High GUD Incidence in the Early 20thCentury Created a
Particularly Permissive Time Window for the Origin and
Initial Spread of Epidemic HIV Strains
Joa ˜o Dinis de Sousa1*, Viktor Mu ¨ller2, Philippe Lemey1, Anne-Mieke Vandamme1,3
1Laboratory for Clinical and Evolutionary Virology, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium, 2Institute of Biology, Eo ¨tvo ¨s
Lora ´nd University, Budapest, Hungary, 3Centro de Mala ´ria e Outras Doenc ¸as Tropicais, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Lisboa,
The processes that permitted a few SIV strains to emerge epidemically as HIV groups remain elusive. Paradigmatic theories
propose factors that may have facilitated adaptation to the human host (e.g., unsafe injections), none of which provide a
coherent explanation for the timing, geographical origin, and scarcity of epidemic HIV strains. Our updated molecular clock
analyses established relatively narrow time intervals (roughly 1880–1940) for major SIV transfers to humans. Factors that
could favor HIV emergence in this time frame may have been genital ulcer disease (GUD), resulting in high HIV-1
transmissibility (4–43%), largely exceeding parenteral transmissibility; lack of male circumcision increasing male HIV
infection risk; and gender-skewed city growth increasing sexual promiscuity. We surveyed colonial medical literature
reporting incidences of GUD for the relevant regions, concentrating on cities, suffering less reporting biases than rural areas.
Coinciding in time with the origin of the major HIV groups, colonial cities showed intense GUD outbreaks with incidences
1.5–2.5 orders of magnitude higher than in mid 20thcentury. We surveyed ethnographic literature, and concluded that male
circumcision frequencies were lower in early 20thcentury than nowadays, with low rates correlating spatially with the
emergence of HIV groups. We developed computer simulations to model the early spread of HIV-1 group M in Kinshasa
before, during and after the estimated origin of the virus, using parameters derived from the colonial literature. These
confirmed that the early 20thcentury was particularly permissive for the emergence of HIV by heterosexual transmission.
The strongest potential facilitating factor was high GUD levels. Remarkably, the direct effects of city population size and
circumcision frequency seemed relatively small. Our results suggest that intense GUD in promiscuous urban communities
was the main factor driving HIV emergence. Low circumcision rates may have played a role, probably by their indirect
effects on GUD.
Citation: Sousa JDd, Mu ¨ller V, Lemey P, Vandamme A-M (2010) High GUD Incidence in the Early 20thCentury Created a Particularly Permissive Time Window for
the Origin and Initial Spread of Epidemic HIV Strains. PLoS ONE 5(4): e9936. doi:10.1371/journal.pone.0009936
Editor: Darren P. Martin, Institute of Infectious Disease and Molecular Medicine, South Africa
Received November 4, 2009; Accepted March 6, 2010; Published April 1, 2010
Copyright: ? 2010 Sousa et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: P.L. was supported by a postdoctoral fellowship from the Fonds voor Wetenschappelijk Onderzoek (FWO; http://www.fwo.be) Flanders, and FWO grant
G.0513.06. V.M. was supported by the Hungarian Scientific Research Fund (Orszagos Tudomanyos Kutatasi Alap (OTKA); http://www.otka.hu) grant NF72791. Both
P.L. and V.M. were also supported by the European Commission Virolab Project (http://www.virolab.org) grant 027446. The funders had no role in study design,
data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: email@example.com
Independent simian immunodeficiency virus (SIV) transfers to
humans have established twelve different known human immu-
nodeficiency virus (HIV) groups [1–10]. Pandemic HIV-1 group
M, and group N descend from SIVcpz endemic in West Central
African chimpanzees [1–5], while the closest relatives of HIV-1
groups O and P are SIVs infecting western lowland gorillas
(SIVgor) in the same region [1,10,11]. All known HIV-2 groups
(A–H) descend from SIVsmm endemic in sooty mangabeys [4–9],
which inhabit a strip of forested coast in West Africa [9,12,13].
Only four of these twelve strains generated successful epidemics
in humans: HIV-1 groups M and O, and HIV-2 groups A and B.
The pandemic group M strain clusters most closely with SIVcpz
endemic in wild chimpanzees from the southeast corner of
Cameroon . There is compelling evidence, both from serology
and AIDS cases, that HIV-1 infections were initially restricted to
the Democratic Republic of Congo (DRC) [13,14]. The
geographical origin of the simian ancestor of HIV-1 group O is
still unknown, but its human epicenter was Cameroon, a country
to which it remains largely restricted . Both HIV-2 groups A
and B cluster more closely with SIVsmm from sooty mangabeys
living in the forests of southwestern Co ˆte d’Ivoire . Both groups
spread abundantly in this country, and have spread only recently
to Guinea, Sierra Leone, and Liberia, while group A was able to
spread to Guinea-Bissau early in its epidemic history [13,16]. This
suggests that Co ˆte d’Ivoire was the main early epicenter of these
HIV-2 groups. Of the four main groups, HIV-1 group O is the
most confined; it currently infects only tens of thousands of people,
mainly in Cameroon and Nigeria [15,17,18]. HIV-1 group N is
much rarer and restricted to Cameroon  and the remaining
HIV groups have been found in just one patient [3,4,7–10],
including the recently identified HIV-1 group P strain . See
Figure S1 for an illustration of HIV biogeography.
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Transmission of simian retroviruses to humans is not excep-
tional. Simian foamy viruses (SFV) have frequently been
transmitted to humans exposed to bushmeat, apparently without
further spread  and the epidemic human T-cell lymphotropic
viruses (HTLV) arose from their simian counterparts (STLV)
through contacts over thousands of years. It is generally accepted
that SFV, STLV, as well as SIV, entered the human population
through bushmeat handling. Although such events are common
today [20–22], and therefore assumed to also have been common
in the recent and distant past, they seldom result in a virus with
epidemic potential. Despite progress in identifying SIVs closely
related to HIV groups [1–3,9], how and why only some of the
transmitted SIV strains established epidemics is subject of ardent
The estimated times of cross-species transmission to humans of
the different HTLV-1 subtypes span between less than 3,000 and
up to about 50,000 years ago [25,26], while HTLV-2 was
transferred to humans between 60,000 and 400,000 years ago
[22,25,26]. In contrast, all main epidemic HIV groups started to
spread in humans only recently, and nearly simultaneously, in the
early 20thcentury [6,27–31]. This fact prompted the search for
factors driving HIV emergence, which can be attributed to
phenomena new in the 20thcentury. As one of many speculative
theories, a hypothesis involving SIV-contaminated polio vaccines
has been extensively debated , but decisively refuted by many
lines of scientific evidence [2–3,6,27–31]. Another hypothesis
proposes that unsterile injections serially transmitted SIV from a
bushmeat handler to other humans in a chain of acutely infected
people, improving its adaptation to the new host [4,23,24]. Also
hunting intensification , social changes, urbanization, and/or
increased human mobility  have been invoked as explanations
for HIV emergence.
It is conceivable that host or circumstantial factors currently
increasing the transmissibility of HIV were also involved in its
origin and initial spread. This notion is implicit in the theories that
proposed unsterile injections as the driving factor [4,23,24].
Standard per-reuse transmissibility of unsterile intravenous
injections is considerably higher than standard per-act sexual
transmissibility (0.6–1.6% vs. 0.05–0.1%) [32,33]. However, the
involvement of genital ulcer disease (GUD) dramatically raises the
latter. GUD-assisted per-act transmissibilities for HIV-1 were
estimated at: 1) man to woman with GUD: 7.4% (95% CI 3.8–
15.7%) ; 2) woman with GUD to man: 16% (95% CI 6–32%)
in a cohort in which two thirds of the men were circumcised; the
measured per-act transmissibility was 4% for the circumcised men,
and 43% for the uncircumcised [33,34]. Although the per-
exposure risk for men with GUD has not been measured, evidence
from observational studies also suggest a very high HIV
transmission risk [35,36]. The effect of GUD infections is also
very strong at the population level: more than half of new HIV
infections in Africa might be attributed to GUD facilitated
transmission . However, to our knowledge no study has
investigated the role of GUD prevalence in the origin, initial
spread and adaptation of HIV. Another host factor linked with
HIV transmissibility is circumcision. For heterosexual men, per-
act risk of HIV-1 acquisition is about 6–11 times higher if they are
uncircumcised [34,38], although more moderate odds ratios have
been estimated over longer periods. For uncircumcised men
exposed to GUD-suffering sex workers, the measured per-act risk
was 43% . Second to transfusions, this is the highest HIV
transmissibility ever measured.
