Simian Immunodeficiency Virus – Research subjects for vaccine and drug development and models for the origin of HIV and AIDS: Difference between revisions

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==The origin of Human Immunodeficiency Virus (HIV) from SIV==
==The origin of Human Immunodeficiency Virus (HIV) from SIV==
Despite both being called HIV and causes AIDS in human, HIV-1 and HIV-2 are only distantly related in the primate lentivirus group (Figure 2)<ref>Perrone/><ref>Chakrabarti, Lisa, Mireille Guyader, Marc Alizon, Muthiah D. Daniel, Ronald C. Desrosiers, Pierre Tiollais, and Pierre Sonigo. 1987. “Sequence of Simian Immunodeficiency Virus from Macaque and Its Relationship to Other Human and Simian Retroviruses.” Nature 328(6130):543–47.</ref>. Each type of HIV belongs to a different lineage of primate lentivirus that contains other SIV species, some of which are considered to be the predecessors or each type of HIV<ref name = Sharp2011/>. Additionally, within HIV-1, there are also 3 major epidemic groups M, N, an O, with groups M and N having a different SIV predecessor from group O<ref name = Sharp2011/><ref name = Keele2006/><ref name = Van2006>Van Heuverswyn, Fran, Yingying Li, Cecile Neel, Elizabeth Bailes, Brandon F. Keele, Weimin Liu, Severin Loul, Christelle Butel, Florian Liegeois, Yanga Bienvenue, Eitel Mpoudi Ngolle, Paul M. Sharp, George M. Shaw, Eric Delaporte, Beatrice H. Hahn, and Martine Peeters. 2006. “SIV Infection in Wild Gorillas.” Nature 444(7116):164.</ref>. These are consistent with the widely accepted knowledge that HIV have arisen multiple times through multiple cross-transmission events from non-human primates.
Despite both being called HIV and causes AIDS in human, HIV-1 and HIV-2 are only distantly related in the primate lentivirus group (Figure 2)<ref name = Perrone/><ref>Chakrabarti, Lisa, Mireille Guyader, Marc Alizon, Muthiah D. Daniel, Ronald C. Desrosiers, Pierre Tiollais, and Pierre Sonigo. 1987. “Sequence of Simian Immunodeficiency Virus from Macaque and Its Relationship to Other Human and Simian Retroviruses.” Nature 328(6130):543–47.</ref>. Each type of HIV belongs to a different lineage of primate lentivirus that contains other SIV species, some of which are considered to be the predecessors or each type of HIV<ref name = Sharp2011/>. Additionally, within HIV-1, there are also 3 major epidemic groups M, N, an O, with groups M and N having a different SIV predecessor from group O<ref name = Sharp2011/><ref name = Keele2006/><ref name = Van2006>Van Heuverswyn, Fran, Yingying Li, Cecile Neel, Elizabeth Bailes, Brandon F. Keele, Weimin Liu, Severin Loul, Christelle Butel, Florian Liegeois, Yanga Bienvenue, Eitel Mpoudi Ngolle, Paul M. Sharp, George M. Shaw, Eric Delaporte, Beatrice H. Hahn, and Martine Peeters. 2006. “SIV Infection in Wild Gorillas.” Nature 444(7116):164.</ref>. These are consistent with the widely accepted knowledge that HIV have arisen multiple times through multiple cross-transmission events from non-human primates.


