Unsolved Questions over
the Origin of HIV and AIDS
Although HIV originated in nonhuman primates, we do not understand
how it became a successful pathogen in its human host
Preston A. Marx
he concept of AIDS as a zoonosis
avian influenza virus and have some leads on the
stems from studies that traced HIV
Ebola and SARS viruses, the shocking fact is
origins to two simian species in West
that we know next to nothing about the factors
and Central Africa—an idea that
that launch animal viruses into epidemics, panwas reinforced by reports in highdemics, or result in dead-end infections. The
profile journals. Although the simian origin of
ecological events that led SIV to become HIV
HIV and other human retroviruses such as huwith epidemic potential remain completely unman T cell leukemia virus and human foamy
known.
viruses is not in dispute, the hypothesis that
simian retroviral infections are zoonoses is.
Simply put, a zoonosis is a disease that is
Looking for SIV
acquired from a vertebrate animal. Some microbiologists also consider vector-borne diseases as
HIV is not one virus but exists as two major viral
zoonoses. But the central meaning of zoonosis is
species, HIV-1 and HIV-2. HIV-1 is further
that the disease, and not just the infection, is
divided into three groups, M, N, and O, with M
acquired from an animal, not from another huthe “main” group, O the “outlier,” and N filling
man being. In the 2003 edition of Zoonoses:
the alphabetic gap between them. HIV-2 conInfectious Diseases Transmissible
sists of seven subtypes, A through
from Animals to Humans, an ASM
G, with a possible eighth group, H.
publication, HIV is dismissed as a
HIV types 1 and 2 do not have a
HIV types 1 and
zoonosis on the first page. It consingle simian species of origin, but
2 do not have a
tains no chapters on simian retrotwo—the chimpanzee and the
viral zoonoses because there are
single simian
sooty mangabey. The three HIV-1
none. When we think of zoonosis,
groups and eight HIV-2 groups are
species of
we should think of rabies, not
different enough from one another
origin but two—
AIDS.
that they probably arose from 11
the chimpanzee
Some experts consider this deseparate crossover events, suggestand the sooty
bate semantic and thus of little iming eight sooty mangabeys and
mangabey
portance. Thus, because every case
three chimpanzees were responsiof human AIDS is acquired from
ble for all known HIV infections
another human being, it cannot be
among humans. After 17 years of
a zoonosis and the discussion could end here.
field research in West, Equatorial, and East AfYet the underlying question of what launches
rica, scientists from several countries have idennew diseases among humans, including not only
tified at least 40 different monkey species that
AIDS but also avian flu, Ebola virus, and severe
are infected with 40 different types of SIV.
acquired respiratory syndrome (SARS), is critiWhen I arrived in West Africa in 1988 in
cal to address because it so often remains a black
search of the source of HIV-2, I believed that
box. While we know the origin of HIV and the
AIDS was a zoonosis and that my search for SIV
T
Preston A. Marx is
a Professor at the
Tulane National
Primate Research
Center and Department of Tropical
Medicine, Covington, La.
Volume 71, Number 1, 2005 / ASM News Y 15
FIGURE 1
Tethered household pet sooty mangabey on a porch in
Panguma, Sierra Leone. This monkey was infected with an
SIV strain that was closely related to an HIV-2 strain found in
a person who had lived nearby.
would entail many months of camping in African forests, trapping monkeys, and collecting
blood samples.
However, it turned out to be a much easier
task than I had imagined. Within days of arriving, I learned that monkeys were everywhere
because they were being kept as household pets.
More importantly, virtually all of them had been
born in the wild. In addition, monkeys were and
are a valued food animal in much of forested
Africa, and monkey carcasses are sold in local
game markets. Often hunters will bring motherless baby monkeys home to raise as pets. Our
field biologist Paul Telfer and others who were
part of the Marx research group in Sierra Leone
in the early 1990s later determined that one of
those pet monkeys (Fig. 1) was infected with an
SIV strain that proved to be an important link to
the ancestor of an HIV-2 strain.
Of the 40 known SIVs from 40 different simian species in Africa, almost all were found in
former household pets or in bush meat tissue.