Here, we aimed to identify which factors could have favored
SIV adaptation to humans and facilitated its emergence and
spread as HIV. First, we investigated the timing of the splits
between HIV-1 groups M and O, and HIV-2 groups A and B and
their respective closest SIV lineage, either by reviewing the
literature or by using phylogenetic methods to narrow down the
missing links. Having established a likely time interval of cross
species transmission, we then reviewed colonial medical, and
demographic literature, including original archival sources, to
investigate how the proposed risk factors, including GUD
incidence, city growth, health systems, gender distribution, and
commercial sex work (CSW), varied in time and space, across the
relevant African regions. Additionally we reviewed ethnographic
literature on male circumcision per ethnic group, and assessed
whether its geographical distribution, in early 20thcentury,
overlapped with the putative epicenters for the HIV groups.
Finally, we developed computer simulations based on detailed
population, sociological and medical data found in our literature
and archival searches to identify the key factors that might have
facilitated the emergence of HIV-1 group M. Since spatial and
temporal coincidence have previously been considered as evidence
for factors involved in the emergence of a pathogen , including
drafting hypotheses on the origins of HIV [3–5,13,23,24], we here
invoke such coincidences to support our hypothesis on the origin
of the HIV groups.
Estimating divergence times between HIV-1 groups M/O
and their simian ancestors
We obtained divergence dates between epidemic HIVs and
their closest simian relatives including recently discovered simian
strains [1–2], through literature survey [6,27–31] or by estimating
new dates. We infer divergence dates using Bayesian relaxed clock
analysis  for two separate data sets representing HIV-1 group
M/SIVcpz and HIV-1 groupO/SIVgor/SIVcpz respectively.
The combined results are listed in Table 1. In general, epidemic
HIV crossed to humans after the 18thcentury (Table 1). The
interspecies transmission of each HIV group occurred between the
split with the closest SIV lineage and the time to the most recent
common ancestor (MRCA; TMRCA) of the group, probably
closer to the latter.
The early 20thcentury constituted a preferential time
window for HIV emergence
The five HIV groups represented in Table 1 are the ones for
which an ongoing epidemic is demonstrated; all the others have
only been found in a single person [3,4,7–10]. Of these five, four
(HIV-1 groups M and O, and HIV-2 groups A and B) have been
able to spread at an epidemic level and are currently infecting at
least tens of thousands of people, and likely adapted to humans
and started to spread in early 20thcentury, whereas HIV-1 group
N may have started to spread in mid century (Table 1). Thus, the
early 20thcentury seems to have constituted a particularly
permissive time window for SIV zoonoses with clear epidemic
consequences; for example, both epidemiological evidence and
population size studies indicate that HIV-1 group M as well as
HIV-2 group A spread epidemically at rates nearly equivalent to a
tenfold increase in each decade [6,13,41].
The narrow time interval in which the four major HIV groups
emerged, contrasting with the origins of HTLVs [22,25,26],
suggests that driving factors specific to early 20thcentury have
assisted HIV emergence in our species. The prevailing theories
would predict more HIV groups emerging after 1950 than before.
Injection intensity was much higher in mid 20thcentury than
before . Urbanization and traffic have also intensified since mid
century [5,42]; for example, among the rural Ngbaka-Mabo
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people of Lobaye, in southwest Central African Republic (CAR),
hunting practice was common, and by 1957, the majority of men,
many of them hunters/bushmeat handlers, had already migrated
to one or more large Central African cities (e.g., Bangui,
Brazzaville) ; other rural peoples also migrated to cities
abundantly, albeit not necessarily to the same extent as the
Ngbaka-Mabo. The mid century also likely generated increased
human exposures to SIV, and particularly SIVcpz, because the
main wild chimpanzee population collapse, partly due to
intensified hunting, happened between 1946 and 1980 [43,44].
To understand why only the early 20thcentury generated all
epidemic HIVs, we aimed to reveal the full spectrum of factors
that might have had the potential to increase SIV/HIV
transmissibility and adaptation in the established critical time
interval. In order to be consistent with a causal relationship, the
factor or factors responsible should coincide both spatially and
temporally with the origin of the epidemic , and thus should
have peaked in early 20thcentury in the geographic areas
coinciding more or less with the ranges of the relevant SIV-
The origin of epidemic HIVs coincided with the peak of
We reviewed colonial medicine articles, reports, and reviews, for
the countries of chimpanzee and sooty mangabey ranges,
searching for information about sexually transmitted diseases
(STDs), GUDs, and diseases requiring intensive injection treat-
ments (see Materials and Methods, section GUD incidences
survey). We found that the most commonly reported GUDs were
syphilis, chancroid (chancrelle, chancre mou), and to a lesser extent,
lymphogranuloma venereum (LGV) (bubon ve ´ne ´rien).
Primary and secondary syphilis (PSS) last a total of about five
months, with exudative genital ulcers being present 30% of the
time in either stage. This is followed by latent and tertiary stages,
with no genital ulceration, and no infectiousness [45,46]. As an
epidemic progresses, a decreasing fraction of all syphilis infections
are PSS; the latent and tertiary stages predominate [45,47,48].
Chancroid’s single chancre lasts ten weeks on average .
[45,46,49] promotes rapid spread and high frequency of genital
ulcers in local sexually promiscuous settings (e.g., PSS may attain
frequencies of 20–60% during initial invasion ). These
conditions, particularly if occurring in populations with many
uncircumcised men, constitute a favorable setting for SIV
adaptation to humans through serial sexual transmission during
In the relevant regions, the early 20thcentury witnessed very
high GUD incidences especially in fast growing cities and socially
changed semi-rural areas. This trend started around 1885, when
European powers decidedly rushed to control the interior. Many
sources explicitly state that syphilis was absent from nearly all
forested areas where chimpanzees, gorillas, and sooty mangabeys
live, up to 1885 [50–54], although it was present before in seaports
with European presence [52,55,56], and in savannah-forest
interface regions connected with Arab states . Yaws (Treponema
pallidum pertenue) has a longstanding and high prevalence in these
forests [47,52], and exhibits cross-immunity with syphilis (Trepo-
nema pallidum pallidum) . However, this is not the explanation of
why syphilis did not generate epidemics there during centuries.
Table 1. TMRCA estimates for HIV groups and their divergence from the most closely related SIV strains.
Calculation Dating estimatesReferences
HIV-1 group M
Group TMRCA 1920 (1902–39)a1937 (1925–49)a
Salemi et al. (2000) 
Group TMRCA 1931 (1915–41) Korber et al. (2000) 
Group TMRCA 1921 (1908–33)b1902 (1873–1922)b1908 (1884–1924)b
Worobey et al. (2008) 
Split from closest SIV1853 (1799–1904) Wertheim & Worobey (2009) 
Split from closest SIV1876 (1847–1907)This study
HIV-1 group O
Group TMRCA1920 (1890–1940) Lemey et al. (2004) 
Group TMRCA1905 (1866–1938)Wertheim & Worobey (2009) 
Split from closest SIV 1741 (1606–1870) This study
HIV-1 group N
Group TMRCA 1963 (1948–77)Wertheim & Worobey (2009) 
HIV-2 group A
Group TMRCA1940 (1924–56) Lemey et al. (2003) 
Group TMRCA1932 (1906–55) Wertheim & Worobey (2009) 
Split from closest SIV1889 (1856–1922) Lemey et al. (2003) 
HIV-2 group A
Group TMRCA1945 (1931–59)Lemey et al. (2003) 
Group TMRCA1935 (1907–61)Wertheim & Worobey (2009) 
Split from closest SIV1889 (1856–1922) Lemey et al. (2003) 
Mean estimates and 95% credible/confidence intervals for group TMRCAs were obtained from previous studies, whereas divergence times from the closest SIVs were
estimated in this study, and taken from .
athe two estimates correspond to different genes used.
bThe three estimates correspond to different coalescent tree priors used.
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Indeed, these populations did experience epidemic syphilis, when
they were recruited to cities, and when social disruption due to
colonial practices entered deep in the yaws-riddled forests (e.g., in
the networks of posts in the Ogooue ´ (Gabon) and Sangha (French
Congo) riversides, in the E´quateur province (Belgian Congo), and
in southern Cameroon [47,54,57–59]). Recent simulations show
that syphilis epidemics are very dependent on highly promiscuous
minorities . Chancroid is also very dependent on CSWs for its
spread [49,60]. Since our review of colonial medical and
ethnographic papers reveals that no CSWs with levels of sexual
promiscuity comparable to those operating in the West existed in
forested equatorial areas before organized colonialism (excepting
in the coast and in the savannah-forest interface regions
frequented by Arab traders) [56,61–63], we assume that it was
this absence of CSWs that was keeping syphilis, chancroid, and the
other STDs at bay.