Surprisingly, HIV-2, which was initially found in West Africa<ref>Campbell-Yesufu, Omobolaji T., and Rajesh T. Gandhi. 2011. “Update on Human Immunodeficiency Virus (HIV)-2 Infection.” Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of America 52(6):780–87.</ref>, was the viral species whose origin was first determined. In the beginning, the SIV species in captive rhesus macaques (<i>Macaca mulatta</i>) (SIVmac) was determined to be the most closely related to human’s HIV type-2. However, feral rhesus macaques were not found to carry SIV, and the infect macaques in captive died quickly of SAIDS<ref name = Garner/>, which suggested that they had only acquired SIV recently. In 1989, the SIV species closely related to the human’s HIV type 2 was discovered naturally infecting the sooty mangabeys (<i>Cercocebus atys</i>) of West Africa. Despite its host-jumped forms being gravely virulence in their new hosts (the Asian macaques), the sooty mangabey’s SIV (SIVsmm) is not virulent in its natural host. In captive environment, SIVsmm must have spread from its natural host to various species of macaques, and eventually human<ref>Hirsch, Vanessa M., Robert A. Olmsted, Michael Murphey-Corb, Robert H. Purcell, and Philip R. Johnson. 1989. “An African Primate Lentivirus (SIVsmclosely Related to HIV-2.” Nature 339(6223):389–92.</ref>. The interspersed origins of different subtypes of HIV-2 among the SIVsmm/HIV-2 lineage suggests there had been multiple cross-species transmission events of SIVsmm and other SIV in captive macaques (<i>Macaca</i> sp.) onto humans. However, only the subtype A and B became pandemic in human<ref name = Sharp2010/>. Even though soot mangabeys are widely accepted as the natural reservoir for HIV-2 predecessors, HIV-2 might not have resulted directly from cross-transmission from sooty mangabeys. Genetic comparison shows that the SIV species from Asian stump-tail macaques in captive (SIVstm), not SIVsmm, is the most closely related to HIV-2<ref>Khan, A. S., T. A. Galvin, L. J. Lowenstine, M. B. Jennings, M. B. Gardner, and C. E. Buckler. 1991. “A Highly Divergent Simian Immunodeficiency Virus (SIVstm) Recovered from Stored Stump-Tailed Macaque Tissues.” Journal of Virology 65(12):7061–65.</ref><ref name = Perrone/>. Thus, HIV-2 seems to be a result of secondary cross-transmission facilitated by the close and frequent interactions between humans and monkeys in the huge monkey export industry that serves pharmaceutical testing in the mid-20th century.
Surprisingly, HIV-2, which was initially found in West Africa<ref>Campbell-Yesufu, Omobolaji T., and Rajesh T. Gandhi. 2011. “Update on Human Immunodeficiency Virus (HIV)-2 Infection.” Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of America 52(6):780–87.</ref>, was the viral species whose origin was first determined. In the beginning, the SIV species in captive rhesus macaques (<i>Macaca mulatta</i>) (SIVmac) was determined to be the most closely related to human’s HIV type-2. However, feral rhesus macaques were not found to carry SIV, and the infect macaques in captive died quickly of SAIDS<ref name = Gardner/>, which suggested that they had only acquired SIV recently. In 1989, the SIV species closely related to the human’s HIV type 2 was discovered naturally infecting the sooty mangabeys (<i>Cercocebus atys</i>) of West Africa. Despite its host-jumped forms being gravely virulence in their new hosts (the Asian macaques), the sooty mangabey’s SIV (SIVsmm) is not virulent in its natural host. In captive environment, SIVsmm must have spread from its natural host to various species of macaques, and eventually human<ref>Hirsch, Vanessa M., Robert A. Olmsted, Michael Murphey-Corb, Robert H. Purcell, and Philip R. Johnson. 1989. “An African Primate Lentivirus (SIVsmclosely Related to HIV-2.” Nature 339(6223):389–92.</ref>. The interspersed origins of different subtypes of HIV-2 among the SIVsmm/HIV-2 lineage suggests there had been multiple cross-species transmission events of SIVsmm and other SIV in captive macaques (<i>Macaca</i> sp.) onto humans. However, only the subtype A and B became pandemic in human<ref name = Sharp2010/>. Even though soot mangabeys are widely accepted as the natural reservoir for HIV-2 predecessors, HIV-2 might not have resulted directly from cross-transmission from sooty mangabeys. Genetic comparison shows that the SIV species from Asian stump-tail macaques in captive (SIVstm), not SIVsmm, is the most closely related to HIV-2<ref>Khan, A. S., T. A. Galvin, L. J. Lowenstine, M. B. Jennings, M. B. Gardner, and C. E. Buckler. 1991. “A Highly Divergent Simian Immunodeficiency Virus (SIVstm) Recovered from Stored Stump-Tailed Macaque Tissues.” Journal of Virology 65(12):7061–65.</ref><ref name = Perrone/>. Thus, HIV-2 seems to be a result of secondary cross-transmission facilitated by the close and frequent interactions between humans and monkeys in the huge monkey export industry that serves pharmaceutical testing in the mid-20th century.


