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Human Immunodeficiency Viruses: Origin
Human Immunodeficiency Viruses: Origin Freed EO (2002) Viral late domains. Journal of Virology 76(10): 4679–4687. Freed EO and Mouland AJ (2006) The cell biology of HIV-1 and other retroviruses. Retrovirology 3: 3–77. Goff SP (2004) Genetic control of retrovirus susceptibility in mammalian cells. Annual Reviews of Genetics 38: 61–85. Klinger PP and Schubert U (2005) The ubiquitin–proteasome system in HIV replication: Potential targets for antiretroviral therapy. Expert Review of Anti-Infective Therapy 3(1): 61–79.
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Li L, Li HS, Pauza CD, Bukrinsky M, and Zhao RY (2005) Roles of HIV-1 auxiliary proteins in viral pathogenesis and host–pathogen interactions. Cell Research 15(11–12): 923–934. Morita E and Sundquist WI (2004) Retrovirus budding. Annual Reviews of Cell and Developmental Biology 20: 395–425. Schubert U and McClure M (2005) Human immunodeficiency virus. In: Mahy BWJ and Ter Meulen V (eds.) Virology, 10th edn., pp. 1322–1346. London: Topley and Wilson.
Human Immunodeficiency Viruses: Origin F van Heuverswyn and M Peeters, University of Montpellier 1, Montpellier, France ã 2008 Elsevier Ltd. All rights reserved.
Glossary Circulating recombinant forms These forms represent recombinant HIV-1 genomes that have infected three of more persons who are not epidemiologically related. Endemic A classification of an infectious disease that is maintained in the population without the need for external inputs. Epidemic A classification of a disease that appears as new cases in a given human population, during a given period, at a rate that substantially exceeds what is expected, based on recent experience. Neighbor-joining method This clustering method constructs trees by sequentially finding of pairs of operational taxonomic units (OTUs) or neighbors that minimize the total branch length at each stage of clustering OTUs starting with a starlike tree. Pandemic An epidemic that spreads through human populations across a large region (for e.g., a continent), or even worldwide. Phylogenetic tree A phylogenetic tree, also called evolutionary tree, is a graphical diagram, showing the evolutionary relationships among various biological species of other entities that are believed to have a common ancestor, comparable to a pedigree showing which genes or organisms are most closely related. In a phylogenetic tree, each node with descendants represents the most common ancestor of the descendants, and the edge lengths in most trees correspond to time estimates. External nodes are often called operational taxonomic units (OTUs), a generic term that can represent many types of comparable taxa. Internal nodes may be called hypothetical taxonomic units (HTUs) to emphasize that they are the hypohetical progenitors of OTUs.
Prevalence The prevalence of a disease in a statistical population is defined as the total number of cases of the disease in the population at a given time, or the number of cases in the population, divided by the number of individuals in the population.
Introduction Infectious diseases have been an ever-present threat to mankind. A number of important pandemics and epidemics arose with the domestication of animals, such as influenza and tuberculosis. Whereas the cause of some of the historic pandemics, such as the bubonic plague (the Black Death) that killed at least 75 million people, have been successfully eradicated, many others still cause high mortality especially in developing countries. Emerging infectious diseases continue to represent a major threat to global health. As such, HIV/AIDS is one of the most important diseases to have emerged in the past century. When on 5 June 1981, a report was published, describing five young gay men infected with Pneumocystis carinii pneumonia (PCP), no one could have imagined that 25 years later, more than 40 million people all over the world would be infected with the human immunodeficiency virus (HIV), the cause of the acquired immunodeficiency syndrome (AIDS). With more than 25 million deaths, HIV/AIDS continues to be one of the most serious public health threats facing humankind in the twenty-first century. It is important therefore to identify where HIV came from, whether a natural host reservoir exists and how it was introduced into the human population. Today it is well established that human immunodeficiency viruses HIV-1 and HIV-2 are the result of several cross-species transmissions from nonhuman primates to humans.
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West-Central African chimpanzees (Pan troglodytes troglodytes) are now recognized as the natural reservoir of the simian immunodeficiency viruses (SIVcpzPtt), that are the ancestors of HIV-1. Similarly, HIV-2, which has remained largely restricted to west Africa, is the result of cross-species transmissions of SIVsmm from sooty mangabeys (Cercocebus atys). Although it is clear now that HIV has a zoonotic origin, it remained for a long time less certain where, when, and how often these viruses entered the human population. In this article, we will describe in more detail the latest findings on the origin of HIV, more specifically of the three groups of HIV-1 (M, N, and O) and HIV-2.
Taxonomy, Classification, and Genomic Structure Taxonomy Human and Simian immunodeficiency viruses (HIV and SIV) belong to the genus Lentivirus of the family Retroviridae, characterized by their structure and replication mode. These viruses have two RNA genomes and rely on the reverse transcriptase (RT) enzyme to transcribe their genome from RNA into a DNA copy, which can then be integrated as a DNA provirus into the genomic DNA of the host cell. This replication cycle is common for all members of the family Retroviridae. As the name suggests, the genus Lentivirus consists of slow viruses, with a long incubation period. Five serogroups are recognized, each reflecting the vertebrate hosts with which they are associated (primates, sheep and goats, horses, cats, and cattle). A feature of the primate lentiviruses, HIV and SIV, is the use of a CD4 protein receptor and the absence of a dUTPase enzyme.
Classification Classification of simian immunodeficiency viruses (SIVs)
SIVs isolated from different primate species are designated by a three-letter code, indicating their species of origin (e.g., SIVrcm from red-capped mangabey). When different subspecies of the same species are infected, the name of the subspecies is added to the virus designation, for example, SIVcpzPtt and SIVcpzPts to differentiate between the two subspecies of chimpanzees P. t. troglodytes and P. t. schweinfurthii, respectively. For chimpanzee viruses, the known or suspected country of origin is often included; for example, SIVcpzCAM and SIVcpzGAB are isolates from Cameroon and Gabon, respectively. Currently, serological evidence of SIV infection has been shown for 39 different primate species and SIV infection has been confirmed by sequence analysis in 32
(see Table 1). Overall, complete SIV genome sequences are available for 19 species. Importantly, 30 species of the 69 recognized Old World monkey and ape species in sub-Saharan Africa have not been tested yet or only very few have been tested. Knowing that the vast majority (90%) of the primate species tested are SIV infected, many of the remaining species would be expected to harbor additional SIV infections. Only Old World primates are infected with SIVs, and only those from the African continent; no SIVs have been identified in Asian primate species. It is important also to note that none of the African primates naturally infected with SIV develop disease. Classification of human immunodeficiency viruses (HIVs)
AIDS can be caused by two related lentiviruses; human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2). On the basis of phylogenetic analyses of numerous isolates obtained from diverse geographic origins, HIV-1 is classified into three groups, M, N, and O. Group M (for Major) represents the vast majority of HIV-1 strains found worldwide and is responsible for the pandemic; group O (for Outlier) and N (non-M–non-O) remain restricted to West-Central Africa. Group M can be further subdivided into nine subtypes (A–D, F-H, J, K), circulating recombinant forms (CRFs, CRF01–CRF32), and unique recombinants. The geographic distribution of the different HIV-1 M variants is very heterogeneous and differs even from country to country. Compared to HIV-1, only a limited number of HIV-2 strains have been genetically characterized and eight groups (A–H) have been reported.
Genomic Structure All primate lentiviruses have a common genomic structure, consisting of the long terminal repeats (LTRs), flanking both ends of the genome, three structural genes, gag, pol, and env and five accessory genes, vif, vpr, tat, rev, and nef. Some primate lentiviruses carry an additional accessory gene, vpx or vpu, in the region between pol and env. Based on this genomic organization, we can distinguish between three patterns (Figure 1): (1) SIVagm, SIVsyk, SIVmnd1, SIVlho, SIVsun, SIVcol, SIVtal, and SIVdeb display the basic structure with three major and five accessory genes; (2) SIVcpz, SIVgsn, SIVmus, SIVden, SIVmon, and also HIV-1 harbor an additional accessory gene, vpu; HIV-1 and SIVcpz differ from the other members of this group by the fact that env and nef genes are not overlapping; (3) SIVsmm, SIVrcm, SIVmnd2, SIVdrl, and SIVmac, and HIV-2 harbor a supplemental accessory gene, vpx. For the remaining SIVs, SIVolc, SIVwrc, SIVasc, SIVbkm, SIVery, SIVblu, SIVpre, SIVagi, and SIVgor, full-length sequences are not yet available.
Human Immunodeficiency Viruses: Origin Table 1
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Serological and/or molecular evidence for SIV infection in the African nonhuman primates
Genus
Species
Common name
SIV
Geographic distribution
Pan Gorilla
troglodytes gorilla
Common chimpanzee Western gorilla
SIVcpz SIVgora
Colobus Piliocolobus Procolobus Lophocebus
guereza badius verus albigena aterrimus anubis cynocephalus ursinus atys torquatus agilis sphinx
Mantled guereza Western red colobus Olive colobus Gray-cheeked managabey Black crested mangabey Olive baboon Yellow baboon Chacma baboon Sooty mangabey Red-capped mangabey Agile mangabey Mandrill
leucophaeus
Drill
SIVcol SIVwrca SIVolca ? SIVbkma ? SIVagm-Vera SIVagm-Vera SIVsmm SIVrcm SIVagia SIVmnd-1, SIVmnd-2 SIVdrl
Allenopithecus Miopithecus
nigroviridis talapoin ogouensis
Allen’s swamp monkey Angolan talapoin Gabon talapoin
? SIVtala SIVtal
Erythrocebus Chlorocebus
patas sabaeus aethiops tantalus pygerythrus diana nictitans
SIVagm-saba SIVagm-Sab SIVagm-Gri SIVagm-Tan SIVagm-Ver ? SIVgsn
mitis albogularis mona campbelli pogonias
Patas monkey Green monkey Grivet Tantalus monkey Vervet monkey Diana monkey Greater spot-nosed monkey Blue monkey Sykes’s monkey Mona monkey Campbell’s mona Crested mona
West to East: Senegal to Tanzania Central: Cameroon, Gabon, Congo, Central Africa Republic Central: Nigeria to Ethiopia/Tanzania West: Senegal to Ghana West: Sierra-Leone to Ghana Central: Nigeria to Uganda/Burundi Central: Democratic Republic of Congo (DRC) West to East: Mali to Ethiopia Central: Angola to Tanzania South: southern Angola to Zambia West: Senegal to Ghana West Central: Nigeria, Cameroon, Gabon Central: northeast Gabon to northeast Congo West Central: Cameroon (south of Sanaga) to Gabon, Congo West Central: southeast Nigeria to Cameroon (north of Sanaga) Central: Congo West Central: East coast of Angola into DRC West Central: Cameroon (south of Sanaga)-Gabon West to East: Senegal to Ethiopia, Tanzania West: Senegal to Volta river in Burkina Faso East: Sudan, Erithrea, Ethiopia Central: Ghana to Uganda South: South Africa to Somalia and Angola West: Sierra-Leone to Ivory Coast Central: forest blocks from West Africa to DRC
denti cephus
Dent’s mona Mustached guenon
SIVden SIVmus
erythrotis
Red-eared monkey
SIVerya
ascanius lhoest
Red-tailed monkey l’Hoest monkey
SIVasca SIVlho
solatus preussi
Sun-tailed monkey Preuss’s monkey
SIVsun SIVprea
hamlyni neglectus
Owl-faced monkey de Brazza’s monkey
? SIVdeb
Papio
Cercocebus
Mandrillus
Cercopithecus
a
SIVblua SIVsyk SIVmon ? ?