In the period 1890–1920, colonization produced generalized
social disruption, sex work flourished, and syphilis (and to a lesser
extent chancroid and LGV) invaded all these areas [50,52–54,57].
Except for tertiary and purely serological diagnoses, colonial
doctors of this period were not mistaking yaws for syphilis. Most
yaws cases are presented in children ; unlike syphilis, yaws is
not venereal, seldom affects mucosa, and does not cause primary
chancres [53,64]. In addition, syphilis appeared correlated in time
and space with other STDs and with presumed sexual promiscuity
in a community (e.g, syphilis was frequent in the colonial posts,
and absent in the still undisturbed villages around, and its
incidence raised in the posts upon arrival of ships, caravans and
military contingents [50,52,54,58]).
A common ironical pun was ‘‘Nous leur avons apporte ´ la
syphilization’’ (‘‘We have brought them syphilization’’). GUD
invasion accompanied the social disruption that resulted from
colonial development of each region [47,48,50,52]. We hypoth-
esize that this promoted sexual transmission of several zoonotic
SIVs. Among these zoonotic strains, those arriving to cities, not
only could rapidly generate a larger hub of infected people but
also, being placed at a major traffic node, would have had more
long-term epidemic possibilities. Cities started to grow fast, and
riverine traffic intensified only after 1920 [47,65].
In Kinshasa (then Leopoldville), capital of the DRC (then
Belgian Congo), GUD was much more intense in its early growth
period, and then declined steadily after the mid 1930s (Figure 1;
Starting to grow fast in 1919, the Kinshasa population tripled to
about 47,000 by 1929 , accompanied by increasing river and
railway traffic. Commercial sex work became widespread, not least
because of the extremely male-biased (4:1) sex-ratio . Of 6,000
women living in the eastern part of the city in 1928, only 1,724
were married, 1,600 lived in ‘‘illegitimate relationships of more or
less duration’’, and the remaining (45% of the female population)
were presumed to ‘‘live mainly on prostitution’’ ; we must
stress that only some of these would be pure CSWs; colonial
authorities commonly used this derogatory categorization when-
ever they suspected that women were having multiple sexual
partners. By this time, PSS and other GUDs had very high
incidences (Figure 1). Before 1919, reports suggest that GUD
incidences were probably higher [67–69], but archival sources are
very incomplete for this period. In 1930–32, large surveys covering
most women from the city showed that about 5% had active
genital ulcers at the moment of the visit .
By 1928, there was a decided colonial response to these medical
conditions. Mass surveys, movement restrictions, monitoring of sex
workers and treatment of venereal diseases were initiated and were
broadened further in scope and technically improved after 1932
[47,48]. Surveillance and treatments were successful, and after the
mid 1930s, GUD incidences declined. During this period, the
proportion of syphilis cases representing PSS also declined, from
being the majority in the twenties, to only 1–9% in 1949–58
[47,48,70], in agreement with epidemiological simulations .
With penicillin adding up to old arsenic, bismuth, and sulfonamide
treatments after 1947, incident ulcerative syphilis, chancroid, and
LGV became residual. PSS cases declined to 40–60 per year in
1949–51, and to 10–25 in 1954–58, these representing incidences
of about 1.5–2.5 orders of magnitude lower than those of the
period 1919–35 [47,48,70] (Figure 1; Text S1).
Similar trends were observed in other African cities [47,71–75],
although their timings were not exactly in concordance with those
of Kinshasa. For example, in Douala, Cameroon, syphilis
represented 13.5% of morbidity in 1923  and only 0.20–
0.91% in the period 1935–39 [71–73], an amelioration attributed
to intensive surveys and treatments . In Brazzaville, syphilis
represented 3.0–7.6% of morbidity in the period 1930–34 ,
and only 0.33–1.11% in the period 1953–57 . In the same city,
the proportion PSS/syphilis also declined from 84–92% in 1933–
34 to 8–34% in 1953–57 [74,75]. After 1945, GUD incidences
became extremely low in urban settings [47,48,70,72,73,75].
Although we cannot exclude reporting biases concerning GUDs
(or any other diseases) in colonial reports, these biases are likely to
be less of an issue for cases detected in the major cities from the
1920s onwards, when health systems became better established.
For this reason, we attempt to quantify GUD incidences only for
cities, and from 1919 onward, despite having reviewed many other
reports beyond these bounds.
Genital herpes (caused by the herpes simplex viruses (HSV),
most often by HSV-2) plays a major role in HIV transmission
nowadays, but its slow monotonic spread made it to be an
important cause of genital ulcers in Africa only after the mid
eighties . Accordingly, HSV-2 seroprevalence in Kinshasa, in
1959, was 21% (and 6% in rural Congo), and it took 26 years to
attain 60% .
In summary, the period 1945–80 is characterized by a low
intensity of the four main GUDs in major cities: PSS, chancroid,
and LGV became rarer due to the better health systems, and
penicillin use; PSS became a small fraction of treated syphilis
cases; and genital herpes prevalence was still low. The incidences
Figure 1. Annual incidences of several GUDs (in %) in Kinshasa.
Declines of 1.5–2.5 orders of magnitude happened between the 1920s
and the 1950s. (Data compilation in Text S1).
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of the three former GUDs in cities showed peaks up to the mid
thirties, when the cities were still small (10,000–50,000 inhabi-
tants), sex ratios were very male-biased, and health systems were
City growth does not match in time and in space with
the origin of epidemic HIV clades
City growth is a factor to be considered when investigating the
emergence of epidemic HIV because a fast growing city potentially
receives more SIV-infected migrants per unit time, and can spread
the virus among more inhabitants. We examined the curves of
population growth of the major Central and West African cities
that lie within or near the chimpanzee, gorilla, or sooty mangabey
ranges, and that received immigrants from within these ranges
(Figure 2). Periods of fast growth span all over the century; growth
rates in mid 20thcentury were among the highest, and involved
much higher absolute number of migrant arrivals.
As Figure 2A shows, up to the early thirties, Kinshasa and
Douala where clearly the largest cities in the chimpanzee and
gorilla ranges. Kinshasa is the recognized early epicenter of HIV-1
group M [2,29,77,78], and Douala was, in early 20thcentury, by
far the largest city of Cameroon, which is most likely the country
where the early epicenter of HIV-1 group O developed [15,17,18].
The two cities were experiencing high GUD incidences at the time
of the TMRCAs of these HIV groups [48,59] (Text S1). Thus, at
the same time, two different epidemic HIV clades emerged in
Central Africa in the early 20thcentury.
Both HIV-2 groups A and B originated most likely in Co ˆte
d’Ivoire . Urban development was tardy in this colony; the
capital Abidjan only grew fast and surpassed 10,000 inhabitants
after 1932 (Figure 2B). GUD levels were high throughout the
thirties [79,80]. It is thus consistent with our hypothesis that the
estimates of both HIV-2 groups’ TMRCAs fall in this timeframe, a
few decades later than HIV-1 groups M and O [6,31]. However,
Freetown was already of considerable size before Abidjan,
Conakry grew strongly after 1933 (Figure 2B), to our knowledge
these cities did not differ much from Ivorian cities in their GUD
levels, and no epidemic HIV-2 seems to have emerged in them.
This motivated us to investigate other factors that may explain
why HIV groups emerged only in particular cities.
City growth is not restricted in time with the emergence of HIV
groups. Cities continued to grow, well after the origin of the
epidemic HIVs. While there is some spatial coincidence in Central
Africa between city size and origin of HIV-1 groups, this is not the
case for West Africa and the origin of the HIV-2 groups.
Male circumcision patterns in Central and West Africa
show some correlation with HIV emergence
Male circumcision reduces the risk of HIV acquisition in men
[34,38,81,82], and HIV/AIDS prevalence correlates inversely
with the level of male circumcision in Africa [83–86]. Recent
randomised trials of male circumcision demonstrated a marked
reduction in male susceptibility to HIV infection [87,88]. We
hypothesized that circumcision levels in cities might also have
influenced the chances of HIV emergence from zoonotic SIV
We studied the geographical distribution of circumcision
patterns in Central and West Africa both today and at the time
of the HIV groups’ TMRCAs, to evaluate if it correlated spatially
and in time with HIV emergence. We reviewed all the
Demographic and Health Surveys (DHS) , pertaining to the
relevant countries, and additional studies [90,91], which reported
circumcision levels. We found that circumcision is nowadays
nearly universal in the countries of the chimpanzee and sooty
mangabey ranges, except for Rwanda, Burundi, Uganda, and
Tanzania (Table S1).