[[Image:HIV1 origin.jpg|thumb|300px|left|<b>Figure 5:</b> The phylogenetic relationships of representative SIVcpz, HIV-1, and SIVgor strains based on a region of the viral pol gene as of 2011, focusing on the relatedness of HIV-1 groups M and N in the clade of SIVcpzPtt/HIV-1 M &N<ref name = Sharp2011>Sharp, Paul M., and Beatrice H. Hahn. 2011a. “Origins of HIV and the AIDS Pandemic.” Cold Spring Harbor Perspectives in Medicine 1(1):a006841.</ref> . Black circles indicate the four branches where cross-species transmission-to-humans has occurred resulting in HIV-1. Brackets at the right denote SIVcpz from the central chimpanzee Pan troglodytes troglodytes (SIVcpzPtt) and the eastern chimpanzee Pan troglodytes schweinfurthii (SIVcpzPts), respectively. Link image: http://perspectivesinmedicine.cshlp.org/content/1/1/a006841/F4.expansion.html]]
[[Image:HIV1 origin.jpg|thumb|300px|left|<b>Figure 5:</b> The phylogenetic relationships of representative SIVcpz, HIV-1, and SIVgor strains based on a region of the viral pol gene as of 2011, focusing on the relatedness of HIV-1 groups M and N in the clade of SIVcpzPtt/HIV-1 M &N<ref name = Sharp2011>Sharp, Paul M., and Beatrice H. Hahn. 2011a. “Origins of HIV and the AIDS Pandemic.” Cold Spring Harbor Perspectives in Medicine 1(1):a006841.</ref> . Black circles indicate the four branches where cross-species transmission-to-humans has occurred resulting in HIV-1. Brackets at the right denote SIVcpz from the central chimpanzee Pan troglodytes troglodytes (SIVcpzPtt) and the eastern chimpanzee Pan troglodytes schweinfurthii (SIVcpzPts), respectively. Link image: http://perspectivesinmedicine.cshlp.org/content/1/1/a006841/F4.expansion.html]]
HIV-1’s origin, on the other hand, is more complicated. Among the epidemic HIV-1 groups, group M is the most prevalent, accounting for the majority of infections<ref name = Sharp2011/>. Despite the discoveries of SIVcpz strains closely related to HIV-1 group M in 1989<ref name = Huet/> and multiple suspicions of the chimpanzee origin of HIV-1 group M (then known only as HIV-1) that follow suits(Sharp et al. 2000), there were still hesitant to conclude on the origin of HIV-1 group M’s origin as no natural infection of chimpanzees with SIVcpz had been detected at that time(Sharp and Hahn 2010). The origin of HIV-1 group M, as well as group N, which was discovered later in 1998(Simon et al. 1998), was only confirmed in the latter half of the 2000s to be from the specific strain of SIVcpz of the central chimpanzee subspecies (Pan troglodytes troglodytes) (SIVcpzPtt)(Sharp and Hahn 2010) (Keele et al. 2006). Genetic analysis showed that both HIV-1 group M and N are very closely related to SIVcpzPtt variants from southern Cameroon, and the 2 subtypes of HIV-1 are interspersed among the variants of SIVcpzPtt (Figure 5)(Keele et al. 2006) (Heuverswyn et al. 2007). This confirmed that HIV-1 group M and N originated from SIVcpzPtt in the central chimpanzee subspecies from two distinct host-jump events. Such findings also made it possible to track the approximate location of the cross-transmission (Sharp & Hahn, 2011; Keele et. al., 2006, Van Heuverswyn, 2007). Nonetheless, it is unclear how exactly human acquired HIV-1 type M and N from chimpanzees, but it was possibly in the context of bushmeat hunting and consumption, which is the most likely situation where humans can have cutaneous or mucous exposure to infective blood or mucosal fluids of SIVcpzPtt-infected chimpanzees (Sharp & Hahn, 2011). Not only facilitated the cross-transmission of SIVcpzPtt to humans, hunting activities are also possible channel for the chimpanzees to acquire their SIV species in the first place. SIVcpz likely hasn’t had a very long host-dependent evolution time comparing to non-pathogenic SIV strains endemic in Old World monkeys (green monkeys, mangabeys) because it still causes grave health and reproductive damages to its infected chimpanzee communities, and the distribution of SIVcpz among chimpanzees is much less even among communities (Sharp & Hahn, 2010; Keele et. al. 2006, Keele et. al., 2009). Thus, SIVcpz, despite having infected its host for a much longer period of time than HIV (Sharp & Hahn, 2011; Sharp et. al, 2009), must be a rather recent (comparing to SIV in Old World monkeys) acquisition of chimpanzees. Genetic analysis showed that SIVcpz is a recombination of SIV species in red-caped mangabeys (Cercocebus torquatu) and greater spot-nosed monkeys (Cercopithecus nictitans), that likely resulted from a co-infection of SIV and SIV due to the chimpanzees’ hunting and consumption of those monkeys (Goodall, 1986 reviewed in Sharp et. al, 2009).