East Central: East Congo to Rift-valley East: Somalia to Eastern Cape West: Niger delta to Cameroon (north of Sanaga) West: Gambia to Liberia West Central: Cross River in Nigeria to Congo (east) Central: south of Congo River West Central: Cameroon (south of Sanaga) to east of Congo River West Central: Cross River in Nigeria to Sanaga in Cameroon, Bioko Central: South-East Congo to West Tanzania Central: eastern Congo–Zaire to western Uganda West Central: tropical forest of Gabon West Central: Cross river in Nigeria to Sanaga in Cameroon, Bioko Central: eastern DRC to Ruanda Central: Angola, Cameroon, Gabon to Uganda, western Kenya
only partial sequences are available, ? only serological evidence for SIV infection.
Evolutionary History HIV-2 and SIVsmm from Sooty Mangabeys Shortly after the identification of HIV-1 as the cause of AIDS in 1983, the first SIV, SIVmac, was isolated from rhesus macaques (Macaca mulatta) at the New England Regional Primate Research Center (NERPRC).
Retrospective research revealed that the newly identified SIV was introduced to the NERPRC by rhesus monkeys, previously housed at the California National Primate Research Center (CNPRC), where they survived an earlier (late 1960s) disease outbreak, characterized by immune suppression and opportunistic infections. A decade after the first outbreak, the story has been repeated in
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SIVagm, SIVsyk, SIVmnd1, SIVlho, SIVsun, SIVcol, SIVtal, SIVdeb tat rev
pol 5⬘LTR
gag
HIV-1, SIVcpz, SIVgsn, SIVmon, SIVmus, SIVden
HIV-2, SIVsmm, SIVrcm, SIVmnd2, SIVdrl vif vpx vpr
3⬘LTR
env
tat rev
pol gag
nef
Vpu
vif vpr
5⬘LTR
nef
tat rev
pol gag
3⬘LTR
env
vpr
5⬘LTR
nef
vif
nef
env
3⬘LTR
Figure 1 Genomic organization of the primate lentiviruses.
stump-nailed macaques (Macaca arctoides) in the same settings and 15 years later a lentivirus, called SIVstm, was isolated from frozen tissue from one of these monkeys. In both cases, the infected rhesus macaques had been in contact with healthy, but retrospectively shown SIVsmm seropositive sooty mangabeys at the CNPRC. The close phylogenetic relationship between SIVmac, SIVstm, and SIVsmm identified mangabeys as the plausible source of SIV in macaques. Since SIVmac induced a disease in rhesus macaques with remarkable similarity to human AIDS, a simian origin of HIV was soon suspected. The discovery in 1986 of HIV-2, the agent of AIDS in West Africa, and the remarkable high relatedness of HIV-2 with SIVsmm, naturally infecting sooty mangabeys in West Africa, reinforced this hypothesis. In addition, the similarities in viral genome organization (the presence of vpx), the geographic coincidence of the natural range of sooty mangabeys and the epicenter of the HIV-2 epidemic in West Africa, as well as the fact that sooty mangabeys are frequently hunted for food or kept as pets, allowed the identification of SIVsmm from sooty mangabeys as the simian source of HIV-2. HIV-1 and SIVcpz from Chimpanzees The first SIVcpz strains, SIVcpzGAB1 and SIVcpzGAB2, were isolated from chimpanzees (P. troglodytes) in Gabon more than 15 years ago; of 50 wild-caught chimpanzees initially tested for SIVcpz infection, two (GAB1 and GAB2) harbored HIV-1 cross-reactive antibodies. Analysis of the SIVcpzGAB1 genome revealed the same genomic organization as HIV-1, including an accessory gene, named vpu, so far only identified in HIV-1. Furthermore, phylogenetic analysis indicated that SIVcpzGAB1 was more closely related to HIV-1 than to any other SIV. A few years later, a third positive chimpanzee, confiscated upon illegal importation into Belgium from the Democratic Republic of Congo (DRC, ex-Zaire), was identified among 43 other wild-caught chimpanzees. A virus,
SIVcpzANT, was isolated and characterized, but this virus showed an unexpected high degree of divergence from the others. A fourth SIVcpz strain (SIVcpzUS) was obtained from a chimpanzee (Marilyn) housed in an American primate center and it was shown that SIVcpzUS was closely related to the SIVcpz strains from Gabon. Subspecies identification of the chimpanzee hosts revealed that the SIVcpzANT strain was isolated from a member of the P.t. schweinfurtii subspecies, whereas the other chimpanzees belonged to the P.t. troglodytes subspecies. These findings suggested two distinct SIVcpz lineages according to the host species: SIVcpzPtt, from the West-Central African chimpanzees, and SIVcpzPts, from eastern chimpanzees. HIV-1 strains are classified into three highly divergent clades, groups M, N, and O, each of which was more closely related to SIVcpz from P. t. troglodytes than to SIVcpz from P. t. schweinfurthii. These data pointed to the West-Central African subspecies, P. t. troglodytes as the natural reservoir of the ancestors of HIV-1. Until recently, only a handful of complete or partial SIVcpz genomes have been derived. In addition to the four previously mentioned viruses, three other strains, SIVcpzCAM3, SIVcpzCAM5, and SIVcpzCAM13, have been identified in Cameroon and all clustered with the previously identified SIVcpzPtt strains consistent with their species of origin. The discovery of HIV-1 group N in a Cameroonian patient in 1998 showed that HIV-1 N is closely related to SIVcpzPtt in the envelope region of the viral genome, suggesting an ancient recombination event. This finding demonstrated the cocirculation of SIVcpz and HIV-1 N viruses in the same geographic area and provided additional evidence that the western part of Central Africa is the likely site of origin of HIV-1. However, the number of identified SIV strains in chimpanzees was low, compared to that of other naturally occurring SIV infections. The major problem in studying SIVcpz infection in chimpanzees is their endangered status and the fact that they live in isolated forest regions. All
Human Immunodeficiency Viruses: Origin
previously studied chimpanzees were among wild-caught but young and captive animals. They were initially captured as infants, mainly as a by-product of the bushmeat trade. Since the age of maturation of chimpanzees is around 9 for males and 10 for females, these infections were most probably the result of vertical transmission and do not reflect true prevalences among wild-living adult animals. Apparently, the frequency of vertical transmission is low among naturally infected primates, which can explain the low prevalence rates initially observed. The recent development of noninvasive methods to detect and characterize SIVcpz in fecal and urine samples from wild ape populations boosted the search for new SIVcpz strains in the vast tropical forests of Central Africa. The first report of a full-length SIVcpz sequence obtained from a fecal sample, SIVcpzTAN1, was from a wild chimpanzee from the P. t. schweinfurtii subspecies in Gombe National Park, Tanzania. Subsequently, additional cases of SIVcpzPts infections were documented in Tanzania (SIVcpzTAN2 to SIVcpzTAN5) and around Kisangani, northeastern DRC (SIVcpzDRC1). All the new SIVcpzPts viruses formed a separate lineage with the initially described SIVcpzANTstrain and suggest that the SIVcpzPts strains are not at the origin of HIV-1 (Figure 2). A recent study in wild chimpanzee communities in southern Cameroon documented a prevalence of SIVcpz infection ranging from 4% to 35%, and identified 16 new SIVcpzPtt strains. All of these newly identified viruses were found to fall within the radiation of SIVcpzPtt strains from captive P. t. troglodytes apes, which also includes HIV-1 groups M and N, but not group O or SIVcpzPts (Figure 2). The new SIVcpzPtt viruses are characterized by high genetic diversity and SIVcpzPtt strains were identified which are much more closely related to HIV-1 groups M and N than were any previously identified SIVcpz strains. Interestingly, the new SIVcpzPtt viruses exhibited a significant geographic clustering and made it possible to trace the origins of present-day human AIDS viruses to geographically isolated chimpanzee communities in southern Cameroon. HIV-1 and SIVgor from Gorillas SIV infection has recently been described in western gorillas (Gorilla gorilla) in Cameroon. Surprisingly, the newly characterized gorilla viruses, termed SIVgor, formed a monophyletic group within the HIV-1/SIVcpzPtt radiation, but in contrast to SIVcpzPtt, they were most closely related to the HIV-1 group O lineage (Figure 2). However, the phylogenetic relationships between SIVcpz, SIVgor, and HIV-1 indicate that chimpanzees represent the original reservoir of SIVs now found in chimpanzees, gorillas, and humans. Given their herbivorous diet and peaceful coexistence with other primate species, especially chimpanzees, it remains a mystery by what route gorillas acquired SIVgor.