This near universality contrasts with what can be inferred from
Murdock’s Ethnographic Atlas [92,93]. Also due to other
inconsistencies in this Atlas, we decided to gather primary
ethnographic papers, putting more focus on the period of HIV
emergence (1900–1940) (see Materials and Methods, section
circumcision study). Our survey extensively expanded upon
currently available circumcision information for the relevant
ethnic groups , and permits a detailed study of the
geographical distribution of male circumcision during colonial
times in the areas of chimpanzees and sooty mangabeys (Table
We found that, in the early 20thcentury, circumcision patterns
in Central and West Africa exhibited much stronger regional
differences than nowadays. Peoples of the Adamawa-Ubangi
linguistic cluster (occupying most CAR and northern DRC), and
many Bantu peoples of the Orientale and E´quateur provinces of
DRC, adopted it in late 19th–early 20thcentury . In Rwanda
and Burundi, circumcision was not practiced, a pattern that
persists today [95,96] (Text S2). In West Africa, most ethnic
groups were circumcised, with some exceptions (e.g., the Akan
Figure 2. The growth of the most relevant Central African (A) and West African (B) cities. Plotted the evolution of the population of the
most relevant cities at or near: (A) chimpanzee and gorilla ranges in Central Africa; (B) sooty mangabey range in West Africa. The supporting
references are listed in Text S2.
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peoples from eastern Co ˆte d’Ivoire and Ghana, and many Gur
peoples from northeastern Co ˆte d’Ivoire, Burkina-Faso, and
Ghana) (Text S2).
For the main cities of the relevant areas, we collected
demographic surveys at several points in time which discriminated
the urban population by ethnic group. To each ethnic group
present in a city, at a given time, we assigned a ‘‘circumcision
class’’ (e.g., generalized at puberty, absent, etc), based on the
information provided in ethnographic sources, and we calculated
upper and lower estimates of frequency of circumcision in male
adults (see Materials and Methods, section Circumcision preva-
lence survey, Text S2, and Dataset S1). This permitted us to
calculate, for each city, and at a given time, the distribution of its
male population by the defined circumcision classes, and lower
and upper estimates of circumcision frequency. The results are
displayed in Figures 3 and 4.
Among the three Central African cities which were clearly
outstanding in size before the 1930s (Kinshasa, Douala, and
Brazzaville (Figure 2A)) the first two (the proposed epicenters of
HIV-1 groups M and O) had lower circumcision rates (Figures 3A
and 4A). During the period 1910–35, Libreville, Bangui, and
Yaounde ´ may have had lower circumcision rates than after World
War II, but we could not ascertain this by lack of adequate tables
of ethnic composition. We did not include Rwandese and
Burundian cities in our study, because they were very small up
to mid 20thcentury , and the cattle raising tradition of these
countries makes bushmeat practice uncommon [93,97,98].
Among the four West African cities that clearly stood out in size
before World War II (Abidjan, Freetown, Monrovia, and Conakry
(Figure 2B)) the first had a much lower circumcision rate
(Figures 3B and 4B). Both HIV-2 epidemic groups (A and B)
appear to have originated in Co ˆte d’Ivoire , as well as the dead-
end/rare infections of groups G and H [7–9]. Therefore, the
match between lack of circumcision in cities and HIV emergence
appears to be stronger for HIV-2 than for HIV-1. Although Co ˆte
d’Ivoire contains only about 5% of the sooty mangabey range
[9,13], it is the country of origin of half of the identified HIV-2
strains, and Ivorian cities, such as Abidjan and Bouake ´, had much
Figure 3. Male circumcision patterns in Central African (A) and West African (B) cities. The charts show, for each city, and at the referred
time, the proportional distribution of the male population by ‘‘circumcision classes’’ which are directly derived from the ethnographic literature and
do not depend on additional assumptions. Each bar is based on either: i) a published census or survey partitioning by ethnicity; ii) assumption of the
same ethnic distribution as in a neighboring time point for which there is a census or survey; iii) published numbers for some ethnic groups, and
estimates for some relevant others. The proportions of red and orange in each bar indicate the proportions of the population belonging to groups
which, respectively had not adopted circumcision by the time of the data point (red), or had adopted it, or started to generalize it from a situation in
which it is described as far from general in the ethnographic literature, less than 15 years before the time of the data point (orange). So, higher
proportions of red and orange (and, to a lesser extent, pink) mean lower circumcision frequencies. See supporting information in Text S2, and
supporting calculations in Dataset S1.
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lower circumcision rates up to World War II than the other West
African cities (Figures 3B and 4B). Our findings of significant
differences between the cities are robust and independent of the
assumptions we introduced to estimate circumcision rates
(expressed in Figure 4); they are clearly demonstrated in Figure 3
(which does not work with circumcision rate estimates).
To further substantiate these observations, we gathered tables of
surgical operations discriminating circumcisions to treat phimosis
and paraphimosis in major cities [71,74,99–106]. Ethnic groups
performing universal circumcision almost always did it either at
puberty with rituals, or in early childhood without rituals (Text S2;
Dataset S1); in the first case, we assume parents would wait for
pubertyto circumcise the boywithinthe tribal rituals, even if he had
phimosis; in the second case, a boy could have phimosis only during
the first years of life. Therefore, ethnic groups performing universal
circumcision should contribute little to the statistics of circumcisions
for phimosis made in the colonial health system. These statistics
should include mainly males from groups not performing universal
circumcision. Therefore, we assume that high numbers of such
recorded operations in a city reflect a relatively high proportion of
uncircumcised adults living there. We display the results in Table 2.
The low incidences of phimosis in Mali and Senegal are
explained by the Islamic practice of circumcision in childhood.
The phimosis data support the findings of our ethnographic study
that circumcision was far from general in Central Africa in 1910–
35, and of lower rates in Kinshasa and Douala than in Brazzaville
(Figures 3A and 4A; Text S2; Dataset S1). Table 2 presents all the
phimosis statistics we found that referred to a city; in addition to
these, we collected many dozens of other phimosis statistics at the
country level. They tend to corroborate the between country
differences in circumcision levels that we obtained through the
ethnographic approach (data not shown).
In our ethnographic study, we seized the opportunity to survey
not only patterns of male circumcision, but also patterns of
primate hunting. We present the results of this survey in Table S3.
Hunting of chimpanzees and gorillas was very widespread among
the ethnic groups of Central Africa, as was the hunting of monkeys
in Central and West Africa (Table S3). Furthermore, SIVcpz and
SIVsmm have a very wide geographical presence across the range
of their primate hosts [2,9,107]. Therefore, differences in hunting
practices are unlikely to be the major factor explaining why HIV
strains emerged only in some countries.
In conclusion, male circumcision rates in Central and West
Africa were generally lower, and showed more pronounced
regional differences in early 20thcentury than nowadays. Low
circumcision levels in cities also appear to match early HIV
epicenters and this is more evident for HIV-2 in West Africa than
for HIV-1 in Central Africa.
Simulating the early spread of HIV in Kinshasa
Finally, we used computer simulations to verify that the time
window for the emergence of epidemic/pandemic HIV strains
indeed offered uniquely favorable conditions for the heterosexual
spread of the virus. Because the window of opportunity may have
involved simultaneous changes in several factors (population size,
sex ratio, sexual promiscuity, GUD and circumcision prevalence),
we also wanted to evaluate the individual contribution of each
factor to successful epidemic emergence.
We focused on the origin of HIV-1 group M in Kinshasa for
which we were able to collect the most complete historical data.
Figure 4. Estimates of male circumcision frequencies in Central African (A) and West African (B) cities. The charts show, for each city,
and at the referred time, the upper and lower estimates of male circumcision frequency. The cities and times of estimates are the same that appear in
the bars of Figure 3. Each estimate is based on either: i) a published census or survey partitioning by ethnicity (filled squares); ii) assumption of the
same ethnic distribution as in a neighboring time point for which there is a census or survey (shallow squares); iii) published numbers for some ethnic
groups, and estimates for some relevant others (lozenges); iv) present time estimates for each city are assumed to be similar to the national
prevalences measured by the DHS, because the latter are above 95% for nearly all relevant countries, and this, considering the current high levels of
ethnic mixing seen in African major cities, leaves little room for a major city to differ from the national average. Except for the situation iv) above,
circumcision frequencies are estimated based on the ethnographic information about the circumcision practices of each group, according to an
algorithm described in Text S2, and the supporting calculations are implemented in Dataset S1.