HIV-1’s origin, on the other hand, is more complicated. Among the epidemic HIV-1 groups, group M is the most prevalent, accounting for the majority of infections<ref name = Sharp2011/>. Despite the discoveries of SIVcpz strains closely related to HIV-1 group M in 1989<ref>Huet, Thierry, Rémi Cheynier, Andreas Meyerhans, Georges Roelants, and Simon Wain-Hobson. 1990. “Genetic Organization of a Chimpanzee Lentivirus Related to HIV-1.” Nature 345(6273):356–59.</ref> and multiple suspicions of the chimpanzee origin of HIV-1 group M (then known only as HIV-1) that follow suits<ref name = Sharp2000/>, there were still hesitant to conclude on the origin of HIV-1 group M’s origin as no natural infection of chimpanzees with SIVcpz had been detected at that time<ref name = Sharp2010/>. The origin of HIV-1 group M, as well as group N, which was discovered later in 1998<ref>Simon, François, Philippe Mauclère, Pierre Roques, Ibtissam Loussert-Ajaka, Michaela C. Müller-Trutwin, Sentob Saragosti, Marie Claude Georges-Courbot, Françoise Barré-Sinoussi, and Françoise Brun-Vézinet. 1998. “Identification of a New Human Immunodeficiency Virus Type 1 Distinct from Group M and Group O.” Nature Medicine 4(9):1032–37.</ref>, was only confirmed in the latter half of the 2000s to be from the specific strain of SIVcpz of the central chimpanzee subspecies (<i>Pan troglodytes troglodytes</i>) (SIVcpzPtt)<ref name = Sharp2010/><ref name = Keele2006/>. Genetic analysis showed that both HIV-1 group M and N are very closely related to SIVcpzPtt variants from southern Cameroon, and the 2 subtypes of HIV-1 are interspersed among the variants of SIVcpzPtt (Figure 5)(<ref name = Keele2006/><ref name = Heuverswyn2007>Heuverswyn, Fran Van, Yingying Li, Elizabeth Bailes, Cecile Neel, Benedicte Lafay, Brandon F. Keele, Katharina S. Shaw, Jun Takehisa, Matthias H. Kraus, Severin Loul, Christelle Butel, Florian Liegeois, Bienvenue Yangda, Paul M. Sharp, Eitel Mpoudi-Ngole, Eric Delaporte, Beatrice H. Hahn, and Martine Peeters. 2007. “Genetic Diversity and Phylogeographic Clustering of SIVcpzPtt in Wild Chimpanzees in Cameroon.” Virology 368(1):155–71.</ref>. This confirmed that HIV-1 group M and N originated from SIVcpzPtt in the central chimpanzee subspecies from two distinct host-jump events. Such findings also made it possible to track the approximate location of the cross-transmission <ref name = Sharp2011/><ref name = Keele2006/><ref name = Heuverswyn2007/>. Nonetheless, it is unclear how exactly human acquired HIV-1 type M and N from chimpanzees, but it was possibly in the context of bushmeat hunting and consumption, which is the most likely situation where humans can have cutaneous or mucous exposure to infective blood or mucosal fluids of SIVcpzPtt-infected chimpanzees <ref name = Sharp2011/>. Not only facilitated the cross-transmission of SIVcpzPtt to humans, hunting activities are also possible channel for the chimpanzees to acquire their SIV species in the first place. SIVcpz likely hasn’t had a very long host-dependent evolution time comparing to non-pathogenic SIV strains endemic in Old World monkeys (like green monkeys or mangabeys) because it still causes grave health and reproductive damages to its infected chimpanzee communities, and the distribution of SIVcpz among chimpanzees is much less even among communities ref name = Sharp2010/><ref name = Keele2006/><ref name = Keele2009/>. Thus, SIVcpz, despite having infected its host for a much longer period of time than HIV<ref name = Sharp2011/><ref name = Sharp2000/>, must be a rather recent (comparing to SIV in Old World monkeys) acquisition of chimpanzees. Genetic analysis showed that SIVcpz is a recombination of SIV species in red-caped mangabeys (Cercocebus torquatu) and greater spot-nosed monkeys (Cercopithecus nictitans), that likely resulted from a co-infection of SIV and SIV due to the chimpanzees’ hunting and consumption of those monkeys (<ref>Goodall, Jane. "The chimpanzees of Gombe: Patterns of behavior." Cambridge Mass (1986).</ref> reviewed in Sharp et. al, 2009<ref name = Sharp2011/>).


