, 20120496, published 12 August 2013368 2013 Phil. Trans. R. Soc. B Alex A. Compton, Harmit S. Malik and Michael Emerman primate lentivirusesHost gene evolution traces the evolutionary history of ancient
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ReviewCite this article: Compton AA, Malik HS,
Emerman M. 2013 Host gene evolution traces
the evolutionary history of ancient
primate lentiviruses. Phil Trans R Soc B 368:
20120496.
http://dx.doi.org/10.1098/rstb.2012.0496
One contribution of 13 to a Theme Issue
‘Paleovirology: insights from the genomic fossil
record’.
Subject Areas:evolution, genetics, microbiology, immunology
Keywords:lentivirus, paleovirology, simian
immunodeficiency virus, human
immunodeficiency virus, primates
Author for correspondence:Michael Emerman
e-mail: [email protected]
& 2013 The Author(s) Published by the Royal Society. All rights reserved.
Host gene evolution traces theevolutionary history of ancientprimate lentiviruses
Alex A. Compton1,2, Harmit S. Malik3,4 and Michael Emerman2,3
1Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA 98195, USA2Division of Human Biology, 3Division of Basic Sciences, and 4Howard Hughes Medical Institute,Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
Simian immunodeficiency viruses (SIVs) have infected primate species long
before human immunodeficiency virus has infected humans. Dozens of
species-specific lentiviruses are found in African primate species, including
two strains that have repeatedly jumped into human populations within the
past century. Traditional phylogenetic approaches have grossly underesti-
mated the age of these primate lentiviruses. Instead, here we review how
selective pressures imposed by these viruses have fundamentally altered the
evolutionary trajectory of hosts genes and, even in cases where there now
remains no trace of the viruses themselves, these evolutionary signatures can
reveal the types of viruses that were once present. Examination of selection
by ancient viruses on the adaptive evolution of host genes has been used to
derive minimum age estimates for modern primate lentiviruses. This type of
data suggests that ancestors of modern SIV existed in simian primates more
than 10 Ma. Moreover, examples of host resistance and viral adaptation have
implications not only for estimating the age and host range of ancient primate
lentiviruses, but also the pathogenic potential of their modern counterparts.
1. Human lentivirus infections emerge from a brimmingreservoir with unclear boundaries
Simian immunodeficiency virus (SIV) is the collective name for a diverse group of
lentiviruses that naturally circulate among African non-human primate species.
With over 40 species-specific strains characterized to date and high seroprevalence
rates among reproductive adults, SIV amounts to an immense viral reservoir with
zoonotic potential (figure 1; [1]). In the early twentieth century, two new lentivirus
infections emerged in human populations. Human immunodeficiency virus type 1
(HIV-1) emerged via cross-species transmissions of SIVcpz from chimpanzees and
gorillas; four independent transmission events gave rise to HIV-1 groups M, N, O
and P. A separate lentiviral lineage, HIV-2, emerged in humans at least eight times
via cross-species transmissions from SIVsmm, found in sooty mangabeys (figure
1) [3]. Therefore, spillover from the pool of non-human lentiviruses can be both
recurrent and hazardous for human health. In fact, despite the species specificity
attributed to each SIV strain, transmissions of SIV between non-human primates
have been documented on numerous occasions and may lead to pathogenic out-
comes in these hosts as well (figure 1).
HIV-1 causes a chronic infection in humans. Nearly all infected individuals
progress to a state of life-threatening immunodeficiency (AIDS) if not treated
with antiretroviral therapy. A recent study spanning nearly 10 years showed
that chimpanzees infected with SIVcpz, the ancestor of HIV-1, also suffer from
decreased lifespan and immunopathologies characteristic of AIDS [4–6]. SIVcpz
is a recombinant lentivirus that arose following cross-species virus transmission(s)
from other ‘natural host’ species that comprise the SIV reservoir [7]. By contrast to
infected humans and chimps, the major predictors of disease progression (loss of
the CD4þ T-cell compartment and chronic immune activation) are notably absent
in natural hosts infected by SIV in the wild [8–11]. The mechanisms by which these
marmosets
tamarins
capuchins
squirrel monkeys
owl monkeys
sakis
howler monkeys
woolly monkeys
Macaques SIVmac, SIVstm
mangabeys SIVsm, SIVrcm
mandrills SIVmnd-1, SIVmnd-2
baboons SIVagm
AGM, guenons SIVagm, SIVmus, etc.