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Our simulations were parameterized to follow the recorded
population size and structure of Kinshasa at several relevant time
points, partly based on the availability of detailed population and
medical records (Table 3). The years 1919 and 1929 were chosen
from the time interval estimated for the origin of HIV-1 group M
[27–29]; both time points were characterized by rampant GUD
epidemics, highly male-biased sex ratio and lower levels of
circumcision than today. The year 1958 was chosen as a time
point beyond the window defined by our phylogenetic dating
study; although the city population had considerably expanded,
GUD infections were generally under control and circumcision
was almost universal. Finally, we have explored a ‘‘pre-colonial
village’’ scenario to reflect a large settlement in the region before
colonization, characterized by a healthy population structure and
the absence of GUD infections and sex work.
Our simulations followed the early spread of the epidemic from
the first zoonotic SIV infection over a dynamic network of sexual
contacts, which was parameterized according to recent surveys
[108–114] (see Materials and Methods and Table 4). Transmission
parameters were modeled after current HIV data, adopting the
estimated relative effects of modifiers (e.g. GUD infection)
[33,34,38,81,82,115,116], but assuming a lower baseline trans-
mission probability for ancestral HIV. The modifier effects of
GUD infections and circumcision were implemented in the
transmission process. We also assumed that transmission of these
early strains (not yet adapted to humans) was limited to acute
infection, as has been observed for recent cross-species SIV
transmissions . The network of contacts was parameterized
according to recent studies [108–114], with the sexual promiscuity
of ‘‘femmes libres’’ (an expression used by colonial writers to refer to
unmarried/unmated women to whom a high rate of sexual
partner change was attributed [13,47,48,70]) adjusted according
to the sex ratio (see Materials and Methods and Table 4 for all
scenario-independent parameters). We provide the code of our
simulations in Text S3.
We defined several markers to characterize the efficiency of
epidemic spread in the simulations (Figure 5). Per simulation, we
determined the total number of infections (Figure 5A) and the
duration of an epidemic (Figure 5B), which characterize the extent
of the first outbreak of infections and the ability of the virus to
persist in the population even in its initial ill-adapted form (with
reduced transmission efficiency compared with modern HIV).
Long-term establishment (epidemic emergence) of HIV probably
also depended on rapid initial adaptation to the new human host
species. The capacity for this adaptation is also determined partly
by the total number of human hosts and the duration of the
Table 2. Incidences of phimosis and paraphimosis in several African cities.
Country City/divisionYears# of casesAnnual incid.Refs.
Belgian CongoKinshasa1907, 1910–12 740.685% [99–102]
Belgian CongoKinshasa 192646 0.357%
Belgian Congo Kinshasa, Matadi, Bomaa
French Congo Brazzaville1930–3489 0.265% 
1932, 1935 3130.635%
Mali Bamako1937 4 0.045%
Senegal Saint Louis19376 0.040%
Presented the joint annual incidences of phimosis and paraphimosis in the males of several African cities, as reported in the medical references listed in the last column.
Demographic data for each city is in  and in the references listed in Text S2.
aThe incidence is calculated over the joint adult male population of the three cities; about 3/5 of the operations were in Kinshasa.
bMost people from Wouri division were in Douala city .
Table 3. Scenario-specific parameters of the simulations.
ParameterPre-colonial villageKinshasa 1919 Kinshasa 1929Kinshasa 1958
Number of women 5003,265 10,08169,159
Number of men 5008,798 31,817 93,064
Number of married couples 4509472,923 48,411
% of women ‘‘femmes libres’’0 6060 10
% of men circumcised0 70 8095
Genital ulcer frequency (%) in:
Commercial sex workers (CSWs)- 15 105
Femmes libres0 7.55a
Other women032 0.3
Men0 1.51 0.3
The parameters are based on archival historical data and colonial medicine articles ([48,66,70,104]; Text S1; Text S2).
aA genital ulcer frequency of 5% in femmes libres in 1929 is supported by two different venereal control surveys made in 1930 and 1932, involving 953 and 1,202 women
(mostly femmes libres) respectively, which showed this frequency to be 4.7% in 1930 and 4.6% in 1932 . The venereal situation was probably even worse in the
decade preceding 1929–32 [48,104], and reports from the years around 1910 [67–69] suggest incidences higher than in the period 1929–32 (see Text S1).
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epidemic (the age of the oldest lineage). However, an additional
important determinant of adaptation is the length of the longest
transmission chain (Figure 5C), i.e. the number of ‘‘serial
passages’’ in human hosts.
In all three quantifiers of epidemic emergence, the performance
of the historical scenarios followed the same pattern: Kinshasa
1919. Kinshasa 1929& Kinshasa 1958& pre-colonial village
(Figure 5). E.g. compared with the 1958 scenario, the 1929
scenario had 5-fold, the 1919 scenario 11-fold higher chance to
generate at least 100 infections (6, 30 and 68 times out of 1,000
simulations); the pre-colonial village scenario never generated
more than two infections. The probability of the ill-adapted virus
to persist until the end of the simulated year was also dramatically
higher for the 1919 and 1929 scenarios compared with the pre-
and post-origin scenarios (73 and 37 vs. 5 and 0 times out of 1,000
simulations), as was the probability of generating a transmission
Table 4. Scenario-independent parameters of the simulations.
Parameter (notation) Default value/Formula [references]Other values tested [references]
Number of non-spousal partners per yearb
Single women (NSW) 1.5 
Married women (NMW) 0.2 (estimated from data in )
Single men (NSM)3  4.5c
Duration of short linksb(weeks) (D)52 (in  as reported by women) 26c(in  as reported by men)
Number of sex acts per weekb
Stable (spousal) link2 [110,111]
Short link0.24 (estimated from data in )2d
CSW visits per man per yearb(C)2 [109,112]0e, 8f
Sex acts per CSW per year (SC) 600  150e(estimated from data in [109,114])
Probability of short link breakup per week (pb) 1/D
Probability of short link formation
Single men (pf,SM)
Number of CSW (Number of men)*C/SC
Probability of CSW visit per man per weekC/52
Duration of acute infection (weeks)12 
Transmission multiplier for acute infection10 4, 26 (estimate for modern HIV-1 )
Maximum per-act transmission probability 0.90.43 (equal to highest observed heterosexual rate )
Per-act transmission probabilitiesh
=RR and RR=(C)0.001 
RR=(NC) 0.0025 [81,82,116]0.01 [34,38,116]
=(GU)RR and R(GU) R=(C)0.04 
R (GU) R=(NC) 0.43 
=(GU)RR(GU) and R(GU)R=(GU)0.43
Duration of GU episodes (weeks)10 [45,46,49]
aThe studies in [108–110,112,114] surveyed several African cities: we used the estimates provided for Yaounde ´, which was the location nearest to Kinshasa.
bThese parameters determined means for random distributions, rather than fixed values.
cBoth combinations of 3 partners per year with 52-week short links and 4.5 partners per year with 26-week short links yielded a concurrency index around 1.5,
consistent with .
dEmploying the same value as for stable links.
eThe line between CSWs and femmes libres is blurred. We therefore ran also simulations without professional CSWs, and with CSWs with intermediate sexual
fThere were 14 CSWs per 1,000 men in Yaounde ´ according to . With 600 acts per CSW per year, this would yield about 8 CSW visits per man per year.
gThis formula implies the same number of concurrent links (including the spousal link) but fewer annual partners for married compared with single men.
h(GU) indicates a partner with an active genital ulcer; (C) indicates a circumcised man; (NC) indicates a non-circumcised man.
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chain of at least length five (81 and 49 vs. 10 and 0 times out of
1,000 simulations; see Table S4 for more detailed simulation
outcomes). We thus found that the scenarios dated around the
origin of HIV-1 group M (1919 and 1929) were indeed much
more permissive for the heterosexual spread of emergent HIV
compared with scenarios dated either before or after the estimated
origin. This result proved to be robust with respect to varying a
number of parameters in the model (Table S4). Note also that even
in the most permissive scenarios, the initial zoonotic infection was
a dead end in more than 50% of the simulation runs.