==Conclusion==
==Conclusion==

Revision as of 03:34, 25 April 2020

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Overview

Figure 1: Rhesus macaque monkey (Macaca mulatta). The first species that were found to harbor a simian immunodeficiency virus (SIVmac), which this species is likely to have acquired from sooty mangabeys (Cerocebus atys) in human’s captivity[1] [2]. Link image: https://www.pinterest.com/pin/458311699574399832/?autologin=true&nic_v1=1aHVhF8U1hKE5kWAieTuB0eqJtM3WP6RMUuzYEZCg0ykT0aO34yDNivz2yveYa%2B35S

Simian immunodeficiency viruses (SIV) are a group within the Lentiviridae genus of retrovirus family, (Retroviridae) whose genome is ribonucleic acid (RNA) but reverse transcribe to deoxyribonucleic acid (DNA) intermediates before making viral proteins. This viral group is found naturally infecting more than 40 African monkeys (or Old World monkeys – Cercopithecidae family) and 2 species of great apes, namely chimpanzee (Pan troglodytes) and gorilla (Gorilla gorilla)[3]. SIV are the most closely related viruses to the human immunodeficiency viruses type 1 and 2 (HIV–1 and HIV–2), which cause acquire immunodeficiency syndrome (AIDS) in human[4]. Despite being called “immunodeficiency viruses”, SIV do not usually result in any AIDS-like syndromes in many of their natural African monkey host communities, such as sooty mangabeys (Cercocebus atys) and Colobus monkeys (Colobinae subfamily) even with high viral counts in infected individuals and high prevalence of infection (up to 59% of a community can be infected)[2][5][6][7]. This suggests that SIV have a long history of coevolution with these natural hosts. However, there has evidence suggesting recent host jumps of SIV from their long-adapted hosts to new host species such as chimpanzees in the wilds, macaques in captives (an example of Asian monkeys who have much less exposure to SIV than the African ones) and humans, where they developed into new strands through combinations and mutations and became pathogenic in the new host [8][9][10][11]. In macaques and chimpanzees, (SAIDS) similar to AIDS in human[8][12]. Thus, researches into SIV, in both their natural reservoir and laboratory model primates, not only reveals the origin of HIV and AIDS, but also help further understandings in HIV’s pathology and developments of HIV and AIDS prevention and treatments.

Taxonomy

Figure 2: Phylogenetic tree of lentiviruses based on the pol gene[4]. Blue stars demonstrate the presence of putative G4 forming sequences in the genome that would form the secondary structure of nucleic acid called G-quadruplexes that has epigenetic regulatory functions. (Graphic links: http://www.freepik.com and http://www.flaticon.com/[13][14][15][16] [17][18]. Image link: https://www.nature.com/articles/s41598-017-02291-1/figures/3.

