The Origins of HIV

There are at least 36 distinct lentiviruses that infect African primates [1]. With only one exception [2] all have been found within African apes and monkeys [3]. Five equidistant phylogenetic lineages based on phylogenetic analysis of full-length pol protein sequences are described in Hahn et al., [4]. These lentiviruses are referred to as simian immunodeficiency virus’s (SIV’s) and in their natural primate hosts appear to cause no adverse effects [4]. Viruses from individual primate species have been observed to be more closely related to each other than to viruses from a different species. For example in the four sub species of African green monkeys (Chlorocebus aethiops, C. pygerythrus, C. sabaeus, and C. tantalus) they form monophyletic clusters that each contain strains that are more closely related to each other than to the SIV’s from the other clusters [4-6]. This along with the lack of virulence in the primate host could convincingly suggest host dependent evolution [4].

However genetic diversity studies indicate that the African Green Monkey (AGM) clade is millions of years old [7] while the most recent common ancestor of SIVagm is far younger [8]. A resemblance between host and pathogen phylogenies could have arisen as a result of preferential host switching followed by subsequent diversification [9]. In fact Wertheim and Worobey observed that AGM mitochondrial DNA and SIVagm sequences did not share a phylogenetic topology that would coincide with long term co-evolution [10]. Similar patterns of clustering can be observed in the two species of chimpanzee that harbour these lentiviruses. Viruses isolated from the chimpanzee Pan troglodytes troglodytes cluster together in the presence of SIV’s isolated from other primate species whereas the SIV isolated from Pan troglodytes schwinfurthii falls outside of the p.t. troglodytes cluster [4, 11, 12]. Once again this would suggest that this pattern has arisen due to preferential host switching [9] and not as a result of long term co-evolution.

The first full length SIV observed to have the same genetic structure as HIV-1 was presented in [13]. This strain was referred to as SIVcpz-gab. The organisation of the genome was found to be 5’ gag-pol-vif-vpr-tat-rev-vpu-env-nef 3’. Specifically there was the presence of a HIV-1 specific vpu gene and the absence of vpx gene, common to HIV-2 and most other SIVs. In [14] a second complete genome of a chimpanzee lentivirus, referred to as SIVcpz-ant, was obtained and found to have a similar genetic organization to SIVcpz-gab. From protein sequence comparisons SIVcpz-ant was found to be a closer relation to SIVcpz-gab and to HIV-1 isolates than to members of the other four major phylogenetic lineages of these primate lentiviruses - but as an out-group. Sequence identity with SIVcpz-gab was fairly low and ranged from 72% (pol), 48% (env) and 25% (vpu). Phylogenetic analysis revealed the possibility that groups O and M emerged as a result of separate cross species transmission events [12]. The ancestral host primate species that gave rise to HIV-1 was still unclear however as there appeared to be very few chimpanzees naturally infected with SIVcpz [15] and thus there was the possibility that both chimpanzees and humans could have acquired the virus from a third reservoir species – for example Gorilla gorilla gorilla [16].

After isolating a third full length SIV strain, SIVcpzUS, and determining, by mitochondrial DNA analysis the subspecies identity of all known infected chimpanzees, Gao et al., observed that one subspecies of chimpanzee, P.t. troglodytes, was the most probable natural ancestral host and reservoir for HIV-1 [12]. More recently [17-19] have confirmed that P. t. troglodytes is the most probable ancestral host for HIV-1 and that groups M, O and N have resulted from three separate cross species transmission events (Fig. 1.7). Keele et al., reported, using newly developed sampling techniques, that up to 35% of individuals in some communities of wild living P. t. troglodytes were infected by the virus [18] – a number that is higher than was previously thought.

In relation to the rare group N the origins were more obscured as the gag, pol and the 3’ end of the vif gene was similar to HIV-1 group M while the env, nef and 3’ end of vif gene was closely related to SIVcpzUS (Fig. 1.7). It has been suggested by Gao et al., that the predecessor to this group, first identified from a strain called YBF30, was created after a recombinant event between two divergent strains of SIVcpz’s within the primate host before its jump in to the human population [12]. Strong evidence in support of this has subsequently been provided [11, 20-22]. Many SIV strains are in fact recombinant strains from earlier ancestors [23-25].