colobus monkeys SIVcol, SIVwrc, SIVolc
Proboscis, leaf monkeys
gibbons
orangutans
chimpanzees SIVcpz
bonobos
humans HIV-1, HIV-2
gorillas SIVgor
tarsiers
New Worldmonkeys
Old Worldmonkeys
hominoids
Colobinae
Cercopithecinae
lemurs
puffed lemurs
aye ayes
Indris, Sifaws
mouse, dwarf lemurs pSIV
bushbabies
lorises
prosimians
Figure 1. A representative phylogeny of primate species and their lentivirus associations. The evolutionary relationship between living primate species is shownwith branching orders reflecting the currently accepted species phylogeny [2]. The Old World Monkeys are subdivided into the Cercopithecinae and Colobinae sub-families. Lentiviruses naturally associated with a given species (green in the online version) include SIVsm/SIVrcm in mangabeys, SIVmnd-1/SIVmnd-2 in mandrills,SIVagm/SIVmus in AGM/guenon, and SIVcol/SIVwrc/SIVolc in colobus monkeys. Lentiviruses arising via cross-species transmission (red in the online version) includeSIVmac/SIVstm in macaques, SIVagm in baboons, SIVcpz in chimpanzees, HIV-1/HIV-2 in humans, and SIVgor in gorillas. Dashed lines depict cross-species virustransfer; lines originate from the donor species and terminate in an arrowhead at the recipient species. pSIV (blue in online version) is an endogenous primatelentivirus identified in the genomes of some lemur species. (Online version in colour.)
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primates remain AIDS-free despite lifelong infection and high
viremia have major implications for our understanding of
HIV-1 pathogenesis [11]. Furthermore, the lack of disease
progression is commonly attributed to coevolution between
the host and the virus, but the time-scale appropriate to describe
these relationships remains controversial.
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In some instances, closely related primate species also
harbour closely related, species-specific lentivirus strains.
Such cases support a scenario of host–virus cospeciation, in
which viral lineages diverge in parallel with diverging host
populations. However, in other instances, lentivirus phyl-
ogeny is discordant with that of their respective hosts.
These discordances reveal that host switching events (cross-
species transmission) can also give rise to lentivirus–host
relationships that must be younger by comparison [12,13].
Adding to the uncertain history of lentiviruses in primates is
the fact that current phylogenetic approaches employing a
molecular clock appear inadequate to reconstruct virus evol-
ution in deep time [14,15]. For example, previous attempts at
assigning a precise date of birth to the SIVsmm lineage have
yielded an age estimate of just centuries, orders of magnitude
less than what would be expected under conditions of host–
virus coevolution [16]. Reasons for this discrepancy likely
include the erosion of phylogenetic signal from viral sequences
by purifying selection [17] and by convergence on similar viral
genotypes (site saturation) over time [18].
Calibration of these time-scales is greatly aided by other
temporal markers. For instance, the discovery of SIV strains
in species endemic to Bioko, an island which became geo-
graphically isolated from the African mainland at least 10 000
years ago, provided a means to more accurately calibrate the
molecular clock phylogenetic analysis [19]. This led to the mini-
mum estimate of the time to most recent common ancestor of
SIV to be pushed back to 32 000 years, although it is likely
that this date still considerably underestimates the age of
the SIV lineage [19]. Because phylogenetic methods based
on viral sequences alone have failed to bridge the time gap
between ancestral viruses and their modern counterparts,
there is a keen interest in alternative approaches which estimate
the evolutionary age of virus families. By unearthing both
endogenous viral imprints in host genomes and instances of
virus-driven evolution of the host genome, we focus our
review on how such approaches have led to an appreciation
for the true antiquity of lentiviruses and their impact on
primate hosts.