SIV are defined as lentiviruses (which itself belongs to the subfamily Orthoretrovirinae in the Retroviridae virus family) that specifically infect non-human primates (simians). The Lentiviridae genus includes a wide variety of primate infecting viruses and a few other viral species that infect felines, cows, horses, goats, and sheep[19][6][20]. Infection of lentiviruses are characterized by long dormant periods (infection may never progress to disease phase as in the case of some natural host monkeys), progressive disease development, permanent damage of tissues, organs, or systems, and, in many cases, lethal outcomes[19]. SIV are a polyphyletic group in the primate lentivirus that also include HIV-1 and HIV-2 (Figure 2)[4]. The SIV species in chimpanzee (SIVcpz) is closely related to the HIV-1 groups M and N[21], while HIV-1 group O is more closely related to the SIV species in gorilla (SIVgor)[22]. And the SIV species that is naturally non-pathogenic in sooty mangabeys (SIVsm) has been shown to be ancestral to HIV-2 and SIV species that cause lethal SAIDS in Asian macaque monkey species[23]. A full phylogeny of SIV along with different types of HIV and other non-primate lentiviruses are demonstrated in Figure 2 (species relatedness was determined by the molecular clock gene pol)[4].

Structure - SIV in non-human primates as an effective and accessible animal model for HIV research

SIV share characteristic traits in morphology and morphogenesis with other member of the lentivirus genus[24]. Genetically, the closest-related viral species to SIV are HIV-1 and HPV-2[21][22][23], the other two members of the primate lentivirus subgenus[4] and the most well-studied species among lentiviruses. Thus, according to a model of lentivirus structured based on HIV-1 and HIV-2, a SIV virion outside of a host cell, along with other lentiviruses’ virions, are either spherical or pleomorphic. SIV virion likely has an outer-membrane derived from host protein with viral spike proteins that binds specifically with host species of each SIV species. Inside the outer-membrane is a protein capsid containing a tightly coiled positive (+) single-stranded RNA genome and a few crucial viral proteins for controlling the host cell’s defense system, reverse transcription, and integration into host genome, such as reverse transcriptase, intergrase, and tRNA lysase. Once inside host cells, SIV and other lentiviruses do not exist as distinct virus particles, but reverse transcribe their RNA genomes into double-stranded DNA and integrate into the host genome with finesse to not cause any lethal mutations or trigger any oncogenes in host cells. Then, the viral double-stranded DNA would exploit the host’s transcribing and translating system to transcribe viral proteins and assemble and disperse progeny virions[25].



Figure 3:Model structure of a lentivirus based on human immunodeficiency virus (HIV) type 1 and 2. Link: https://viralzone.expasy.org/264?outline=all_by_species.

SIV in non-human primates as an effective and accessible animal model for HIV research

Due to the close resemblance and relatedness of SIV to HIV, the most similar anatomies of SIV’s hosts (non-human primates) and human, and the ability of some SIV speciess to induce simian AIDS in the common primate model organisms, the Asian macaques (Macaca spp.), with rapid disease progression and pathology similar to human AIDS, SIV effectively serves as models to study HIV and AIDS in animals[26][12][10]. However, the SIV species that infect Asian macaques are in the lineage SIVsmm/HIV-2 (Figure 2), which is relatively distant from the common global pandemic HIV-1 species, the macaques model still has certain differences in disease progression and drug response from the more common HIV-1[26] that researchers need to keep in mind when adopting this model organism for HIV researches. On the other hand, the closest animal model to HIV-1, and probably HIV-1-caused AIDS, has been shown to the SIVcpz found in the natural reservoir of central and eastern chimpanzee subspecies (Pan troglodytes troglodytes and Pan troglodytes schweinfurthii respectively), each of them have their own distinct type of SIVcpz infecting only that on subspecies[2]. Previously, all SIV found in natural reservoirs were not thought to be pathogenic, however, fecal sampling for SIV antibodies and behavioral studies in feral chimpanzees revealed that SIVcpz infection in wild chimpanzees can be pathologic progress to SAIDS with histopathology similar to what is seen in human’s AIDS[8]. Moreover, transmission of SIVcpz in the wild is also well-documented to be mostly sexual transmission and mother-to-infants transmission similar to what is observed in humans[8][27]. One limit to this SIV model is that chimpanzees (Pan troglodytes) and their counterparts, the bonobos (Pan paniscus), are rare, endangered species, thus limiting researchers’ ability to study them in laboratory settings. However, chimpanzee species and subspecies are the best-studied primate species in the wild with many groups studying chimpanzee and bonobos communities for multiple decades[28]. Thus, studying virology and pathology of SIVcpz in the wild and documenting behaviors and social interactions of infected chimpanzee communities in the wild can produce great insights into the virology, transmission, pathology, and social factors related to transmission of HIV-1.