The discovery of SIV from the red-capped
mangabey (RCM) illustrates the importance of
pets in the search for SIV. SIVrcm was first
discovered in a red-capped mangabey in the
town of Lambarene, Gabon.
The setting in which this infected monkey was
found tells a story of serendipity and science.
Telfer, the field biologist, spent an entire day in
Lambarene searching for pet RCMs with no
success. This town is located well within the
16 Y ASM News / Volume 71, Number 1, 2005
natural range of RCMs, and despite their being
endangered, they are fairly common in this area.
After a long day, Telfer decided to visit a local
bar, where he found an RCM being kept as a
pet. This bar monkey was the first known
SIVrcm-infected monkey.
SIVrcm proves an interesting virus because it
is a key part of the ancestry of SIV from chimpanzees (cpz). SIVcpz is a recombinant between
an SIVrcm-like virus and an SIVgsn-like virus
from the greater spot-nosed monkeys (Cercopithecus nictitans). SIVcpz, in turn, is most likely the ancestral lineage of HIV-1.
What Do We Really Know about the
Origins of HIV and AIDS?
With at least 40 species harboring SIV, where
did HIV come from? To answer the question
requires characterizing SIVs from the blood or
tissue of monkeys and chimpanzees. When
blood is not available, as is the case with bush
meat, DNA or RNA is extracted directly from
the tissue of naturally infected animals. Phylogenetic analyses show that the closest genetic
match with HIV type 1 is an SIV from the central
African chimpanzee, Pan troglodytes, troglodytes (Fig. 2a, green).
Meanwhile, the closest match for HIV-2 is the
SIV found in sooty mangabeys (Fig. 2b, black).
The sooty mangabey (Fig. 1) that Telfer found
harbored a particularly important SIVsm strain
(SIVsm92b [red]). When members of my group
sequenced and analyzed the genome of this virus, we learned that its closest phylogenetic
match is a version of HIV infecting a man in Los
Angeles, Calif. Moreover, this virus, HIV-2 PA,
(orange, Fig. 2b) is the only known example of
this HIV-2 strain, and that man is the only
person known to be infected with that virus.
On the surface, our analyses looked like they
resulted from a bad experiment. Was it laboratory contamination? We rejected that explanation because no samples were ever shared
between the two groups that conducted the sequence analyses. That part of the mystery was
solved when we learned that the Los Angeles
man was an immigrant from Sierra Leone who
had lived in a village only 50 miles from where
the infected SM was found. This study is the
most convincing to date that HIV-2 has its direct
origins in infected monkeys in forested Africa.
FIGURE 2
A—env gene
0.05 substitutions
per site
B—gag gene
0.91.MVP5180
0.87.ANT70
0.99.SEMP1299
SIVcpzGAB1
SIVcpzCAM3
SIVcpzCAM5
SIVcpzUS
N.95.YBF30
N.97.YBF106
M:U.83CD003
M:A1.U455
M:A1.92UG037
M:A2.97CDKTB48
M:A2.94CY017
M:G.92NG083
M:G.SE6165
M:J.SE7887
M:J.SE7022
M:C.92BR025
M:C.ETH2220
M:H.VI991
M:H.90CF056
M:B.HXB2
M:B.RF
M:D.NDK
M:D.94UG1141
M:K.EQTB11C
M:K.MP535
M:F1.93BR020
M:F1.MP411
M:F2.MP255
M:F2.MP257
Persons infected
HIV-1 group M: 45 million+
HIV-1 group O: 100,000
HIV-1 group N: 6
HIV-2/E.PA from infected
person from Siera Leone
SIVsmSL92B from the
infected pet in figure 1
HIV-2/C.2238
HIV-2/A.D194
HIV-2/A.ROD
HIV-2/A.ST
HIV-2/B.UC1
HIV-2/B.D205
HIV-2/B.EHO
0.01 substitutions
per site
HIV-2/G.ABT96
SIVmacSTM
SIVsmF098
HIV-2/D.FO784
SIVsmLIB1
SIVsmA023
SIVsmM949
SIVsmM940
SIVsmM951
SIVsmD177
SIVsmM933
SIVsmM946
SIVsmG932
SIVmacMNE
SIVmac142
SIVmac251
SIVsmE039
SIVsmPGM
SIVsmM930
SIVsmM922
SIVsmM935
SIVsmD174
SIVsmSME543
SIVsmH4
SIVsmPBJA
SIVsmM923
SIVsmM947
SIVsmE041
HIV-2 Phylogenetic trees:
Only 2 subtypes— A and B are epidemic; the remaining
5 HIV-2 subtypes C through G are single person
infections without AIDS or an Epidemic