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The data on SIV in wild chimpanzee and gorilla populations showed that distinct chimpanzee communities in southern Cameroon transmitted divergent SIVcpz to humans giving rise to HIV-1 groups M and N; and that chimpanzees transmitted HIV-1 group O-like viruses either to gorillas and humans independently, or first to gorillas which then transmitted the virus to humans. Additional studies are needed to determine if the other African great ape species, the eastern gorillas (Gorilla berengei) and the bonobo (Pan paniscus) harbor any SIV.
Cross-Species Transmission Where? HIV-1 Based on mitochondrial DNA sequences, common chimpanzees (P. troglodytes) are classified into four subspecies: P. t. verus in West Africa; P. t. vellerosus, restricted to a geographical area between the Cross River in Nigeria and the Sanaga River in Cameroon; P. t. troglodytes in southern Cameroon, Gabon, Equatorial Guinea, and the Republic of Congo; and P. t. schweinfurtii in the Democratic Republic of Congo, Uganda, Rwanda, and Tanzania. No evidence of SIV infection is found in P. t. verus, despite testing of more than 2000 chimpanzees, mostly captive animals exported to zoos or research centers in the US. Wild P. t. vellerosus apes have not been found to harbor SIVcpz, but only about 100 samples have been screened. The single reported SIV infection of P. t. vellerosus, SIVCAM4, was most probably the result of a cage transmission from a P. t. troglodytes ape, infected with SIVcpzCAM3. Since the three groups of HIV-1 (M, N, and O) all fall within the HIV-1/SIVcpzPtt/SIVgor lineage, the cross-species transmissions giving rise to HIV-1 most likely occurred in western equatorial Africa. Furthermore, no human counterpart is found for SIVcpzPts from P. t. schweinfurtii, which undermines the idea of a human-induced origin of HIV-1 by oral polio vaccine (OPV) programs in East-Central Africa in the late 1950s. It has been suggested that tissues derived from SIVcpz-infected chimpanzees, captured in the northeastern part of DRC were used for the polio vaccine production. However, this geographical region is situated in the middle of the P. t. schweinfurtii range and the characterization of a partial SIV genome (SIVcpzDRC1) from a wild chimpanzee in this region proved once more the inconsistency of the OPV theory (Figure 2). The recent studies in wild chimpanzee communities in Cameroon, not only confirm the West-Central African origin of HIV-1, but also indicate that HIV-1 group M and N arose from geographically distinct chimpanzee populations. Phylogenetic analysis showed that all SIVcpz strains collected in southeast Cameroon formed a cluster with HIV-1 group M, whereas SIVcpz isolates from chimpanzee communities of a well-defined region in
0.1
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HIV-1 O SIVcpzDRC1 SIVcpzTAN3 SIVcpzTAN2 SIVcpzTAN1 SIVcpzANT
SIVcpzCAM_BM1034 SIVcpzCAM-EK505 SIVcpzUS SIVcpzCAM5 SIVcpzCAM3 SIVcpzGAB2 SIVcpzGAB1 SIVcpzCAM13 SIVcpzCAM-MT145 SIVgorCAM-CP684 SIVgorCAM-CP1436
HIV-1 N
HIV-1 M
SIVcpzCAM-CM66 SIVcpzCAM-MB317 SIVcpzCAM-LB7 100 SIVcpzCAM-MB189 SIVcpzCAM-MB24
SIVcpzPts
SIVgor
SIVcpzPtt
G. gorilla
P. t. schweinfurtii
P. t. troglodytes
P. t. vellerosus
P. t. verus
Cote d’ lvoire
go n Co
. aR nag a S
R.
gi R .
DRC
Congo R.
Uba n
Tanzania
Uganda
Figure 2 Natural range of chimpanzee subspecies and phylogeny of the HIV-1/SIVcpz/SIVgor lineage. The ranges of the four recognized chimpanzee subspecies are color-coded. The SIVcpzPtt and SIVcpzPts sequences in the phylogenetic tree are colored in red and blue, respectively, in accordance to the chimpanzee subspecies, illustrating that HIV-1 is more closely related to SIVcpz from West-Central African chimpanzees. The natural range for western gorillas (Gorilla gorilla) overlaps with the P. t. troglodytes range in West-Central Africa; SIVgor sequences are indicated in gray. The country of origin where SIVcpz strains were identified is indicated with a three-letter code: CAM for Cameroon, GAB for Gabon, TAN for Tanzania, DRC for the Democratic Republic of Congo, US for an animal in a primate center in the USA, and ANT for a captive animal in Antwerp, Belgium. This tree was derived by neighbor-joining analysis of partial env/nef nucleotide sequences. Horizontal branch lengths are drawn to scale.
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only, HIV-1 group M strains have spread across Africa and all the other continents.
south-central Cameroon clustered with the nonpandemic HIV-1 group N. It is also interesting to note that there is an uneven dissemination of SIV infection among chimpanzee populations, with the absence of SIV infection in some of them and with major geographical elements, like rivers, that can serve as important barriers. As discussed above, HIV-1 group N resulted from an ancestral recombination event between divergent lineages. The discovery of such a recombinant virus in a geographically isolated chimpanzee community in southern Cameroon shows that HIV-1 N was already a recombinant in its natural hosts prior to its transmission to humans. The origin of the third group of HIV-1, group O, remained uncertain until the recent identification of HIV-1 group O-like viruses in two different wild-living gorilla populations, in southern Cameroon (SIVgor). So all three HIV-1 groups seem to have their seeds in WestCentral Africa. While HIV-1 group O infections remained restricted to West-Central Africa (Cameroon, Nigeria, Gabon, Equatorial Guinea) and HIV-1 N to Cameroon
HIV-2 A close phylogenetic relatedness is also observed between SIVsmm from sooty mangabeys (Cercocebus atys) and HIV-2 in West Africa. Sooty mangabeys are indigenous to West Africa, from Senegal to Ivory Coast, coinciding with the endemic center of HIV-2 (Figure 3). Eight groups (A–H) of HIV-2 have been described so far, but only subtypes A and B are largely represented in the HIV-2 epidemic, with subtype A in the western part of West Africa (Senegal, Guinea-Bissau) and subtype B being predominant in Ivory Coast. The other subtypes have been documented in one or few individuals only. Except for groups G and H, groups C, D, E, and F were isolated in rural areas in Sierra Leone and Liberia and these viruses are more closely related to the SIVsmm strains obtained from sooty mangabeys found in the same area than to any other HIV-2 strains. This suggests that the
SIVsmmSL92F 78
SIVsmmSL92E SIVsmmSL93_134 HIV-2H12034 HIV-2 H C_22381 HIV-2 C SIVsmmTAI3 SIVsmmTAI22 SIVsmmCI8 SIVsmmSL92D SIVstm22579 SIVsmmSL93_080
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SIVsmmH4 SIVmac251 SIVsmmLIB-1 D_FO784
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SIVsmmTAI32 SIVsmmTAI31 SIVsmmTAI23 HIV-2/G B_UC1 B_EHOA B_D205 A_GH1 HIV-2SL93A A_ROD HIV-2SL93F SIVsmmSL93_063
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SIVsmmSL93_119 SIVsmmSL92C SIVsmmSL92B AE_PA1
HIV-2 D
HIV-2 G HIV-2 B
HIV-2 A HIV-2 F
A
cd ef
g, h B
HIV-2 E
Figure 3 Geographic distribution of the different HIV-2 groups and phylogeny of the HIV-2/SIVsmm lineage. Countries where HIV-2 is endemic are colored in grey and overlap with the range of sooty mangabeys (Cercocebus atys) in West Africa. SIVsmm strains obtained from mangabeys in different regions are colored: green for Ivory Coast, blue for Sierra Leone, and pink for Liberia. SIVsmm strains isolated from mangabeys or macaques in US zoo’s or primate centers are indicated in italic. This tree was derived by neighbor-joining analysis of partial gag nucleotide sequences from HIV-2 and SIVsmm sequences from West Africa. Horizontal branch lengths are drawn to scale.