Evolution of SIV

Figure 4:Maximum clade credibility tree from amino acid sequences, with node heights (year before present) representing the mean value of the posterior sample of the Bayesian analysis from Worobey and their team’s research[29]. Well-supported nodes (0.95 or greater posterior probability) are marked with asterisks. The SIV species of monkeys on the Bioko island (Equatorial Guinea, West Africa), the subject of this research, are highlighted in colors. Link image: https://science.sciencemag.org/content/329/5998/1487.full

Molecular efforts in dating the age of the SIV, or more precisely, the primate lentivirus lineage, based on the modeled mutation rate of HIV-1 and HIV-2 (the most well-studied primate lentiviruses) have bred great controversies. Dating methods using nucleotide molecular clocks that use the mutation rate of HIV-1 and HIV-2 as standard references suggest the most recent common ancestor of the primate lentivirus to be around a few hundreds to a few thousands of years before present[30][9]. This contradicts with the pathological and epidemiological evidences suggesting SIV might have evolved in a host-dependent manner to be non-pathogenic in some African monkeys [2][5][6][7]. However, a study in 2010[29] combining the viruses’ molecular clock dating and phylogeny analysis with the host species’ phylogenic studies and biogeographical history suggests that the SIV lineage have existed for at least 32,000 years. Another research into the existence of SIV in the ring-tailed lemur of south-western Madagascar showed the existence of antigens against SIV in ring-tailed lemurs here. If there was no cross-contamination of SIV from mainland and SIV in primates evolved in a host-dependent way from a common ancestor (as seen in the case of green monkeys (Chlorocebus sp.)[7], this can push the possible date of the oldest common ancestor of the SIV lineage to 85 million years ago, the approximate date of the last primate common ancestor, also around the time of the total separation of Madagascar from the Indian continent[31].

These directs and indirect evidence of SIV’s historic existence among the primates, especially those of the more ancient orders (monkeys and lemurs) who SIV have evolved natural co-existing relationships with, suggest a terrible bias in the HIV-based molecular clock assay, which points to a possible, drastic increase in HIV comparing to their more ancient SIV counterparts. On the other hand, it’s also HIV’s notoriously rapid mutation rate that is the main obstacles against development of vaccines against HIV and the primary cause of drug resistance in treatments. Thus, further research into the infections and mutating and replicating activities of older, naturally non-pathogenic SIV species can help us understand the genetic difference that enables the rapid mutation rate in their human-infecting counterparts, as well as develop vaccines against HIV. Moreover, considering the long existence of SIV (at least 32,000 years ago), it is likely that human has come into contact with SIV multiple times and cross-transmission of SIV to human are likely to have occurred many times throughout the past 32,000 years. Thus, there must be recent social and biological factors that the rapid spread of HIV only during the past 100 years or so[32][33].

The origin of Human Immunodeficiency Virus (HIV) from SIV

Despite both being called HIV and causes AIDS in human, HIV-1 and HIV-2 are only distantly related in the primate lentivirus group (Figure 2)[4][34]. Each type of HIV belongs to a different lineage of primate lentivirus that contains other SIV species, some of which are considered to be the predecessors or each type of HIV[3]. Additionally, within HIV-1, there are also 3 major epidemic groups M, N, an O, with groups M and N having a different SIV predecessor from group O[3][21][35]. These are consistent with the widely accepted knowledge that HIV have arisen multiple times through multiple cross-transmission events from non-human primates.