Furthermore, the more permissive 1919 and 1929 scenarios
yielded a bimodal distribution of outcomes indicating the effect of
early stochastic events: after the first few transmissions, the
epidemics that happened to reach the highly connected core of the
sexual network can spread extensively; those that fail to do so, are
likely to die out quickly.
While the resistance of the pre-colonial village to HIV
emergence is not surprising, the dramatic decrease in permissive-
ness between 1929 and 1958, in spite of continued explosive
population growth, demands further explanation. Furthermore,
the 1919 scenario proved to be consistently more permissive than
the 1929 scenario, in spite of considerable population growth over
the decade. To identify the key factor(s) behind the observed
differences, we explored systematically the effect of removing or
reducing several factors that have been implicated in the
emergence of HIV. Based on the most permissive 1919 scenario,
we tested 10-fold reduced population size, balanced sex ratio (with
90% of the sexually active population in stable relationship),
absence of GUD infections and universal circumcision. The
removal of GUD infections proved to have by far the most
dramatic effect (Figure 6). Remarkably, both a strongly reduced
population size (,1,200 sexually active individuals) and universal
circumcision had a much weaker effect on the spread of ill-adapted
HIV in the simulations. We also explored all combinations of these
mitigating factors and found a consistently dominant effect of
GUD prevalence (Table S5). We thus conclude that the period
around the estimated origin of HIV-1 group M was uniquely
permissive for the emergence of the virus by heterosexual
transmission, and that the unprecedented GUD epidemics of the
time were the main contributor to this high permissiveness.
We present multiple lines of evidence favorable to the
hypothesis of rampant GUD epidemics having played a key role
in the origin of the major HIV strains.
In agreement with earlier studies our molecular dating confirmed
that all major epidemic HIV lineages were transmitted to our
species in a narrow time frame. We dated the divergence of the
HIV-1 groups M and O from their closest related SIVs using a
different,butcomplementary approach compared to Wertheim and
Worobey (2009) . Whereas Wertheim and Worobey (2009)
aimed at estimating the TMRCA of SIV in chimpanzees and sooty
mangabeys , we focused on obtaining an upper bound on the
cross-species transmission from the chimpanzee species. To this
purpose, we focused on separate pol data sets for HIV-1 group M/
SIVcpz and HIV-1 group O/SIVgor/SIVcpz. Because the
relatively conserved pol gene does not contain sufficient temporal
signal (which may explain the relatively low rate and old TMRCAs
of Wertheim and Worobey (2009) for a similar pol data set), we
calibrated the phylogenies using the group M and group O
TMRCAs respectively. Therefore, we essentially extrapolated on
 noted that the SIVcpz sequences could not be used on their
own for meaningful date estimates. We obtained a relatively narrow
timeframe for the interspecies transmissions, defined, for each HIV
group, by the period between the split from the closest SIV and the
intragroup TMRCA. Moreover, interspecies transmission and
possible adaptation to humans probably happened close to the
latter date, which would restrict the timeframe even further.
Thus, we looked for factors to explain why emergence of HIV is
temporally and spatially restricted to the era and areas observed.
Figure 5. Comparison of early spread of HIV in simulated historical scenarios. The graphs depict frequency distributions of the total
number of infections per simulation (A), the duration of the epidemic (B) and the longest chain of transmission (C) from 1,000 simulations of Kinshasa
in 1919 (red dots and bars), 1929 (blue dots and bars) and 1958 (green dots and bars), and a pre-colonial village (black dots and bars). The duration of
an epidemic was defined as the time until the resolution of the last acute infection: its lower bound was defined by the length of acute infection in
patient zero (12 weeks), its upper bound by the length of the simulations (52 weeks). The longest transmission chain was defined as the number of
individuals in the longest chain of subsequent transmissions in each simulation. All frequencies (number of observations) are plotted on a log scale.
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Our review of the co-factors of sexual transmission indicated GUD
as paramount and lack of male circumcision of secondary
importance. GUD provides a portal of entry and attracts cells
carrying CCR5, the co-receptor most used by HIVs and SIVs
upon sexual transmission. In addition, GUD and especially
syphilis induces a potent inflammatory response, and tumor-
necrosis-factor (TNF)-a production , which is a major
enhancer of HIV replication . Genital ulceration and
inflammation in humans contributes strongly to the odds of
acquisition of more than one HIV-1 viral variant ; and
transmission of multiple viral variants was shown to contribute to
adaptation to a different host species in experimental infection of
chimpanzees with HIV-1 [120,121] and rhesus macaques with
SIVsmm . These processes suggest that GUD may contribute
to SIV adaptation in ways beyond increased transmissibility.
Most theories for the origin of HIVs depend on a specific
mechanism to facilitate the first few serial transmissions of the virus
in humans, and largely limit the problem to initial adaptation
[4,5,13,23]. However, the emergence of an epidemic might also
have depended on the conditions for large scale spread in the
general population by the conventional route, i.e. by heterosexual
transmission. Without favorable conditions for further spread,
even a virus that passed initial adaptation might quickly go extinct.
While we cannot exclude that the initial adaptation of HIVs
depended on specific transmission routes (e.g. parenteral trans-
mission), we investigated the possibility that epidemic emergence
may have depended on large population centers riddled with
sexual promiscuity and GUD. Bearing in mind that few cities in
Central and West Africa were well developed during the peak
GUD period (Figure 2), our hypothesis may explain why few well-
adapted strains emerged; and it may not be coincidence that
exactly two HIV-1 groups emerged in Central Africa, at a time
when two cities (Kinshasa and Douala) stood out in the region
(Figure 2A). Therefore we focused on the co-factors sexual
promiscuity, GUD, and lack of circumcision in cities. Our review
of the colonial medical literature established that GUD, particu-
larly syphilis, chancroid, and LGV, peaked in the relevant cities, in
the period 1910–35, with incidences 1.5–2.5 orders of magnitude
higher than in mid 20thcentury, coinciding in time with the
narrow timeframe of the emergence of epidemic HIV groups.
Our computer simulations of detailed historical scenarios for
Kinshasa confirmed that the period around the origin of HIV-1
group M in the city was uniquely permissive for the emergence of
an epidemic by heterosexual transmission. While exact probabil-
ities of HIV emergence cannot be computed (e.g. we have no
information on the initial infectivity of a novel zoonotic HIV), our
semi-quantitative approach could robustly predict an increased
relative probability associated with this time period. Furthermore,
our simulations suggested that the peak in GUD prevalence was
the most important contributor to chains of transmission of ill-
adapted HIV. A related important result of the simulations is the
inability of zoonotic HIV to generate epidemics in the pre-colonial
village scenario (characterized by the absence of GUD and CSWs),
which explains the long standing absence of HIV epidemics in the
pre-colonial environments. According to these results, the window
of high permissivity for epidemic HIV emergence was open by the
spread of GUD infections due to the organized colonization of the
relevant African areas, and probably closed by the aggressive
treatment campaigns against GUDs from the mid thirties.
Therefore, we predict that newly emerging HIV groups will have
a less dramatic spread if GUD remains under control. Remark-
ably, the direct effect of population size and circumcision proved
to be relatively small, although their effect is recognized and they
may have acted indirectly.
In the simulations, the probabilities for sexual link formation
and breakup were the same for all individuals of a class (e.g. single
men, married women, etc). For the sake of simplicity, we did not
implement a ‘‘small world network’’ [123,124]. However, the role
Figure 6. The effect of selected factors on the simulated early spread of HIV for Kinshasa 1919. The graphs depict frequency
distributions of the total number of infections (A), the duration of the epidemic (B) and the longest chain of transmission (C) from 1,000 simulations of
Kinshasa with default parameters (black dots and bars), 10-fold reduced population size (red dots and bars), balanced sex ratio (blue dots and bars),
no GUD (green dots and bars) and universal circumcision (gray dots and bars). The duration of an epidemic was defined as the time until the
resolution of the last acute infection: its lower bound was defined by the length of acute infection in patient zero (12 weeks), its upper bound by the
length of the simulations (52 weeks). The longest transmission chain was defined as the number of individuals in the longest chain of subsequent
transmissions in each simulation. All frequencies (number of observations) are plotted on a log scale.
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of highly-connected ‘‘hubs’’ was explored by adding highly
promiscuous CSWs with various settings to the simulations.
Furthermore, increasing the proportion of highly-connected
individuals in the population by employing a power-law
distribution for the number of partners would only have enhanced
heterosexual transmission even further.