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Human Immunodeficiency Viruses: Origin
different groups of HIV-2 must be the result of multiple independent cross-species transmissions of SIVsmm into the human population. Importantly, HIV-2 prevalence remains low and is even decreasing, since HIV-1 M is now predominating also in West Africa. When? It is clear now that each group of HIV-1 (M, N, and O) and HIV-2 (A–H) resulted from an independent cross-species transmission, followed by different viral evolution rates and possibly by one or more recombination events. HIV-1 group M can be further subdivided into subtypes, circulating recombinant forms and many unique recombinants, which had a heterogeneous geographical spread. The highest genetic diversity, in number of co-circulating subtypes and intrasubtype diversity has been observed in Central Africa, more precisely the western part of DRC, suggesting this region being the epicenter of HIV-1 M. Moreover, the earliest known HIV-1 virus, ZR59, isolated from an individual in Le´opoldville (now Kinshasa) in 1959. The virus has been characterized as a member of HIV-1 M, subtype D. So, the common ancestor of this group should be dated prior to 1959. Molecular clock analyses estimated the date of the most recent common ancestor of HIV-1 group M around 1930 with a confidence interval of 1915–1941. A similar time frame is estimated for the origin of the HIV-1 group O radiation: 1920 with a range from 1931 to 1940. The oldest HIV-1 group O sample has been documented in a Norwegian sailor in 1964 infected in Cameroon (Douala), both groups show an exponential increase of the number of HIV infections during the twentieth century. However, the growth rate of HIV-1 group O (r ¼ 0.08 [0.05–0.12]) is slower than the rate estimated for HIV-1 group M in Central Africa (r ¼ 0.17). This is not surprising, considering the much lower prevalence of group O in Cameroon. Since the first identification of HIV-1 group N in 1998, about 10 group N infections have been described and all were from Cameroonian patients. The intra-group genetic diversity is significant lower for group N than for group M or O, which suggests a more recent introduction of the HIV-1 N lineage into the human population. Similar analyses traced the origin of the pandemic HIV-2 groups A and B to be around 1940 with a confidence interval of 16 years, and around 1945 with a confidence interval of 1931–59, respectively. How? Although the precise conditions and circumstances of the SIVcpz and SIVsmm transmissions remain unknown, human exposure to blood or other secretions of infected primates, through hunting and butchering of primate bushmeat, represents the most plausible source for
human infection. Also bites and other injuries caused by primates kept as pets can increase the probability of viral transmission. Direct evidence of human infection with other SIVs is not yet reported, but that retroviruses can jump from primates to humans has been documented for simian foamy viruses (SFV) and simian T-cell leukemia viruses (STLVs). For example, SFV infection has been detected in rural Central Africa among individuals who hunt monkeys and apes. The infection with SFV in an Asian man, who regularly visited an ancient temple, was most probably the result of a bite from a macaque. An analysis of the man’s blood indicated the presence of an SFV strain similar to a strain from macaques living around the temple. So far, SFV has not been shown to cause disease in humans, but the long-term effects of SFV in humans are not yet known. These effects are well documented for SIV and its human counterpart HIV; the HIV-1 group M epidemic clearly illustrates the devastating results of a single cross-species transmission. Other SIV Cross-Species Transmissions, Risk for Novel HIV? A recent study on primate bushmeat in Cameroon revealed that about 10% is SIV infected and illustrates an ongoing exposure to a plethora of different SIVs. Today, 69 different nonhuman primate species are identified in Africa and for 32 species (47%) SIV infection could already be proved by genomic amplification of the virus. This means that, in addition to sooty mangabeys, chimpanzees, and possibly gorillas, at least 29 other primate species harbor SIV’s, which poses a potential risk for transmission to humans, especially for those in direct contact with infected blood and tissues. Therefore, efforts to reduce exposure to SIV-infected primates should be a primary concern. However, the opposite is occuring; the bushmeat trade has increased significantly during the last few decades, especially through the development of the logging industry. As a consequence, roads are now penetrating the formerly isolated forest areas and create a free passage for transport of wood, bushmeat, people, and subsequently different pathogens. The surrounding villages change from modest, little communities to real trade centers, with up to several thousand inhabitants. In addition, human migration and social and economic networks support this industry. It is very likely that the estimated prevalence of SIV infection of wild monkey species is underestimated for three reasons: first, only half of the recognized species have been tested; second, for some species only a few monkeys were tested; and third, and the most important reason, the sensitivity of the available diagnostic tools, initially developed for HIV detection, may be inaccurate for the detection of divergent SIVs. The increasing magnitude of human exposure to SIVs, combined with socioeconomic changes, which
Human Immunodeficiency Viruses: Origin
favor the dissemination of a plausible SIV transmission into the human population, could be the basis of novel zoonoses that lead in turn to novel HIV epidemics. It is important to note that there is more needed than transmission of a virus to initiate an epidemic. After the virus has crossed the species barrier, adaptation to the new host is necessary to be able to spread efficiently within a population. The pathogenic potential of the virus and host genetic differences between individuals, as well as between species, determine susceptibility or resistance to further disease progression. In addition, environmental, social, and demographic factors play a major role in the further spread of new viruses.
Evolution of SIVs in their Natural Primate Hosts: The Origin of SIVcpz With the increasing number of full-length SIV sequences from different primate species it becomes clear that crossspecies transmissions and subsequent recombinations have occurred frequently among primates lentiviruses. Crossspecies transmissions among co-habiting species in the wild has been observed between African green monkeys and patas monkeys in West Africa; between African green monkeys and baboons in southern Africa; and between different Cercopithecus species in Central Africa, that is, greater spot-nosed guenons (C. nictitans) and moustached (C. cephus) monkeys in Cameroon. One of the most striking examples of cross-species transmission, followed by recombination, is SIVcpz in chimpanzees. Chimpanzees are known to hunt other primates for food, such as red-capped mangabeys (Cercocebus torquatus), greater spot-nosed guenons (Cercopithecus nictitans), and colobus monkeys (Colobinae). The isolation and characterization of the SIV genomes from the former monkey species revealed an unexpected high level of similarity between some parts of the SIVcpz genome and SIVrcm and SIVgsn. The 50 region of SIVcpz (gag, pol, vif, and vpr) is most similar to SIVrcm, except for the accessory gene vpx, which is characteristic for the SIVrcm lineage, but absent in the HIV-1 and SIVcpz strains. The 30 region of SIVcpz (vpu, env, and nef ) is closely related to SIVgsn. Furthermore, SIVgsn is the first reported monkey virus to encode a vpu gene, the accessory gene characteristic of the HIV-1/SIVcpz lineage. Most probably, the recombination of these monkey viruses occurred within chimpanzees and gave rise to the common ancestor of today’s SIVcpz lineages, which in turn were subsequently transmitted to humans. The cross-species transmission of this recombinant virus, or its progenitors, happened some time after the split of P. t. verus and P. t. vellerosus from the other subspecies, but possibly before the divergence between P. t. troglodytes and P. t. schweinfurtii.
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The fact that gorillas are infected with an SIV from the SIVcpz lineage, represents a mystery, since only peaceful encounters have been documented among these sympatric apes. The evolutionary history of primate lentiviruses is complex and likely involved a series of consecutive interspecies transmissions, the timelines and directions of which remain to be deciphered.
Conclusion We now have a clear picture of the origin of HIV and the seeds of the AIDS pandemic. SIVcpz, the progenitor of HIV-1, resulted from a recombination among ancestors of SIV lineages presently infecting red-capped mangabeys and Cercopithecus monkeys in West-Central Africa. HIV-1 groups M and O resulted from independent cross-species transmissions early in the twentieth century. The SIVcpzPtt strains that gave rise to HIV-1 group M belonged to a viral lineage that persists today in P. t. troglodytes apes in south Cameroon. Most likely this virus was transmitted locally, but made its way to Kinshasa where the group M pandemic was spawned. HIV-1 group N, which has been identified in only a small number of AIDS patients from Cameroon, derived from a second SIVcpzPtt lineage in south-central Cameroon and remained geographically more restricted. HIV-1 group O-related viruses are present in a second African great ape species, the western gorilla (Gorilla gorilla), but chimpanzees were the original reservoir of SIVgor. Similarly, only HIV-2 group A and B play a major role in the HIV-2 epidemic, and most other groups (C–H) represent unique sequences found in a single patient. A possible explanation could be that some viruses were not able to adapt to the new host or that the environment was not suitable for epidemic spread. Viral adaptation to the new host is one of the requirements for the generation of an epidemic, but also the interaction of sociocultural factors, such as deforestation, urbanization, and human migration, have been crucial in the emergence of the HIV-1 pandemic. While the origin of the HIV-1 and HIV-2 viruses has become clearer, important questions concerning pathogenicity and epidemic spread of certain SIV variants needs to be further elucidated. See also: AIDS: Disease Manifestation; AIDS: Global Epidemiology; AIDS: Vaccine Development; Human Immunodeficiency Viruses: Antiretroviral agents; Human Immunodeficiency Viruses: Molecular Biology; Human Immunodeficiency Viruses: Pathogenesis; Simian Immunodeficiency Virus: Animal Models of Disease; Simian Immunodeficiency Virus: General Features; Simian Immunodeficiency Virus: Natural Infection.
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Further Reading Aghokeng AF and Peeters M (2005) Simian immunodeficiency viruses (SIVs) in Africa. Journal of Neurovirology 11(supplement 1): 27–32. Hahn BH, Shaw GM, De Cock KM, and Sharp PM (2000) AIDS as a zoonosis: Scientific and public health implications. Science 287: 607–614. Keele BF, Van Heuverswyn F, Li Y, et al. (2006) Chimpanzee: Reservoirs of pandemic and nonpandemic HIV-1. Science 313: 523–526. Korber B, Muldoon M, Theiler J, et al. (2000) Timing the ancestor of the HIV-1 pandemic strains. Science 288: 1789–1796. Lemey P, Pybus OG, Rambaut A, et al. (2004) The molecular population genetics of HIV-1 group O. Genetics 167: 1059–1068.
Santiago ML, Range F, Keele BF, et al. (2005) Simian immunodeficiency virus infection in free-ranging sooty mangabeys (Cercocebus atys atys) from the Tai Forest, Cote d’Ivoire: Implications for the origin of epidemic human immunodeficiency virus type 2. Journal of Virology 79: 12515–12527. Sharp PM, Shaw GM, and Hahn BH (2005) Simian immunodeficiency virus infection of chimpanzees. Journal of Virology 79: 3891–3902. VandeWoude S and Apetrei C (2006) Going wild: Lessons from naturally occurring T-lymphotropic lentiviruses. Clinical Microbiological Reviews 19: 728–762. Van Heuverswyn F, Li Y, Neel C, et al. (2006) Human immunodeficiency viruses: SIV infection in wild gorillas. Nature 44: 164. Worobey M, Santiago ML, Keele BF, et al. (2004) Origin of AIDS: Contaminated polio vaccine theory refuted. Nature 428: 820.
Human Immunodeficiency Viruses: Pathogenesis N R Klatt, A Chahroudi, and G Silvestri, University of Pennsylvania School of Medicine, Philadelphia, PA, USA ã 2008 Elsevier Ltd. All rights reserved.
Glossary Apoptosis Programmed cell death. Bystander cell death The death of HIV-uninfected cells. CCR5 A G-protein-coupled, seven transmembrane spanning receptor for the chemokines RANTES (CCL5), MIP-1a (CCL3), and MIP-1b (CCL4) that is primarily expressed on T lymphocytes, dendritic cells, macrophages, and microglial cells. CD4þ T lymphocytes (also called T-helper cells) Cells bearing CD4, a co-receptor of the T-cell receptor (TCR) complex, that recognize peptide antigens bound to MHC class II molecules and are important for both humoral and cellular immunity. Cytotoxic T lymphocytes (CTLs) Cells that are capable of killing other cells. Most CTLs express CD8, a co-receptor of the TCR complex, and recognize antigenic peptides from cytosolic pathogens, particularly viruses, that are bound to MHC class I molecules. Generalized immune activation The activation of all lymphocyte subsets in HIV infection, leading to increased cell death. Mucosal-associated lymphoid tissue (MALT) The system of lymphoid cells found in the epithelia and lamina propria of the body’s mucosal sites, including the gastrointestinal tract, lungs, eyes, nose, and the female reproductive tract. Neutralizing antibodies Antibodies that can limit the infectivity of a pathogen or the toxic effects of a toxin by binding to the receptor-binding site on the pathogen/ toxin and thus block entry into the target cell.
