987–200730,36–41

  a 50–9 years

  b ≥≥ 60 years

  Bissau-Guineans had fought on both sides. Some were guerilleros of the liberation movement, which controlled rural areas whose size increased as the war progressed, while others had been conscripted into the colonial army, alongside Portuguese soldiers, which controlled the cities. There were problems with this ‘promiscuous soldier’ theory. First, the initial study showed no associations between HIV-2 infection and either having served in the Portuguese army or the duration of military service. Second, the underlying idea that sexual activity was higher during wartime remained unproven. The conflict in Guinea-Bissau had been a guerrilla war, with fighters from the liberation movement constantly moving to avoid the better armed Portuguese troops and their small aeroplanes. While soldiers stationed in peaceful countries certainly tend to frequent sex workers and acquire STDs, there is little evidence that such prostitution occurs close to combat areas. Recent experiences in Ivory Coast and the DRC revealed, if anything, decreasing HIV-1 prevalence after a period of conflict. When survival becomes the main concern, there is less time and energy for sex, and in disciplined armies rapes are too uncommon to have a measurable effect on HIV transmission. Then Portuguese doctors tested almost 2,000 blood donors who had served in the colonial army in Guinea-Bissau (and who would have been more exposed to prostitutes than their guerrilla opponents): not a single one of them was HIV-2-infected. Either the Portuguese soldiers were extremely virtuous or they were resistant to HIV-2 infection – or the hypothesis was wrong.36,42–44

  To reconstruct the past dynamics of HIV-2 in Guinea-Bissau, the same approaches were used as for HIV-1. Archival samples obtained in rural areas during a 1980 yellow fever survey were tested. Out of 1,234 specimens, eleven were HIV-2-reactive. Prevalence increased with age and 6% of those more than forty-five years of age were infected. These are the oldest specimens from that country. HIV-2 antibodies were found in a few specimens obtained in the late 1960s or early 1970s in Ivory Coast, Mali, Nigeria, Senegal and Gabon, but not in samples from Liberia, Sierra Leone, Togo, Chad, Niger and Ghana.45–47

  Cases of HIV-2 AIDS, confirmed by serology, were recognised retrospectively, first in a Portuguese patient who had lived in Guinea-Bissau between 1956 and 1966 and died in 1979. Another case was diagnosed in 1978 in a Portuguese man who had served in the colonial army in Angola between 1968 and 1974 and then travelled between Angola and Mozambique. A Portuguese couple developed AIDS in the early 1980s, and HIV-2 infection could be traced to the man having served in the colonial army in Guinea-Bissau between 1966 and 1969. A Portuguese woman who had received a blood transfusion in Guinea-Bissau in 1967 remained asymptomatic twenty-seven years later, albeit with decreased CD4 lymphocyte counts. These case reports demonstrated that HIV-2 had been present in Guinea-Bissau and other Portuguese colonies at least since the 1960s, and that the incubation period between infection and AIDS was longer than with HIV-1.48–51

  Molecular clock analyses estimated that the most recent common ancestors for HIV-2 group A existed around 1940, and for HIV-2 group B around 1945, two decades later than for HIV-1 group M. Using mathematical models, it was estimated that in Caio, a high-prevalence village of Guinea-Bissau, a period of exponential growth occurred between 1955 and 1970. A more recent study using slightly different methods dated the most recent common ancestors to 1932 (group A) and 1935 (group B). These findings are in line with the notion that the sooty mangabey became extinct in Guinea Bissau a few decades ago, so that the initial cross-species event must have occurred earlier.52–53

  The evolution over time in the distribution of HIV-2 infection is also of interest. Surveys in Guinea-Bissau, Ivory Coast and other West African countries over the last two decades reached the same conclusion: HIV-2 is slowly disappearing while HIV-1 becomes prevalent. In countries outside West Africa with past colonial links to Portugal, HIV-2 has already vanished, with the exception of India. In France, out of 164 cases of HIV-2 infection diagnosed in 2003–6, only twenty occurred among French nationals, showing that the virus has had limited epidemiological success despite having been imported into the country by hundreds of migrants from West Africa. In Guinea-Bissau, as the elderly cohorts slowly age and die, HIV-2 prevalence among adults is waning. Among women delivering at the Simao Mendes national hospital, HIV-2 prevalence decreased from 8.3% in 1987 to 2.5% in 2004; over the same period, HIV-1 prevalence rose from 0 to 4.8%. In the Bandim area of Bissau, HIV-2 prevalence among adults dropped from 8.9% in 1987 to 3.9% in 2006 while HIV-1 prevalence increased from 0 to 4.6%. These trends confirmed that HIV-2 is transmitted less effectively than HIV-1 during sexual intercourse. But then, how did it become so prevalent among the generation of elderly Bissau-Guineans?8,41,54

  To address this question, and exploit the fact that HIV-2 is compatible with prolonged survival (which offers an opportunity to document associations with exposures that took place decades earlier), we conducted a survey of 1,608 individuals aged fifty and over living in Bissau. HIV-2 prevalence was 15% in women and 8% in men. HIV-2 was not associated with previous STDs or with having sold (women) or bought (men) sexual services. Among men, HIV-2 infection was not more common in those who had fought for either side during the independence war. Among women, however, HIV-2 infection was associated with ritual e
xcision of the clitoris. When both genders were combined, HIV-2 was associated with having been treated for sleeping sickness and with having received IM streptomycin for the treatment of tuberculosis. These three independent associations pointed to parenteral rather than sexual modes of transmission, all of which could have played a role only in the distant past.55

  Sleeping sickness in Guiné Portuguesa peaked in 1952. Most patients were treated with IV melarsoprol (up to fifteen injections, to be repeated if a relapse was diagnosed) while some early cases received IM pentamidine (usually ten injections). The disease eventually disappeared completely so that virtually all participants who reported having previously been treated for trypanosomiasis were in fact treated before the country became independent in 1974. Meanwhile, streptomycin was used to treat tuberculosis until 1992, when a regimen using only oral drugs was adopted. Prior to this change, tuberculosis patients received at least 60 and sometimes more than 100 IM injections of streptomycin. Finally, excision of the clitoris used to be practised in Muslim ethnic groups during the fanado, an initiation ritual during which dozens of girls were excised on the same day by elderly women using the same ceremonial knife. These ethnic groups still practise excision, but now during individual procedures rather than collective ceremonies.56–60