(a) Phylogenetic tree for the env gene showing relationships between HIV-1 and SIV found in chimpanzees. The horizontal distance between
viruses is proportional to their genetic relatedness. Vertical distances are for clarity only. HIV-1 group M (red) is the cause of the AIDS
pandemic. Group O HIV-1 is shown in purple. The rare group of HIV-1 is group N (orange). SIVcpz (green) is the most likely ancestral lineage
of HIV-1. The closest relative of SIVcpz is HIV-1 group N (orange). (b) Phylogenetic tree for the gag gene showing relationships between
HIV-2 and SIV found in sooty mangabeys (sm). SIV from sooty mangabeys is the ancestral lineage for HIV-2. The closest relative of SIVsm
is HIV-2 PA shown in orange. SIVsmSL92b in red was isolated from the sooty mangabey pictured in figure 1. All other HIV-2 subtypes are
shown in blue. Other members of this SIVsm group are in black.
The HIV Epidemic That Wasn’t
With that information, we considered it a relatively simple matter to test persons living in that
area of Sierra Leone, searching for small outbreaks of HIV-2. We anticipated finding local
cases of AIDS to be an example of a zoonosis
Volume 71, Number 1, 2005 / ASM News Y 17
from local villagers contacting infected
sooty mangabeys.
Table 1. Uneven distribution of HIV
Again, however, our expectations
HIV group or
No. of infections
were not met. Although we tested more
subtype
(% of total)
than 11,000 individuals in Sierra Leone,
HIV-1
only 2 were infected with HIV-2. Our
Group M
45,000,000a (99.6)
hypotheses were further confounded by
Group N
6 (0.000013)
Group O
100,000a (0.22)
findings that HIV-2 infections by groups
C through G typically are dead-ended,
HIV-2
meaning the infected individual does not
Subtype A
50,000a (0.11)
transmit the virus to other persons.
Subtype B
25,000a (0.06)
Therefore, outbreaks of AIDS, the disSubtype C
1 (0.0000002)
Subtype D
1 (0.0000002)
ease, could not be traced to contact with
Subtype
E
1
(0.0000002)
sooty mangabeys.
Subtype F
1 (0.0000002)
HIV groups A and B (blue, Fig. 2b) are
Subtype G
1 (0.0000002)
epidemic in about 100,000 persons. But,
a
groups C-G were found only as singleEstimates.
person infections. HIV-2 PA, the virus
that matched the SIV-infected household
years, and only one resulted in a human panpet, must have infected this man for 20 years
demic, involving HIV-1 group M (Table 1).
because he resided outside Sierra Leone for that
What is the difference among these viruses? The
long. Yet neither HIV-2 PA nor any other HIV-2
answer could solve a great riddle as to why the
belonging to groups C through G had spread to
AIDS epidemic emerged in the second half of the
other persons.
20th century, and not before.
Although the man from Sierra Leone carried
The closest relatives of SIVs are HIV-1 group
HIV-2 antibodies, the virus was never recovN
(orange, Fig. 1a) and HIV-2 groups C through
ered from his blood despite repeated attempts
G
(Fig.
2b). Each of these viruses is extremely rare,
over 4 years. HIV-PA virus is known only from
with
only
six known HIV-1 group N-infected
its gag sequence (Fig. 2b), which was amplified
persons
and
only single individuals infected by
from his peripheral blood cells. HIV-2 PA,
HIV-2
groups
C through G. Most SIVs are thus
therefore, appears to be a dead-end infection of
epidemiological
failures in humans and not
extremely low pathogenicity. Indeed, all HIVs
virulent
zoonotic
agents of disease and epidemexcept HIV-1 group M are relatively ineffectual
ics.
pathogens—and epidemiological wimps (Table
Second, in Central and West Africa human
1).
exposure
to retroviruses through hunting and
We wondered how AIDS could be a zoonosis
butchering
is ancient, but the AIDS epidemic
if the simian virus is not causing AIDS in persons
emerged
only
in the second half of the 20th cenwho are in frequent contact with SIV-infected
tury.