Simian immunodeficiency virus (SIV) Like HIV it is a single-stranded, positive-sense, enveloped RNA virus that is classified as a member of the genus Lentivirus of the family Retroviridae. The virus infecting chimpanzees (SIVcpz) is the origin of HIV-1 and the virus infecting sooty mangabeys (SIVsmm) is the origin of HIV-2.
Introduction The AIDS pandemic, with an estimated 40 million individuals infected with the causative agent, human immunodeficiency virus (HIV), is without question one of the key medical challenges of modern times. Twenty-four years after the first identification of HIV, the situation in the fields of AIDS research, prevention, and treatment reflects several major advances as well as a number of areas where the progress has been slow or nonexistent (Table 1). While the #1 challenge (low rate of treatment in developing countries, particularly sub-Saharan Africa) is, in essence, a reflection of the sociopolitical climate arising from a lack of stability, development, and healthcare infrastructure in these countries, challenges #2 and #3 (absence of a preventative vaccine or a cure for HIV infection and AIDS) are a direct consequence of our incomplete understanding of the pathogenesis of HIV infection. Here we summarize the key advances that have improved our understanding of the mechanisms underlying the immunodeficiency that follows HIV infection. While it is clear and universally accepted that HIV is the etiologic agent of AIDS and that the main
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Li L, Li HS, Pauza CD, Bukrinsky M, and Zhao RY (2005) Roles of HIV-1 auxiliary proteins in viral pathogenesis and host–pathogen interactions. Cell Research 15(11–12): 923–934. Morita E and Sundquist WI (2004) Retrovirus budding. Annual Reviews of Cell and Developmental Biology 20: 395–425. Schubert U and McClure M (2005) Human immunodeficiency virus. In: Mahy BWJ and Ter Meulen V (eds.) Virology, 10th edn., pp. 1322–1346. London: Topley and Wilson.
Human Immunodeficiency Viruses: Origin F van Heuverswyn and M Peeters, University of Montpellier 1, Montpellier, France ã 2008 Elsevier Ltd. All rights reserved.
Glossary Circulating recombinant forms These forms represent recombinant HIV-1 genomes that have infected three of more persons who are not epidemiologically related. Endemic A classification of an infectious disease that is maintained in the population without the need for external inputs. Epidemic A classification of a disease that appears as new cases in a given human population, during a given period, at a rate that substantially exceeds what is expected, based on recent experience. Neighbor-joining method This clustering method constructs trees by sequentially finding of pairs of operational taxonomic units (OTUs) or neighbors that minimize the total branch length at each stage of clustering OTUs starting with a starlike tree. Pandemic An epidemic that spreads through human populations across a large region (for e.g., a continent), or even worldwide. Phylogenetic tree A phylogenetic tree, also called evolutionary tree, is a graphical diagram, showing the evolutionary relationships among various biological species of other entities that are believed to have a common ancestor, comparable to a pedigree showing which genes or organisms are most closely related. In a phylogenetic tree, each node with descendants represents the most common ancestor of the descendants, and the edge lengths in most trees correspond to time estimates. External nodes are often called operational taxonomic units (OTUs), a generic term that can represent many types of comparable taxa. Internal nodes may be called hypothetical taxonomic units (HTUs) to emphasize that they are the hypohetical progenitors of OTUs.
Prevalence The prevalence of a disease in a statistical population is defined as the total number of cases of the disease in the population at a given time, or the number of cases in the population, divided by the number of individuals in the population.
Introduction Infectious diseases have been an ever-present threat to mankind. A number of important pandemics and epidemics arose with the domestication of animals, such as influenza and tuberculosis. Whereas the cause of some of the historic pandemics, such as the bubonic plague (the Black Death) that killed at least 75 million people, have been successfully eradicated, many others still cause high mortality especially in developing countries. Emerging infectious diseases continue to represent a major threat to global health. As such, HIV/AIDS is one of the most important diseases to have emerged in the past century. When on 5 June 1981, a report was published, describing five young gay men infected with Pneumocystis carinii pneumonia (PCP), no one could have imagined that 25 years later, more than 40 million people all over the world would be infected with the human immunodeficiency virus (HIV), the cause of the acquired immunodeficiency syndrome (AIDS). With more than 25 million deaths, HIV/AIDS continues to be one of the most serious public health threats facing humankind in the twenty-first century. It is important therefore to identify where HIV came from, whether a natural host reservoir exists and how it was introduced into the human population. Today it is well established that human immunodeficiency viruses HIV-1 and HIV-2 are the result of several cross-species transmissions from nonhuman primates to humans.
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West-Central African chimpanzees (Pan troglodytes troglodytes) are now recognized as the natural reservoir of the simian immunodeficiency viruses (SIVcpzPtt), that are the ancestors of HIV-1. Similarly, HIV-2, which has remained largely restricted to west Africa, is the result of cross-species transmissions of SIVsmm from sooty mangabeys (Cercocebus atys). Although it is clear now that HIV has a zoonotic origin, it remained for a long time less certain where, when, and how often these viruses entered the human population. In this article, we will describe in more detail the latest findings on the origin of HIV, more specifically of the three groups of HIV-1 (M, N, and O) and HIV-2.
Taxonomy, Classification, and Genomic Structure Taxonomy Human and Simian immunodeficiency viruses (HIV and SIV) belong to the genus Lentivirus of the family Retroviridae, characterized by their structure and replication mode. These viruses have two RNA genomes and rely on the reverse transcriptase (RT) enzyme to transcribe their genome from RNA into a DNA copy, which can then be integrated as a DNA provirus into the genomic DNA of the host cell. This replication cycle is common for all members of the family Retroviridae. As the name suggests, the genus Lentivirus consists of slow viruses, with a long incubation period. Five serogroups are recognized, each reflecting the vertebrate hosts with which they are associated (primates, sheep and goats, horses, cats, and cattle). A feature of the primate lentiviruses, HIV and SIV, is the use of a CD4 protein receptor and the absence of a dUTPase enzyme.
Classification Classification of simian immunodeficiency viruses (SIVs)
SIVs isolated from different primate species are designated by a three-letter code, indicating their species of origin (e.g., SIVrcm from red-capped mangabey). When different subspecies of the same species are infected, the name of the subspecies is added to the virus designation, for example, SIVcpzPtt and SIVcpzPts to differentiate between the two subspecies of chimpanzees P. t. troglodytes and P. t. schweinfurthii, respectively. For chimpanzee viruses, the known or suspected country of origin is often included; for example, SIVcpzCAM and SIVcpzGAB are isolates from Cameroon and Gabon, respectively. Currently, serological evidence of SIV infection has been shown for 39 different primate species and SIV infection has been confirmed by sequence analysis in 32
(see Table 1). Overall, complete SIV genome sequences are available for 19 species. Importantly, 30 species of the 69 recognized Old World monkey and ape species in sub-Saharan Africa have not been tested yet or only very few have been tested. Knowing that the vast majority (90%) of the primate species tested are SIV infected, many of the remaining species would be expected to harbor additional SIV infections. Only Old World primates are infected with SIVs, and only those from the African continent; no SIVs have been identified in Asian primate species. It is important also to note that none of the African primates naturally infected with SIV develop disease. Classification of human immunodeficiency viruses (HIVs)
AIDS can be caused by two related lentiviruses; human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2). On the basis of phylogenetic analyses of numerous isolates obtained from diverse geographic origins, HIV-1 is classified into three groups, M, N, and O. Group M (for Major) represents the vast majority of HIV-1 strains found worldwide and is responsible for the pandemic; group O (for Outlier) and N (non-M–non-O) remain restricted to West-Central Africa. Group M can be further subdivided into nine subtypes (A–D, F-H, J, K), circulating recombinant forms (CRFs, CRF01–CRF32), and unique recombinants. The geographic distribution of the different HIV-1 M variants is very heterogeneous and differs even from country to country. Compared to HIV-1, only a limited number of HIV-2 strains have been genetically characterized and eight groups (A–H) have been reported.
Genomic Structure All primate lentiviruses have a common genomic structure, consisting of the long terminal repeats (LTRs), flanking both ends of the genome, three structural genes, gag, pol, and env and five accessory genes, vif, vpr, tat, rev, and nef. Some primate lentiviruses carry an additional accessory gene, vpx or vpu, in the region between pol and env. Based on this genomic organization, we can distinguish between three patterns (Figure 1): (1) SIVagm, SIVsyk, SIVmnd1, SIVlho, SIVsun, SIVcol, SIVtal, and SIVdeb display the basic structure with three major and five accessory genes; (2) SIVcpz, SIVgsn, SIVmus, SIVden, SIVmon, and also HIV-1 harbor an additional accessory gene, vpu; HIV-1 and SIVcpz differ from the other members of this group by the fact that env and nef genes are not overlapping; (3) SIVsmm, SIVrcm, SIVmnd2, SIVdrl, and SIVmac, and HIV-2 harbor a supplemental accessory gene, vpx. For the remaining SIVs, SIVolc, SIVwrc, SIVasc, SIVbkm, SIVery, SIVblu, SIVpre, SIVagi, and SIVgor, full-length sequences are not yet available.