Simulation models have been used before to estimate the
contribution of sexually transmitted infections/GUDs to the
current heterosexual spread of HIV [37,125]. However, our study
is the first to attempt a semi-quantitative assessment of the role of
GUDs in the origin of the epidemics. Our model was tailored to
focus on the early spread of HIV, which allowed for a simplified
We hypothesized that differences in male circumcision levels
between cities may help to explain why HIV zoonotic strains
emerged only in particular countries. Our extensive survey
revealed circumcision patterns that were historically low in the
putative centers of HIV emergence (Kinshasa, Douala, and
Abidjan). Our simulations showed only a moderate direct effect
of circumcision in the probability of generating long chains of
transmission. However, lack of circumcision also favors GUD
transmission [49,126,127], and low circumcision levels might have
correlated with high GUD incidence. The prevalence of
circumcision might thus have affected HIV emergence indirectly
through its effect on GUD incidence. Lack of circumcision may
have been more important for HIV-2 emergence, because
epidemic HIV-2 groups emerged only in Co ˆte d’Ivoire, a country
which cities had much lower circumcision rates than the others of the
region in the critical period (Figure 3B).
Independently of the regional differences encountered, our
finding of a very widespread trend of adoptions of circumcision, in
early 20thcentury, by ethnic groups previously not practicing it,
and the resulting temporal increase of circumcision rates in most
relevant countries, is a solid result. It explains, as far as we know
for the first time, the discrepancy between modern levels of
circumcision, as showed by the Demographic and Health Surveys
(DHS) , and the levels inferred from the Ethnographic Atlas
Independent of whether lack of circumcision was important to
HIV adaptation, its geographical distribution may have deter-
mined to a large extent, which secondary foci developed in the
decades after early emergence. Our finding of a relatively low
circumcision rate in Guinea-Bissau may reinvigorate the debate
about why this country became an early important focus of HIV-2
group A. In this regard it is important to note that some of the
earliest transnational jumps of pandemic HIV-1 happened to
countries where circumcision is uncommon: Haiti , Rwanda,
Burundi, Zambia [83–86,89], and Thailand .
Our simulations suggest that city size per se was not an important
factor for initial HIV transmission. Therefore, we cannot rule out
that the first transmissions (and possible initial adaptation of the
virus) occurred in smaller settlements such as Bangui, Yaounde ´,
Kribi or Brazzaville. However, the larger size of Kinshasa and
Douala in that period may have been important for, at least, three
reasons. First, a larger city attracts more immigrants per unit time,
and hence potentially more SIV infections. Second, their larger
size reflected early industrialization associated with start-up
infrastructure projects (fluvial and sea harbors, railways), and this
led to hasty recruitment of young male labor force, and thus to a
extremely male-biased sex ratio, favoring commercial sex work
and GUD. In the 1920s and 1930s, industry, public works, and
business in general, were more advanced in Kinshasa and Douala
than in the other Central African cities. Accordingly, sex work was
‘‘by far more flourishing’’ in Kinshasa than in Brazzaville .
Douala was also a major center of sex work and GUD
[59,71,130,131]. In West Africa, sex work was widespread in
Abidjan [79,132], whereas it only ‘‘existed on a small scale’’ in
Monrovia . Thus, high GUD prevalence might have
depended indirectly on population size.
Third, while initial bursts of SIV spread, and resulting
adaptation, might have happened in small settlements, further
spread of the epidemic was probably centered on cities with large
populations. Large cities were at the center of star-like traffic
networks, connecting them to nearby settlements, and allowing for
quick transfer of the virus from a local initial outbreak.
Furthermore, outbreaks in small settlements might quickly become
self-limiting by exhausting the supply of susceptible individuals,
and sustained epidemics probably depended on the early
transmission of the virus to a large center with fast replenishment
of susceptible individuals to maintain the epidemic. Thus, major,
well-connected centers, such as Kinshasa and Douala (which were
better served by railway and fluvial connections, and had far more
traffic than the other cities), may have acted as an ‘‘attractor’’ and
a ‘‘hub’’ for HIV epidemics. Although these ideas were not
explicitly modeled in this study, they may help to understand why
exactly two HIV-1 strains evolved and spread considerably in
Central Africa, and perhaps may give clues on the origin of the
Our proposal that Kinshasa, Douala, and Abidjan constituted
the initial hubs of the epidemic HIV groups can also explain the
following historical facts: 1) the presence of already diversified
HIV-1 group M in Kinshasa in 1959–60, as evidenced by two
seropositive samples (a subtype B/D and a subtype A) in only a few
hundred stored blood and tissue samples available for screening
[29,134]; 2) the serologically confirmed evidence that HIV-1
group O was present in Douala’s communities of sex workers by
1962 ; 3) the widespread presence of HIV-2 in separated
locations in Co ˆte d’Ivoire and in Guinea-Bissau (a country
1,000 km away) in the early sixties ; this fact is better
understood assuming that HIV-2 had expanded in the previous
decades in a major, internationally connected, Ivorian city.
Our hypothesis satisfies both temporal and spatial coincidence
between the factors which we invoke and the emergence of a
pathogen. Such coincidence has previously been considered
evidence that the factors are causally implicated , including
by authors drafting hypotheses on the origins of HIV [3–
5,13,23,24]. It also offers a conceptual simplicity because it
proposes as causal factors for SIV adaptation to humans and initial
spread the very same factors that most promote the continued
spread of HIV nowadays: promiscuous sex, particularly involving
sex workers, GUD, and possibly lack of circumcision. However,
we are aware that the evidence we provide does not rule out the
possibility of other processes having contributed to HIV
emergence and/or adaptation. For example, parenteral transmis-
sion might also have contributed to the initial adaptation and/or
initial spread of HIV (as seems to have been the case for SIVmac
), or to further epidemic expansion. What we claim is that
this is not necessary to explain the spatial and temporal patterns of
HIV emergence, while high GUD incidence seems to have been
the key determinant.
In this study, we narrowed down the origin of the epidemic HIV
clades (HIV-1 groups M and O, HIV-2 groups A and B) to the first
half of the 20thcentury, using phylogenetic molecular clock
calculations. Our colonial archival literature survey shows that
GUD epidemics peaked in cities in their early phases of
development, providing a better coincidence with this narrow
time frame than the driving factors proposed by other theories.
Ethnographic literature illustrates that circumcision frequencies
GUD and HIV Emergence
PLoS ONE | www.plosone.org12April 2010 | Volume 5 | Issue 4 | e9936
were historically considerably lower, and spatially more variable,
than they are currently; in particular for HIV-2, low circumcision
prevalence in cities indeed showed a geographical match with
emerging HIV epicenters. Through epidemiological modeling we
could simulate that early ill-adapted HIV could generate long
chains of transmission only during a period of high GUD intensity.
The effects of circumcision and city size were more likely indirect,
through their capacity to enhance GUD intensity and allowing the
initial hub of infections to potentially reach a threshold, and to
spawn secondary foci. We conclude that intense GUD in nascent
cities was probably the main factor that permitted zoonotic SIV to
emerge as epidemic HIV, possibly in association with low
We hope our hypothesis will increase awareness of the dangers
posed by GUD in promoting transfer of SIV, STLV, and possibly
other sexually transmitted viruses, to our species. These observa-
tions recommend close monitoring and treatment of GUD in
Africa, and raise concern over the currently high prevalence of
HSV-2 associated genital ulcers. We also underscore the
importance of male circumcision in the prevention of novel HIV
Materials and Methods
SIVcpz–HIV-1 group M and SIVgor–HIV-1 group O
divergence dates were estimated using a Bayesian relaxed clock
analysis implemented in BEAST . For SIVcpz–HIV-1 group
M, we analyzed the partial pol gene sequences (nucleotide 3887 to
4775 according to the HXB2 numbering) recently obtained from
chimpanzees , three additional SIVcpz lineages (X52154,
AY169968 and AF382828), and HIV-1 group M sequences
previously analyzed by Lemey et al. (2005) . For SIVgor–
HIV-1 group O, we analyzed partial pol gene sequences
(nucleotide 4230 to 4775 according to the HXB2 numbering)
from three SIVgor , two SIVcpz (U42720 and X52154), and
HIV-1 group O sequences previously analyzed by Lemey et al.