No Image Yet! Figure 1.7: Cross Species Transmission Maximum likelihood tree displaying the relationship between the three groups of HIV-1 and their SIV relatives across two different regions of the genome. The * represent separate cross-species transmission events. Note how strains belonging to each of the groups cluster together closely.

The predecessor to group M (SIVcpzptt) appears to have also been a recombinant strain between two monkey SIV’s – red-capped mangabeys and greater spot-nosed monkeys [1, 26]. Each of these SIV’s displays similarities to SIVcpzptt but at different locations across the genome (Fig. 1.8, Panels A and B). SIVgsn was the first monkey virus found to possess the vpu gene and its 3’ half of the genome was observed to be closely related to SIVcpzptt [27] while the 5’ end of the SIVcpzptt genome was found to be closely related to SIVrcm [11, 28]. Both SIV from red-capped mangabeys and greater spot-nosed monkeys could have ended up within a single chimpanzee host as it is known that chimpanzees hunt smaller monkeys for food in overlapping geographical locations within central Africa overlap [29, 30]. After the divergence of P. t. schwinfurthii and P. t. troglodytes Leitner et al., suggested that there is evidence for subsequent SIV superinfection followed by further recombination events within both lineages – resulting in the potential for further differences in their evolutionary histories than was previously thought [31]. Group O strains also show evidence of ancient recombination events between SIV strains within their ancestral primate hosts [32].

When a virus enters a new host species successfully for the first time there can be a wide range of different outcomes ranging from incidental infection to epidemic spread [4]. Despite group M’s common ancestor existing within the human population at a similar time to the common ancestor of group O [33-35], the prevalence [36, 37] and geographical location [38] of the latter remains highly limited. Group O’s prevalence has actually been gradually decreasing [39]. Reasons for group M’s success in relation to group O are poorly understood but initial studies suggest that group O may have a reduced replicative and transmission fitness [40]. After a cross species transmission the viral population must adapt to a new genetic and immunologic environment [41]. The mechanism of adaptation is in the from of alterations in its amino acid sequence which result in: (i) altering the efficiency of cell entry, (ii) blocking interactions with detrimental host proteins and (iii) promoting escape from the immune system [42].

No Image Yet! Figure 1.8 Recombinant origin of SIVcpz (A) Maximum likelihood phylogenies of primate lentiviruses Pol and Env sequences. The close genetic relationship of SIVcpz to SIVrcm from red-capped mangabeys in Pol, and to SIVgsn, SIVmus, and SIVmon from greater spot-nosed, mustached, and mona monkeys in Env, are highlighted in green and magenta, respectively. (B) Schematic diagram of the genomic organization of SIVcpz. Genomic regions are colored according to their genetic relationship to SIVrcm (green) or the SIVgsn / SIVmus / SIVmon lineage (magenta).Grey areas in SIVcpz are of unknown norigin. Vpu and vpx genes are highlighted. (Diagram and legend taken from [1]).

Recent evidence of SIV’s adapting to new hosts is presented in [42] where selection within a rhesus macaque host was found to be acting strongly with the V2 loop after the primate was inoculated from a SIV strain found within sooty mangabeys. In HIV-1 a host specific adaptation has been observed to occur at a site within the p17 region [43]. In SIVcpzPtt a methionine (Met) is present at the site while in each HIV-1 group Arginine (Arg) is present. On passage of the human virus through chimpanzees the Arg reverted to Met. SIV and HIV sequences have substantial differences in their major proteins but the relevance of these differences to the biology of the viruses is poorly understood [43]. As well as host specific adaptation other reasons why group M is far more prevalent than group O may include behavioural, demographic and epidemiological history of transmission [44].

Hahn et al., proposed that the primate ancestral host of HIV-2 was the sooty mangabey [4]. Each of the different lineages of HIV-2, termed subtypes A–F, are due to multiple-cross-species transfer events from sooty mangabeys to humans [45]. Geographic evidence also supports the theory that HIV-2 originated from the sooty mangabey as the virus is only common in West Africa – which is where the habitat for these monkeys is found [45]. The mode of transmission between humans and sooty mangabeys was thought to have been hunters becoming infected by the latter that they hunt for food [46].


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