Human Immunodeficiency Viruses: Origin Table 1
527
Serological and/or molecular evidence for SIV infection in the African nonhuman primates
Genus
Species
Common name
SIV
Geographic distribution
Pan Gorilla
troglodytes gorilla
Common chimpanzee Western gorilla
SIVcpz SIVgora
Colobus Piliocolobus Procolobus Lophocebus
guereza badius verus albigena aterrimus anubis cynocephalus ursinus atys torquatus agilis sphinx
Mantled guereza Western red colobus Olive colobus Gray-cheeked managabey Black crested mangabey Olive baboon Yellow baboon Chacma baboon Sooty mangabey Red-capped mangabey Agile mangabey Mandrill
leucophaeus
Drill
SIVcol SIVwrca SIVolca ? SIVbkma ? SIVagm-Vera SIVagm-Vera SIVsmm SIVrcm SIVagia SIVmnd-1, SIVmnd-2 SIVdrl
Allenopithecus Miopithecus
nigroviridis talapoin ogouensis
Allen’s swamp monkey Angolan talapoin Gabon talapoin
? SIVtala SIVtal
Erythrocebus Chlorocebus
patas sabaeus aethiops tantalus pygerythrus diana nictitans
SIVagm-saba SIVagm-Sab SIVagm-Gri SIVagm-Tan SIVagm-Ver ? SIVgsn
mitis albogularis mona campbelli pogonias
Patas monkey Green monkey Grivet Tantalus monkey Vervet monkey Diana monkey Greater spot-nosed monkey Blue monkey Sykes’s monkey Mona monkey Campbell’s mona Crested mona
West to East: Senegal to Tanzania Central: Cameroon, Gabon, Congo, Central Africa Republic Central: Nigeria to Ethiopia/Tanzania West: Senegal to Ghana West: Sierra-Leone to Ghana Central: Nigeria to Uganda/Burundi Central: Democratic Republic of Congo (DRC) West to East: Mali to Ethiopia Central: Angola to Tanzania South: southern Angola to Zambia West: Senegal to Ghana West Central: Nigeria, Cameroon, Gabon Central: northeast Gabon to northeast Congo West Central: Cameroon (south of Sanaga) to Gabon, Congo West Central: southeast Nigeria to Cameroon (north of Sanaga) Central: Congo West Central: East coast of Angola into DRC West Central: Cameroon (south of Sanaga)-Gabon West to East: Senegal to Ethiopia, Tanzania West: Senegal to Volta river in Burkina Faso East: Sudan, Erithrea, Ethiopia Central: Ghana to Uganda South: South Africa to Somalia and Angola West: Sierra-Leone to Ivory Coast Central: forest blocks from West Africa to DRC
denti cephus
Dent’s mona Mustached guenon
SIVden SIVmus
erythrotis
Red-eared monkey
SIVerya
ascanius lhoest
Red-tailed monkey l’Hoest monkey
SIVasca SIVlho
solatus preussi
Sun-tailed monkey Preuss’s monkey
SIVsun SIVprea
hamlyni neglectus
Owl-faced monkey de Brazza’s monkey
? SIVdeb
Papio
Cercocebus
Mandrillus
Cercopithecus
a
SIVblua SIVsyk SIVmon ? ?
East Central: East Congo to Rift-valley East: Somalia to Eastern Cape West: Niger delta to Cameroon (north of Sanaga) West: Gambia to Liberia West Central: Cross River in Nigeria to Congo (east) Central: south of Congo River West Central: Cameroon (south of Sanaga) to east of Congo River West Central: Cross River in Nigeria to Sanaga in Cameroon, Bioko Central: South-East Congo to West Tanzania Central: eastern Congo–Zaire to western Uganda West Central: tropical forest of Gabon West Central: Cross river in Nigeria to Sanaga in Cameroon, Bioko Central: eastern DRC to Ruanda Central: Angola, Cameroon, Gabon to Uganda, western Kenya
only partial sequences are available, ? only serological evidence for SIV infection.
Evolutionary History HIV-2 and SIVsmm from Sooty Mangabeys Shortly after the identification of HIV-1 as the cause of AIDS in 1983, the first SIV, SIVmac, was isolated from rhesus macaques (Macaca mulatta) at the New England Regional Primate Research Center (NERPRC).
Retrospective research revealed that the newly identified SIV was introduced to the NERPRC by rhesus monkeys, previously housed at the California National Primate Research Center (CNPRC), where they survived an earlier (late 1960s) disease outbreak, characterized by immune suppression and opportunistic infections. A decade after the first outbreak, the story has been repeated in
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Human Immunodeficiency Viruses: Origin
SIVagm, SIVsyk, SIVmnd1, SIVlho, SIVsun, SIVcol, SIVtal, SIVdeb tat rev
pol 5⬘LTR
gag
HIV-1, SIVcpz, SIVgsn, SIVmon, SIVmus, SIVden
HIV-2, SIVsmm, SIVrcm, SIVmnd2, SIVdrl vif vpx vpr
3⬘LTR
env
tat rev
pol gag
nef
Vpu
vif vpr
5⬘LTR
nef
tat rev
pol gag
3⬘LTR
env
vpr
5⬘LTR
nef
vif
nef
env
3⬘LTR
Figure 1 Genomic organization of the primate lentiviruses.
stump-nailed macaques (Macaca arctoides) in the same settings and 15 years later a lentivirus, called SIVstm, was isolated from frozen tissue from one of these monkeys. In both cases, the infected rhesus macaques had been in contact with healthy, but retrospectively shown SIVsmm seropositive sooty mangabeys at the CNPRC. The close phylogenetic relationship between SIVmac, SIVstm, and SIVsmm identified mangabeys as the plausible source of SIV in macaques. Since SIVmac induced a disease in rhesus macaques with remarkable similarity to human AIDS, a simian origin of HIV was soon suspected. The discovery in 1986 of HIV-2, the agent of AIDS in West Africa, and the remarkable high relatedness of HIV-2 with SIVsmm, naturally infecting sooty mangabeys in West Africa, reinforced this hypothesis. In addition, the similarities in viral genome organization (the presence of vpx), the geographic coincidence of the natural range of sooty mangabeys and the epicenter of the HIV-2 epidemic in West Africa, as well as the fact that sooty mangabeys are frequently hunted for food or kept as pets, allowed the identification of SIVsmm from sooty mangabeys as the simian source of HIV-2. HIV-1 and SIVcpz from Chimpanzees The first SIVcpz strains, SIVcpzGAB1 and SIVcpzGAB2, were isolated from chimpanzees (P. troglodytes) in Gabon more than 15 years ago; of 50 wild-caught chimpanzees initially tested for SIVcpz infection, two (GAB1 and GAB2) harbored HIV-1 cross-reactive antibodies. Analysis of the SIVcpzGAB1 genome revealed the same genomic organization as HIV-1, including an accessory gene, named vpu, so far only identified in HIV-1. Furthermore, phylogenetic analysis indicated that SIVcpzGAB1 was more closely related to HIV-1 than to any other SIV. A few years later, a third positive chimpanzee, confiscated upon illegal importation into Belgium from the Democratic Republic of Congo (DRC, ex-Zaire), was identified among 43 other wild-caught chimpanzees. A virus,
SIVcpzANT, was isolated and characterized, but this virus showed an unexpected high degree of divergence from the others. A fourth SIVcpz strain (SIVcpzUS) was obtained from a chimpanzee (Marilyn) housed in an American primate center and it was shown that SIVcpzUS was closely related to the SIVcpz strains from Gabon. Subspecies identification of the chimpanzee hosts revealed that the SIVcpzANT strain was isolated from a member of the P.t. schweinfurtii subspecies, whereas the other chimpanzees belonged to the P.t. troglodytes subspecies. These findings suggested two distinct SIVcpz lineages according to the host species: SIVcpzPtt, from the West-Central African chimpanzees, and SIVcpzPts, from eastern chimpanzees. HIV-1 strains are classified into three highly divergent clades, groups M, N, and O, each of which was more closely related to SIVcpz from P. t. troglodytes than to SIVcpz from P. t. schweinfurthii. These data pointed to the West-Central African subspecies, P. t. troglodytes as the natural reservoir of the ancestors of HIV-1. Until recently, only a handful of complete or partial SIVcpz genomes have been derived. In addition to the four previously mentioned viruses, three other strains, SIVcpzCAM3, SIVcpzCAM5, and SIVcpzCAM13, have been identified in Cameroon and all clustered with the previously identified SIVcpzPtt strains consistent with their species of origin. The discovery of HIV-1 group N in a Cameroonian patient in 1998 showed that HIV-1 N is closely related to SIVcpzPtt in the envelope region of the viral genome, suggesting an ancient recombination event. This finding demonstrated the cocirculation of SIVcpz and HIV-1 N viruses in the same geographic area and provided additional evidence that the western part of Central Africa is the likely site of origin of HIV-1. However, the number of identified SIV strains in chimpanzees was low, compared to that of other naturally occurring SIV infections. The major problem in studying SIVcpz infection in chimpanzees is their endangered status and the fact that they live in isolated forest regions. All
Human Immunodeficiency Viruses: Origin
previously studied chimpanzees were among wild-caught but young and captive animals. They were initially captured as infants, mainly as a by-product of the bushmeat trade. Since the age of maturation of chimpanzees is around 9 for males and 10 for females, these infections were most probably the result of vertical transmission and do not reflect true prevalences among wild-living adult animals. Apparently, the frequency of vertical transmission is low among naturally infected primates, which can explain the low prevalence rates initially observed. The recent development of noninvasive methods to detect and characterize SIVcpz in fecal and urine samples from wild ape populations boosted the search for new SIVcpz strains in the vast tropical forests of Central Africa. The first report of a full-length SIVcpz sequence obtained from a fecal sample, SIVcpzTAN1, was from a wild chimpanzee from the P. t. schweinfurtii subspecies in Gombe National Park, Tanzania. Subsequently, additional cases of SIVcpzPts infections were documented in Tanzania (SIVcpzTAN2 to SIVcpzTAN5) and around Kisangani, northeastern DRC (SIVcpzDRC1). All the new SIVcpzPts viruses formed a separate lineage with the initially described SIVcpzANTstrain and suggest that the SIVcpzPts strains are not at the origin of HIV-1 (Figure 2). A recent study in wild chimpanzee communities in southern Cameroon documented a prevalence of SIVcpz infection ranging from 4% to 35%, and identified 16 new SIVcpzPtt strains. All of these newly identified viruses were found to fall within the radiation of SIVcpzPtt strains from captive P. t. troglodytes apes, which also includes HIV-1 groups M and N, but not group O or SIVcpzPts (Figure 2). The new SIVcpzPtt viruses are characterized by high genetic diversity and SIVcpzPtt strains were identified which are much more closely related to HIV-1 groups M and N than were any previously identified SIVcpz strains. Interestingly, the new SIVcpzPtt viruses exhibited a significant geographic clustering and made it possible to trace the origins of present-day human AIDS viruses to geographically isolated chimpanzee communities in southern Cameroon. HIV-1 and SIVgor from Gorillas SIV infection has recently been described in western gorillas (Gorilla gorilla) in Cameroon. Surprisingly, the newly characterized gorilla viruses, termed SIVgor, formed a monophyletic group within the HIV-1/SIVcpzPtt radiation, but in contrast to SIVcpzPtt, they were most closely related to the HIV-1 group O lineage (Figure 2). However, the phylogenetic relationships between SIVcpz, SIVgor, and HIV-1 indicate that chimpanzees represent the original reservoir of SIVs now found in chimpanzees, gorillas, and humans. Given their herbivorous diet and peaceful coexistence with other primate species, especially chimpanzees, it remains a mystery by what route gorillas acquired SIVgor.