(2004) . We applied a general time reversible model with
gamma-distributed rate variation among sites combined with an
uncorrelated lognormal relaxed clock model and a piecewise
constant population size model . These conserved gene
regions in the HIV genome are less subject to substitution
saturation, but contain poor temporal signal . Therefore, we
used a normal prior distribution on the TMRCA for both HIV-1
group M (193168 years) and HIV-1 group O (1915617 years),
based on published dates and their uncertainty [28,30], to
calibrate the molecular clock. Posterior distributions were obtained
using Markov chain Monte Carlo (MCMC) analysys and MCMC
runs were investigated using Tracer (http://tree.bio.ed.ac.uk/
GUD incidences survey
We compiled STD and GUD incidence data for all the
countries at or near the ranges of chimpanzees and sooty
mangabeys through a survey of the relevant literature, of the
period 1890–1960, from the following sources:
1) Official colonial reports about health, or containing sections
about health, and covering also demographic issues. A) For the
Belgian Congo, collected in the Afrika Archief, Federale Over-
heidsdients–Buitenlandse Zaken, Buitenlandse Handel en Ont-
Affairs), Brussels; B) For French Equatorial Africa (AEF), and
French West Africa (AOF), collected in the Centre des Archives
d’Outre-Mer (CAOM), Aix-en-Provence (France), and in the
Institut de Me ´decine Tropicale du Service de Sante ´ des Arme ´es
(IMTSSA), Marseille (France).
2) We complemented this information with articles in the main
colonial and tropical medicine journals (Ann Me ´d Pharm
Coloniales, Ann Hyg Me ´d Coloniales, Ann Soc Belge Me ´d Trop,
Bull Soc Pathol Exotique, West African Med J, and others), and
with books on the subject.
We did a complete survey of the GUD incidences in Kinshasa:
supporting data and methods are described in Text S1.
We obtained the relevant demographic data about the relevant
cities from articles, books, and archival reports (references in Text
Circumcision prevalence survey
We obtained circumcision information on ethnic groups from
the Revised Ethnographic Atlas (Gray (1999) , which is based
on Murdock (1967) ). We considered all relevant ethnic groups
in the Ethnologue database . We collected primary ethno-
graphic articles and books to complement the circumcision
information provided by the Atlas, thus covering all important
ethnic groups, and almost all groups with more than 20,000
people, of the areas at or near chimpanzee and sooty mangabey
ranges. Most observations were from the period 1880–1940 (both
those on which the Atlas is based, and those of our ethnographic
collection). For each ethnic group, we gathered information on
male circumcision practice, including generality, approximate
time of adoption (if adopted recently), associated initiations and
rituals if any, and age of circumcision. We collected demographic
surveys specifying ethnic group composition of Central and West
African cities, at several points in time. We generated lower and
upper estimates of circumcision frequency in urban male adults of
each ethnic group, based on the method explained in Text S2 and
implemented in Dataset S1. We then computed the distribution of
adults in cities by circumcision classes displayed in Figure 3, and
the estimates of circumcision frequencies displayed in Figure 4.
The full tables of ethnic composition, and the supporting
references of this study are in Text S2 and Dataset S1.
We developed a stochastic, individual-based simulation model
to track the initial spread of HIV over a dynamic network of sexual
contacts. The model distinguished married and single men and
women, ‘‘femmes libres’’ and commercial sex workers (CSW).
During the timeframe of the simulations (one year), the population
was assumed to be constant (no birth, death or migration). The
sexual network consisted of stable (spousal) links, short-term links
and male visits to CSWs. Stable links were fixed throughout a
simulation; short-term links were allowed to form and break up at
each time step, and involved both married and single men and
women, and femmes libres. Network parameters for married and
single men and women were set according to modern studies from
Yaounde ´ (the closest available survey location) (see Table 4 and
references therein). Femmes libres were assigned with replacement to
the remaining ‘‘open’’ short links of men: their sexual promiscuity
was thus governed by the sex ratio (the shortage of short links by
single and married women compared with short links of men) in
each scenario. The number of CSWs was also automatically set in
each scenario to match the demand for CSW visits.
Simulations had a time step of one week. All runs were preceded
by an initialization phase restricted to link formation and breakup
until the sexual network settled to a steady state. The initial HIV
infection was then introduced into a single male to reflect the most
likely source of a bushmeat hunter, and the spread of the virus was
followed for a year. At each time step, sexual contacts were
GUD and HIV Emergence
PLoS ONE | www.plosone.org13 April 2010 | Volume 5 | Issue 4 | e9936
generated randomly over stable and short links; CSW visits
involved a single sexual contact. HIV transmission was restricted
to acute infection; its probability per contact was modified by
GUD and circumcision status. Transmission rates were scaled
according to estimates on modern HIV (Table 4), assuming
multiplicative modifier effects and bounded from above by a
maximum allowed rate. The basic acute transmission rate of early
HIV was per default assumed to be lower than that of modern
HIV, but higher than modern rates of chronic transmission.
Circumcision status in men was fixed for the duration of the
simulations. GUD dynamics was not modeled explicitly: healed
genital ulcers were replaced randomly from the appropriate class
of individuals. The age of GUD episodes and HIV infections was
updated at the end of each time step. Chronic HIV infection was
per default not transmissible, but protected against repeated acute
infection. Population figures were set to reflect historical scenarios
as described in the main text. Simulations were implemented in
the R software package . All code is provided in Text S3.
Africa (A), and West Africa (B). The ranges of the primates that
were the source of SIVs that gave rise to HIV strains are indicated
(based on [2,11–13]). The circles mark the locations where SIVs
most closely matching HIV-1 group M  and HIV-2 groups A
and B  were found. Compelling evidence suggests that the
countries indicated in red were the most likely epicenters of
particular HIV groups [13–17,77,78]. The references cited in this
legend are listed in the main article.
Found at: doi:10.1371/journal.pone.0009936.s001 (8.73 MB TIF)
The biogeography of epidemic HIV strains in Central
countries of Central and West Africa.
Found at: doi:10.1371/journal.pone.0009936.s002 (0.02 MB
Modern levels of male circumcision in relevant
attained by our ethnographic survey.
Found at: doi:10.1371/journal.pone.0009936.s003 (0.02 MB
The coverage of male circumcision information
and West Africa.
Found at: doi:10.1371/journal.pone.0009936.s004 (0.06 MB
Killing and consumption of apes/monkeys in Central
Found at: doi:10.1371/journal.pone.0009936.s005 (0.04 MB
Summary of the simulations outcomes for the four
variants of the Kinshasa 1919 scenario.
Found at: doi:10.1371/journal.pone.0009936.s006 (0.05 MB
Summary of simulation outcomes for combinatorial
Found at: doi:10.1371/journal.pone.0009936.s007 (0.14 MB
GUD incidences in Leopoldville/Kinshasa.
Found at: doi:10.1371/journal.pone.0009936.s008 (0.12 MB
Circumcision prevalences in Central and West Africa.
Found at: doi:10.1371/journal.pone.0009936.s009 (0.03 MB ZIP)
Source code of the simulations.
West African cities.
Found at: doi:10.1371/journal.pone.0009936.s010 (0.67 MB
Circumcision classes and frequencies in Central and
We are grateful to Prof Emeritus Jozef Vandepitte (Katholieke Universiteit
Leuven, Belgium), to Prof Emeritus Stefaan Pattyn, (Tropical Institute of
Medicine, Antwerp, Belgium), to Father Honore ´ Vinck and Prof Motingea
Mangulu (Aequatoria, Belgium, and Democratic Republic of Congo), and
to Prof Tamara Giles-Vernick (Univ of Minnesotta), for enlightening
discussions. We thank Prof Charles Becker (Centre National de Recherche
Scientifique, France), for guidance over the use of French colonial archives,
Prof Barry Hewlett (Univ of Vancouver, Canada) for having provided us
his original ethnographic dataset. We thank Drs Pierre Dandoy and Rafael
Storme (Afrika Archief, Federale Overheidsdients–Buitenlandse Zaken,
Buitenlandse Handel en Ontwikkelingssamenwerking (FO-BZBHO),
Brussels), Dr Evelyne Camara (Centre des Archives d’Outre-Mer (CAOM),
Aix-en-Provence, France), and Dr Aline Pueyo (Institut de Me ´decine
Tropicale du Service de Sante ´ des Arme ´es (IMTSSA), Marseille, France),
for their attention and help to our research in their respective Archives.
Conceived and designed the experiments: JDdS VM PL AMV. Performed
the experiments: VM PL. Analyzed the data: JDdS VM PL AMV. Wrote
the paper: JDdS VM PL AMV.
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PLoS ONE | www.plosone.org 15April 2010 | Volume 5 | Issue 4 | e9936