Anthropologists
have documented 50,000
SMs. Thus, we questioned the hypothesis that
years
of
human
habitation
in Central and West
AIDS is a zoonosis. Although we appear to have
Africa.
If
AIDS
were
a
simple
zoonosis that
identified the animal origins of HIV, nothing is
could
spread
from
person
to
person,
it would
known about the circumstances that led to the
have emerged there or perhaps in the Americas
AIDS epidemic.
early during the slave trade. Indeed, slaves were
taken to the Americas from the very same reArguments against AIDS as a Zoonosis
gions where SIV-infected sooty mangabeys and
chimpanzees were present and hunted for food
There are several strong arguments against AIDS
(Fig. 3). During 300 years of the slave trade, 20
being a zoonosis. First, SIV commonly infects
million Africans were landed from coastal
monkeys, including bush meat and household
Maryland to Rio de Janeiro. A pathogenic SIV
pets in sub-Saharan Africa, leading to highamong them would have quickly spread to the
frequency exposure of humans. However, reEuropean colonists in the Americas. Yet it did
searchers have documented only 11 cross-species transmissions to humans from the last 45
not. Some factor must have changed in the
18 Y ASM News / Volume 71, Number 1, 2005
FIGURE 3
North America
HI
West
Indies
1
Sooty
Mangabey
H
av
IV
Sl
V-
-2
e
ad
e
Brazil
Chimp
1
9
tr
Spanish
Central and
South America
16
45
00
—1
9
70
—1 8
6
0
Main
source
of slaves
Map of Africa showing the area of the slave trade and the range of apes and monkeys infected with the SIV ancestral lineages of both HIV-1
and HIV-2. The area of slave trade (black) overlaps with the ranges of the chimpanzee (green) and mangabey (red) species that harbor the
SIV ancestral lineages of both HIV-1 and HIV-2. HIV infections began to spread as early as the end of World War II, but no later than the
1960s. AIDS, the disease, began to appear outside the African continent in the late 1970s. Because the western areas of the slave trade
overlapped chimpanzee and sooty mangabeys ranges, HIV/AIDS would have spread with the slave trade of AIDS were a simple zoonosis
with the capacity to spread further in human populations. There is no evidence of HIV/AIDS outside or inside of Africa before the mid-20th
century, indicating that HIV/AIDS was new in Africa as well as in the rest of the world.
mid-20th century to disrupt the ecology between humans and nonvirulent SIVs.
Third, new species often can clear experimentally or accidentally inoculated SIV, indicating
that SIV infections do not always lead to clinical
signs of AIDS. In two cases in which SIVsmderived viruses were accidentally transmitted to
humans in laboratories in the United States, one
infection was cleared and the second, involving
SIVsmB670, caused a persistent but asymptomatic infection. This virus, now called SIVhu, also
fails to produce active infections when inoculated
into macaques. Thus, SIVsm-related virus infections are of low pathogenicity in humans.
Finally, there is the matter of how readily SIVs
replicate in human peripheral blood cells. Most
SIVs are known only from their DNA sequences,
making it impossible to test whether they can
grow in human cells. In fact, only 4 of 13 SIVs
were isolated from Cercopithecus monkeys, and
only one of those (SIVlhoest) actually grew in
human peripheral blood cells. The remaining
viruses (SIVsun, SIVsyk, and SIVtal) show very
restrictive host-related tropisms.
These arguments suggest that there is a missing link in our understanding of the roots of
AIDS. Most HIV groups are only weakly pathogenic and not highly infectious for humans. Despite many opportunities, in only one instance
did SIV transform into an infectious, virulent
form of HIV during the past 50,000 years of
human contract with SIV. If it were not for
HIV-1 group M, AIDS and SIV would most
likely still be undiscovered.