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The data on SIV in wild chimpanzee and gorilla populations showed that distinct chimpanzee communities in southern Cameroon transmitted divergent SIVcpz to humans giving rise to HIV-1 groups M and N; and that chimpanzees transmitted HIV-1 group O-like viruses either to gorillas and humans independently, or first to gorillas which then transmitted the virus to humans. Additional studies are needed to determine if the other African great ape species, the eastern gorillas (Gorilla berengei) and the bonobo (Pan paniscus) harbor any SIV.
Cross-Species Transmission Where? HIV-1 Based on mitochondrial DNA sequences, common chimpanzees (P. troglodytes) are classified into four subspecies: P. t. verus in West Africa; P. t. vellerosus, restricted to a geographical area between the Cross River in Nigeria and the Sanaga River in Cameroon; P. t. troglodytes in southern Cameroon, Gabon, Equatorial Guinea, and the Republic of Congo; and P. t. schweinfurtii in the Democratic Republic of Congo, Uganda, Rwanda, and Tanzania. No evidence of SIV infection is found in P. t. verus, despite testing of more than 2000 chimpanzees, mostly captive animals exported to zoos or research centers in the US. Wild P. t. vellerosus apes have not been found to harbor SIVcpz, but only about 100 samples have been screened. The single reported SIV infection of P. t. vellerosus, SIVCAM4, was most probably the result of a cage transmission from a P. t. troglodytes ape, infected with SIVcpzCAM3. Since the three groups of HIV-1 (M, N, and O) all fall within the HIV-1/SIVcpzPtt/SIVgor lineage, the cross-species transmissions giving rise to HIV-1 most likely occurred in western equatorial Africa. Furthermore, no human counterpart is found for SIVcpzPts from P. t. schweinfurtii, which undermines the idea of a human-induced origin of HIV-1 by oral polio vaccine (OPV) programs in East-Central Africa in the late 1950s. It has been suggested that tissues derived from SIVcpz-infected chimpanzees, captured in the northeastern part of DRC were used for the polio vaccine production. However, this geographical region is situated in the middle of the P. t. schweinfurtii range and the characterization of a partial SIV genome (SIVcpzDRC1) from a wild chimpanzee in this region proved once more the inconsistency of the OPV theory (Figure 2). The recent studies in wild chimpanzee communities in Cameroon, not only confirm the West-Central African origin of HIV-1, but also indicate that HIV-1 group M and N arose from geographically distinct chimpanzee populations. Phylogenetic analysis showed that all SIVcpz strains collected in southeast Cameroon formed a cluster with HIV-1 group M, whereas SIVcpz isolates from chimpanzee communities of a well-defined region in
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Figure 2 Natural range of chimpanzee subspecies and phylogeny of the HIV-1/SIVcpz/SIVgor lineage. The ranges of the four recognized chimpanzee subspecies are color-coded. The SIVcpzPtt and SIVcpzPts sequences in the phylogenetic tree are colored in red and blue, respectively, in accordance to the chimpanzee subspecies, illustrating that HIV-1 is more closely related to SIVcpz from West-Central African chimpanzees. The natural range for western gorillas (Gorilla gorilla) overlaps with the P. t. troglodytes range in West-Central Africa; SIVgor sequences are indicated in gray. The country of origin where SIVcpz strains were identified is indicated with a three-letter code: CAM for Cameroon, GAB for Gabon, TAN for Tanzania, DRC for the Democratic Republic of Congo, US for an animal in a primate center in the USA, and ANT for a captive animal in Antwerp, Belgium. This tree was derived by neighbor-joining analysis of partial env/nef nucleotide sequences. Horizontal branch lengths are drawn to scale.
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only, HIV-1 group M strains have spread across Africa and all the other continents.
south-central Cameroon clustered with the nonpandemic HIV-1 group N. It is also interesting to note that there is an uneven dissemination of SIV infection among chimpanzee populations, with the absence of SIV infection in some of them and with major geographical elements, like rivers, that can serve as important barriers. As discussed above, HIV-1 group N resulted from an ancestral recombination event between divergent lineages. The discovery of such a recombinant virus in a geographically isolated chimpanzee community in southern Cameroon shows that HIV-1 N was already a recombinant in its natural hosts prior to its transmission to humans. The origin of the third group of HIV-1, group O, remained uncertain until the recent identification of HIV-1 group O-like viruses in two different wild-living gorilla populations, in southern Cameroon (SIVgor). So all three HIV-1 groups seem to have their seeds in WestCentral Africa. While HIV-1 group O infections remained restricted to West-Central Africa (Cameroon, Nigeria, Gabon, Equatorial Guinea) and HIV-1 N to Cameroon
HIV-2 A close phylogenetic relatedness is also observed between SIVsmm from sooty mangabeys (Cercocebus atys) and HIV-2 in West Africa. Sooty mangabeys are indigenous to West Africa, from Senegal to Ivory Coast, coinciding with the endemic center of HIV-2 (Figure 3). Eight groups (A–H) of HIV-2 have been described so far, but only subtypes A and B are largely represented in the HIV-2 epidemic, with subtype A in the western part of West Africa (Senegal, Guinea-Bissau) and subtype B being predominant in Ivory Coast. The other subtypes have been documented in one or few individuals only. Except for groups G and H, groups C, D, E, and F were isolated in rural areas in Sierra Leone and Liberia and these viruses are more closely related to the SIVsmm strains obtained from sooty mangabeys found in the same area than to any other HIV-2 strains. This suggests that the
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Figure 3 Geographic distribution of the different HIV-2 groups and phylogeny of the HIV-2/SIVsmm lineage. Countries where HIV-2 is endemic are colored in grey and overlap with the range of sooty mangabeys (Cercocebus atys) in West Africa. SIVsmm strains obtained from mangabeys in different regions are colored: green for Ivory Coast, blue for Sierra Leone, and pink for Liberia. SIVsmm strains isolated from mangabeys or macaques in US zoo’s or primate centers are indicated in italic. This tree was derived by neighbor-joining analysis of partial gag nucleotide sequences from HIV-2 and SIVsmm sequences from West Africa. Horizontal branch lengths are drawn to scale.
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different groups of HIV-2 must be the result of multiple independent cross-species transmissions of SIVsmm into the human population. Importantly, HIV-2 prevalence remains low and is even decreasing, since HIV-1 M is now predominating also in West Africa. When? It is clear now that each group of HIV-1 (M, N, and O) and HIV-2 (A–H) resulted from an independent cross-species transmission, followed by different viral evolution rates and possibly by one or more recombination events. HIV-1 group M can be further subdivided into subtypes, circulating recombinant forms and many unique recombinants, which had a heterogeneous geographical spread. The highest genetic diversity, in number of co-circulating subtypes and intrasubtype diversity has been observed in Central Africa, more precisely the western part of DRC, suggesting this region being the epicenter of HIV-1 M. Moreover, the earliest known HIV-1 virus, ZR59, isolated from an individual in Le´opoldville (now Kinshasa) in 1959. The virus has been characterized as a member of HIV-1 M, subtype D. So, the common ancestor of this group should be dated prior to 1959. Molecular clock analyses estimated the date of the most recent common ancestor of HIV-1 group M around 1930 with a confidence interval of 1915–1941. A similar time frame is estimated for the origin of the HIV-1 group O radiation: 1920 with a range from 1931 to 1940. The oldest HIV-1 group O sample has been documented in a Norwegian sailor in 1964 infected in Cameroon (Douala), both groups show an exponential increase of the number of HIV infections during the twentieth century. However, the growth rate of HIV-1 group O (r ¼ 0.08 [0.05–0.12]) is slower than the rate estimated for HIV-1 group M in Central Africa (r ¼ 0.17). This is not surprising, considering the much lower prevalence of group O in Cameroon. Since the first identification of HIV-1 group N in 1998, about 10 group N infections have been described and all were from Cameroonian patients. The intra-group genetic diversity is significant lower for group N than for group M or O, which suggests a more recent introduction of the HIV-1 N lineage into the human population. Similar analyses traced the origin of the pandemic HIV-2 groups A and B to be around 1940 with a confidence interval of 16 years, and around 1945 with a confidence interval of 1931–59, respectively. How? Although the precise conditions and circumstances of the SIVcpz and SIVsmm transmissions remain unknown, human exposure to blood or other secretions of infected primates, through hunting and butchering of primate bushmeat, represents the most plausible source for
human infection. Also bites and other injuries caused by primates kept as pets can increase the probability of viral transmission. Direct evidence of human infection with other SIVs is not yet reported, but that retroviruses can jump from primates to humans has been documented for simian foamy viruses (SFV) and simian T-cell leukemia viruses (STLVs). For example, SFV infection has been detected in rural Central Africa among individuals who hunt monkeys and apes. The infection with SFV in an Asian man, who regularly visited an ancient temple, was most probably the result of a bite from a macaque. An analysis of the man’s blood indicated the presence of an SFV strain similar to a strain from macaques living around the temple. So far, SFV has not been shown to cause disease in humans, but the long-term effects of SFV in humans are not yet known. These effects are well documented for SIV and its human counterpart HIV; the HIV-1 group M epidemic clearly illustrates the devastating results of a single cross-species transmission. Other SIV Cross-Species Transmissions, Risk for Novel HIV? A recent study on primate bushmeat in Cameroon revealed that about 10% is SIV infected and illustrates an ongoing exposure to a plethora of different SIVs. Today, 69 different nonhuman primate species are identified in Africa and for 32 species (47%) SIV infection could already be proved by genomic amplification of the virus. This means that, in addition to sooty mangabeys, chimpanzees, and possibly gorillas, at least 29 other primate species harbor SIV’s, which poses a potential risk for transmission to humans, especially for those in direct contact with infected blood and tissues. Therefore, efforts to reduce exposure to SIV-infected primates should be a primary concern. However, the opposite is occuring; the bushmeat trade has increased significantly during the last few decades, especially through the development of the logging industry. As a consequence, roads are now penetrating the formerly isolated forest areas and create a free passage for transport of wood, bushmeat, people, and subsequently different pathogens. The surrounding villages change from modest, little communities to real trade centers, with up to several thousand inhabitants. In addition, human migration and social and economic networks support this industry. It is very likely that the estimated prevalence of SIV infection of wild monkey species is underestimated for three reasons: first, only half of the recognized species have been tested; second, for some species only a few monkeys were tested; and third, and the most important reason, the sensitivity of the available diagnostic tools, initially developed for HIV detection, may be inaccurate for the detection of divergent SIVs. The increasing magnitude of human exposure to SIVs, combined with socioeconomic changes, which
Human Immunodeficiency Viruses: Origin
favor the dissemination of a plausible SIV transmission into the human population, could be the basis of novel zoonoses that lead in turn to novel HIV epidemics. It is important to note that there is more needed than transmission of a virus to initiate an epidemic. After the virus has crossed the species barrier, adaptation to the new host is necessary to be able to spread efficiently within a population. The pathogenic potential of the virus and host genetic differences between individuals, as well as between species, determine susceptibility or resistance to further disease progression. In addition, environmental, social, and demographic factors play a major role in the further spread of new viruses.