Surprisingly, HIV-2, which was initially found in West Africa[36], was the viral species whose origin was first determined. In the beginning, the SIV species in captive rhesus macaques (Macaca mulatta) (SIVmac) was determined to be the most closely related to human’s HIV type-2. However, feral rhesus macaques were not found to carry SIV, and the infect macaques in captive died quickly of SAIDS[10], which suggested that they had only acquired SIV recently. In 1989, the SIV species closely related to the human’s HIV type 2 was discovered naturally infecting the sooty mangabeys (Cercocebus atys) of West Africa. Despite its host-jumped forms being gravely virulence in their new hosts (the Asian macaques), the sooty mangabey’s SIV (SIVsmm) is not virulent in its natural host. In captive environment, SIVsmm must have spread from its natural host to various species of macaques, and eventually human[37]. The interspersed origins of different subtypes of HIV-2 among the SIVsmm/HIV-2 lineage suggests there had been multiple cross-species transmission events of SIVsmm and other SIV in captive macaques (Macaca sp.) onto humans. However, only the subtype A and B became pandemic in human[2]. Even though soot mangabeys are widely accepted as the natural reservoir for HIV-2 predecessors, HIV-2 might not have resulted directly from cross-transmission from sooty mangabeys. Genetic comparison shows that the SIV species from Asian stump-tail macaques in captive (SIVstm), not SIVsmm, is the most closely related to HIV-2[38][4]. Thus, HIV-2 seems to be a result of secondary cross-transmission facilitated by the close and frequent interactions between humans and monkeys in the huge monkey export industry that serves pharmaceutical testing in the mid-20th century.

Figure 5: The phylogenetic relationships of representative SIVcpz, HIV-1, and SIVgor strains based on a region of the viral pol gene as of 2011, focusing on the relatedness of HIV-1 groups M and N in the clade of SIVcpzPtt/HIV-1 M &N[3] . Black circles indicate the four branches where cross-species transmission-to-humans has occurred resulting in HIV-1. Brackets at the right denote SIVcpz from the central chimpanzee Pan troglodytes troglodytes (SIVcpzPtt) and the eastern chimpanzee Pan troglodytes schweinfurthii (SIVcpzPts), respectively. Link image: http://perspectivesinmedicine.cshlp.org/content/1/1/a006841/F4.expansion.html

HIV-1’s origin, on the other hand, is more complicated. Among the epidemic HIV-1 groups, group M is the most prevalent, accounting for the majority of infections[3]. Despite the discoveries of SIVcpz strains closely related to HIV-1 group M in 1989[39] and multiple suspicions of the chimpanzee origin of HIV-1 group M (then known only as HIV-1) that follow suits[9], there were still hesitant to conclude on the origin of HIV-1 group M’s origin as no natural infection of chimpanzees with SIVcpz had been detected at that time[2]. The origin of HIV-1 group M, as well as group N, which was discovered later in 1998[40], was only confirmed in the latter half of the 2000s to be from the specific strain of SIVcpz of the central chimpanzee subspecies (Pan troglodytes troglodytes) (SIVcpzPtt)[2][21]. Genetic analysis showed that both HIV-1 group M and N are very closely related to SIVcpzPtt variants from southern Cameroon, and the 2 subtypes of HIV-1 are interspersed among the variants of SIVcpzPtt (Figure 5)([21][41]. This confirmed that HIV-1 group M and N originated from SIVcpzPtt in the central chimpanzee subspecies from two distinct host-jump events. Such findings also made it possible to track the approximate location of the cross-transmission [3][21][41]. Nonetheless, it is unclear how exactly human acquired HIV-1 type M and N from chimpanzees, but it was possibly in the context of bushmeat hunting and consumption, which is the most likely situation where humans can have cutaneous or mucous exposure to infective blood or mucosal fluids of SIVcpzPtt-infected chimpanzees [3]. Not only facilitated the cross-transmission of SIVcpzPtt to humans, hunting activities are also possible channel for the chimpanzees to acquire their SIV species in the first place. SIVcpz likely hasn’t had a very long host-dependent evolution time comparing to non-pathogenic SIV strains endemic in Old World monkeys (like green monkeys or mangabeys) because it still causes grave health and reproductive damages to its infected chimpanzee communities, and the distribution of SIVcpz among chimpanzees is much less even among communities ref name = Sharp2010/>[21][8]. Thus, SIVcpz, despite having infected its host for a much longer period of time than HIV[3][9], must be a rather recent (comparing to SIV in Old World monkeys) acquisition of chimpanzees. Genetic analysis showed that SIVcpz is a recombination of SIV species in red-caped mangabeys (Cercocebus torquatu) and greater spot-nosed monkeys (Cercopithecus nictitans), that likely resulted from a co-infection of SIV and SIV due to the chimpanzees’ hunting and consumption of those monkeys ([42] reviewed in Sharp et. al, 2009[3]).

Conclusion

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Authored by [Minh Pham] for BIOL 238 Microbiology, taught by Joan Slonczewski, 2020, Kenyon College.