Volume 71, Number 1, 2005 / ASM News Y 19
What Caused the AIDS Epidemic?
We do not know what caused the AIDS epidemic, and this lack of knowledge is profound,
extending beyond this particular epidemic.
Thus, we do not know why a few new viruses
succeed, while most fail to become dangerous to
humans. Avian influenza is a good case in point.
The flu virus is one of the most readily transmitted viruses that plagues mankind. Avian flu virus
is highly lethal, with a mortality rate greater
than 50%. Yet outbreaks so far are confined to
individuals who have had close contact with
infected chickens. Why are some influenza viruses spread easily in epidemics, while others are
epidemiological failures? It may be as important
to understand the failed viruses as much as the
successful ones.
There are a few clues as to how SIV transformed into a dangerous virus, transmissible
among humans. One clue to the possibility that
a single factor launched the AIDS virus in the
last century lies in the finding that HIV broke
out in two different African locations. Taking
the long view, HIV-1 and HIV-2 did not emerge
for 50,000 years, yet appeared at about the same
time last century. The range of sooty mangabeys
and their ancestral HIV-2 virus is in far western
Africa—from Guinea-Bissau east to the Ivory
Coast. There is a big geographic gap of almost
1,000 miles before reaching the range of the
chimpanzee where HIV-1 emerged. Why did
HIV/AIDS not emerge in 50,000 years, but then
emerged twice at nearly the same time in two
different locations in Africa?
This unlikely coincidence demands a unifying
hypothesis, and two are currently being considered. The first concerns unprecedented defores-
tations in this region during the 20th century
and the possibility that particular strains of
SIV are much more pathogenic than those that
have been identified so far. According to this
hypothesis, deforestation and increased hunting
significantly increased the odds of exposure for
humans to those pathogenic, but formerly sequestered SIV strains. This explanation is the modern equivalent of the “cut hunter hypothesis.”
The second theory is that HIV/AIDS arose
from an increase in the use of unsafe injections
and transfusions in postcolonial Africa. Moreover, transfusions might have enabled SIV to
adapt to humans through serial passage and by
other mechanisms such as recombination.
Research Does Not End when HIV
Ancestors Are Identified
Uncovering the complete story of the emergence
of the AIDS epidemic entails further study. Although identifying HIV’s immediate ancestors
proved a successful research venture, that finding does not contribute much to preventing future viral crossovers from animals into humans.
If all of Africa were to stop trading in bush meat
tomorrow, the AIDS epidemic would continue
unabated. Preventing new viruses from plaguing
humans will require us to develop an understanding of the nature of pathogenesis of a microbe in a new host species. We lack this important knowledge.
We must come to understand the adaptive
processes in potential new hosts that will or will
not enable viruses or other potential pathogens
to launch emerging diseases. We know much
about emerging viruses, but almost nothing
about emerging viral diseases.
SUGGESTED READING
Apetrei, C., and P. A. Marx. 2004. Simian retroviral infections in human beings. Lancet 364:137–138.
Apetrei, C., D. L. Robertson, and P. A. Marx. 2004. The history of SIVs and AIDS: epidemiology, phylogeny and biology of
isolates from naturally SIV infected non-human primates (NHP) in Africa. Frontiers Biosci. 9:225–254.
Bailes, E., F. Gao, F. Bibollet-Ruce, M. Peeters, P. A. Marx, B. H. Hahn, and P. M. Sharp. 2003. Hybrid origin of SIV in
chimpanzees. Science 300:1713.
Drucker, E., P. G. Alcabes, and P. A. Marx. 2001. The injection century: consequences of massive unsterile injecting for the
emergence of human pathogens. Lancet 358:1989.
Hahn, B. H., G. M. Shaw, K. M. DeCock, and P. M. Sharp. 2000. AIDS as a zoonosis: scientific and public health implications.
Science 287:607– 614.
Krauss, H., A. Weber, M. Appel, B. Enders, H. D. Isenberg, H. G. Schiefer, W. Slenczka, A. von Graevenitz, and H. Zahner.
2003. Zoonoses: infectious diseases transmissible from animals to humans. ASM Press, Washington, D.C.
20 Y ASM News / Volume 71, Number 1, 2005