Evolution of SIVs in their Natural Primate Hosts: The Origin of SIVcpz With the increasing number of full-length SIV sequences from different primate species it becomes clear that crossspecies transmissions and subsequent recombinations have occurred frequently among primates lentiviruses. Crossspecies transmissions among co-habiting species in the wild has been observed between African green monkeys and patas monkeys in West Africa; between African green monkeys and baboons in southern Africa; and between different Cercopithecus species in Central Africa, that is, greater spot-nosed guenons (C. nictitans) and moustached (C. cephus) monkeys in Cameroon. One of the most striking examples of cross-species transmission, followed by recombination, is SIVcpz in chimpanzees. Chimpanzees are known to hunt other primates for food, such as red-capped mangabeys (Cercocebus torquatus), greater spot-nosed guenons (Cercopithecus nictitans), and colobus monkeys (Colobinae). The isolation and characterization of the SIV genomes from the former monkey species revealed an unexpected high level of similarity between some parts of the SIVcpz genome and SIVrcm and SIVgsn. The 50 region of SIVcpz (gag, pol, vif, and vpr) is most similar to SIVrcm, except for the accessory gene vpx, which is characteristic for the SIVrcm lineage, but absent in the HIV-1 and SIVcpz strains. The 30 region of SIVcpz (vpu, env, and nef ) is closely related to SIVgsn. Furthermore, SIVgsn is the first reported monkey virus to encode a vpu gene, the accessory gene characteristic of the HIV-1/SIVcpz lineage. Most probably, the recombination of these monkey viruses occurred within chimpanzees and gave rise to the common ancestor of today’s SIVcpz lineages, which in turn were subsequently transmitted to humans. The cross-species transmission of this recombinant virus, or its progenitors, happened some time after the split of P. t. verus and P. t. vellerosus from the other subspecies, but possibly before the divergence between P. t. troglodytes and P. t. schweinfurtii.
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The fact that gorillas are infected with an SIV from the SIVcpz lineage, represents a mystery, since only peaceful encounters have been documented among these sympatric apes. The evolutionary history of primate lentiviruses is complex and likely involved a series of consecutive interspecies transmissions, the timelines and directions of which remain to be deciphered.
Conclusion We now have a clear picture of the origin of HIV and the seeds of the AIDS pandemic. SIVcpz, the progenitor of HIV-1, resulted from a recombination among ancestors of SIV lineages presently infecting red-capped mangabeys and Cercopithecus monkeys in West-Central Africa. HIV-1 groups M and O resulted from independent cross-species transmissions early in the twentieth century. The SIVcpzPtt strains that gave rise to HIV-1 group M belonged to a viral lineage that persists today in P. t. troglodytes apes in south Cameroon. Most likely this virus was transmitted locally, but made its way to Kinshasa where the group M pandemic was spawned. HIV-1 group N, which has been identified in only a small number of AIDS patients from Cameroon, derived from a second SIVcpzPtt lineage in south-central Cameroon and remained geographically more restricted. HIV-1 group O-related viruses are present in a second African great ape species, the western gorilla (Gorilla gorilla), but chimpanzees were the original reservoir of SIVgor. Similarly, only HIV-2 group A and B play a major role in the HIV-2 epidemic, and most other groups (C–H) represent unique sequences found in a single patient. A possible explanation could be that some viruses were not able to adapt to the new host or that the environment was not suitable for epidemic spread. Viral adaptation to the new host is one of the requirements for the generation of an epidemic, but also the interaction of sociocultural factors, such as deforestation, urbanization, and human migration, have been crucial in the emergence of the HIV-1 pandemic. While the origin of the HIV-1 and HIV-2 viruses has become clearer, important questions concerning pathogenicity and epidemic spread of certain SIV variants needs to be further elucidated. See also: AIDS: Disease Manifestation; AIDS: Global Epidemiology; AIDS: Vaccine Development; Human Immunodeficiency Viruses: Antiretroviral agents; Human Immunodeficiency Viruses: Molecular Biology; Human Immunodeficiency Viruses: Pathogenesis; Simian Immunodeficiency Virus: Animal Models of Disease; Simian Immunodeficiency Virus: General Features; Simian Immunodeficiency Virus: Natural Infection.
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Further Reading Aghokeng AF and Peeters M (2005) Simian immunodeficiency viruses (SIVs) in Africa. Journal of Neurovirology 11(supplement 1): 27–32. Hahn BH, Shaw GM, De Cock KM, and Sharp PM (2000) AIDS as a zoonosis: Scientific and public health implications. Science 287: 607–614. Keele BF, Van Heuverswyn F, Li Y, et al. (2006) Chimpanzee: Reservoirs of pandemic and nonpandemic HIV-1. Science 313: 523–526. Korber B, Muldoon M, Theiler J, et al. (2000) Timing the ancestor of the HIV-1 pandemic strains. Science 288: 1789–1796. Lemey P, Pybus OG, Rambaut A, et al. (2004) The molecular population genetics of HIV-1 group O. Genetics 167: 1059–1068.
Santiago ML, Range F, Keele BF, et al. (2005) Simian immunodeficiency virus infection in free-ranging sooty mangabeys (Cercocebus atys atys) from the Tai Forest, Cote d’Ivoire: Implications for the origin of epidemic human immunodeficiency virus type 2. Journal of Virology 79: 12515–12527. Sharp PM, Shaw GM, and Hahn BH (2005) Simian immunodeficiency virus infection of chimpanzees. Journal of Virology 79: 3891–3902. VandeWoude S and Apetrei C (2006) Going wild: Lessons from naturally occurring T-lymphotropic lentiviruses. Clinical Microbiological Reviews 19: 728–762. Van Heuverswyn F, Li Y, Neel C, et al. (2006) Human immunodeficiency viruses: SIV infection in wild gorillas. Nature 44: 164. Worobey M, Santiago ML, Keele BF, et al. (2004) Origin of AIDS: Contaminated polio vaccine theory refuted. Nature 428: 820.
Human Immunodeficiency Viruses: Pathogenesis N R Klatt, A Chahroudi, and G Silvestri, University of Pennsylvania School of Medicine, Philadelphia, PA, USA ã 2008 Elsevier Ltd. All rights reserved.
Glossary Apoptosis Programmed cell death. Bystander cell death The death of HIV-uninfected cells. CCR5 A G-protein-coupled, seven transmembrane spanning receptor for the chemokines RANTES (CCL5), MIP-1a (CCL3), and MIP-1b (CCL4) that is primarily expressed on T lymphocytes, dendritic cells, macrophages, and microglial cells. CD4þ T lymphocytes (also called T-helper cells) Cells bearing CD4, a co-receptor of the T-cell receptor (TCR) complex, that recognize peptide antigens bound to MHC class II molecules and are important for both humoral and cellular immunity. Cytotoxic T lymphocytes (CTLs) Cells that are capable of killing other cells. Most CTLs express CD8, a co-receptor of the TCR complex, and recognize antigenic peptides from cytosolic pathogens, particularly viruses, that are bound to MHC class I molecules. Generalized immune activation The activation of all lymphocyte subsets in HIV infection, leading to increased cell death. Mucosal-associated lymphoid tissue (MALT) The system of lymphoid cells found in the epithelia and lamina propria of the body’s mucosal sites, including the gastrointestinal tract, lungs, eyes, nose, and the female reproductive tract. Neutralizing antibodies Antibodies that can limit the infectivity of a pathogen or the toxic effects of a toxin by binding to the receptor-binding site on the pathogen/ toxin and thus block entry into the target cell.
Simian immunodeficiency virus (SIV) Like HIV it is a single-stranded, positive-sense, enveloped RNA virus that is classified as a member of the genus Lentivirus of the family Retroviridae. The virus infecting chimpanzees (SIVcpz) is the origin of HIV-1 and the virus infecting sooty mangabeys (SIVsmm) is the origin of HIV-2.
Introduction The AIDS pandemic, with an estimated 40 million individuals infected with the causative agent, human immunodeficiency virus (HIV), is without question one of the key medical challenges of modern times. Twenty-four years after the first identification of HIV, the situation in the fields of AIDS research, prevention, and treatment reflects several major advances as well as a number of areas where the progress has been slow or nonexistent (Table 1). While the #1 challenge (low rate of treatment in developing countries, particularly sub-Saharan Africa) is, in essence, a reflection of the sociopolitical climate arising from a lack of stability, development, and healthcare infrastructure in these countries, challenges #2 and #3 (absence of a preventative vaccine or a cure for HIV infection and AIDS) are a direct consequence of our incomplete understanding of the pathogenesis of HIV infection. Here we summarize the key advances that have improved our understanding of the mechanisms underlying the immunodeficiency that follows HIV infection. While it is clear and universally accepted that HIV is the etiologic agent of AIDS and that the main