2. Paleovirology: endogenous viruses andvirus-driven evolution of host immunity
Roughly 5–8% of the human genome consists of endogenous
retroviruses, the remnants of ancient, exogenous viruses that
integrated into the germline (reviewed in [20]). The availability
of sequenced genomes from a variety of organisms has led
to the discovery of additional endogenous viral elements
(EVEs), revealing that several virus families with relevance
to human health have far more distant origins than previ-
ously appreciated [21,22]. Dating of these EVEs does not rely
on using molecular clocks of virus evolution, but rather on
well-established dates of host species divergence. One such
endogenous lentiviral ‘fossil’ uncovered in the genomes of
Malagasy prosimians (mouse and dwarf lemurs, figure 1) pro-
vided the first genetic evidence of an early association between
primates and lentiviruses. This germline integration event
called prosimian SIV (pSIV), establishes that lentiviruses were
circulating among some primates at least 4 Ma [23,24]. pSIV is
a transitional viral form, sharing some aspects of genomic archi-
tecture with non-primate lentiviruses (such as dUTPase) while
lacking genes typically found in extant primate lentiviruses
(such as vpr) [23]. However, no trace of an endogenous
lentivirus-like entity has been identified in the genomes of
simian primates, which comprise the hosts for the known,
extant primate lentiviruses. Thus, despite its utility for other
viruses and for lentiviruses in other mammals [18,22], the
‘fossil’ record of viral imprints has been mostly uninformative
of the lentiviruses harboured by modern simian primates.
On the other hand, even in the absence of direct evidence
of past infections, ancient viruses can also be detected
indirectly by examining how they have driven adaptive
changes in antiviral immunity over time [25]. The discovery
of an extremely diverse set of innate immune genes with lenti-
virus-blocking potential, known as host restriction factors, has
provided a means to understand how lentiviruses impact
host evolution [26]. The rate at which non-synonymous
mutations accumulate between species is a classic measure of
adaptive evolution. Many restriction factors are evolving
under selection, and in fact it has been proposed that this is a
criterion by which they should be defined [26]. Furthermore,
because many of these cellular factors are directly antagonized
by the lentiviruses they have evolved to restrict, adaptive evo-
lution at the host–virus interface signals when lentivirus
infections likely occurred in the past [25]. Selective pressure
applied by virus-encoded antagonists will select adaptive
‘escape’ mutations in host factors at sites critical for the host–
virus interaction (figure 2a). Adaptive evolution of the host is
followed by virus counter-evolution in order to re-establish
the interaction, inciting a perpetual ‘genetic conflict’ character-
ized by host–virus antagonistic coevolution (figure 2a). (See
[27] for more comprehensive review of positive selection as a
result of virus–host interactions.)
Analysis of amino acid changes in restriction factor genes
isolated from a broad panel of extant primates, representing
tens of millions of years of evolution, provides a temporal
axis to determine when cases of virus-driven evolution
occurred in the past (figure 2b). Within the framework of the
host phylogeny, signatures of selection can be read like a gen-
etic ledger, documenting when a given host population
was exposed to a lentivirus threat. In order to gain specific
insights into the age and provenance of primate lentiviruses,
we focus only on restriction factors with antiviral specificity
for lentiviruses, which is assumed to reflect selection by ancient
lentiviral infections. Alternatively, even if the restriction factor
acts generally on a wider class of viruses or retroelements, the
positive selection of residues at known lentivirus-interacting
surfaces (figure 2c) permits deconvolution of the multiple
selective forces that may have acted on it and on the phylogeny
(figure 2d). These criteria allow us to discern positive selec-
tion signatures that are likely to have been driven exclusively
by lentiviruses.
As primate genomes encode a diverse arsenal of antiviral
effectors with lentivirus-blocking potential, SIV has left its
mark on the evolution of several host restriction factors that
block the viral life cycle at different stages. We discuss restriction
factors that serve as examples of lentivirus-driven evolution.
The analysis of the host restriction factor APOBEC3G
(A3G) has provided the most precise details in calculating
the age of ancient primate lentiviruses. A3G is an antiviral
cytidine deaminase that incorporates itself into virions and
mutates viral DNA produced during reverse transcription
[28]. While many retroviruses have evolved mechanisms to
evade or directly antagonize the activity of A3G [29–31],
the primate lentiviruses devote an entire accessory gene, vif,
time
restrictionfactor
(a) (b)
(c) (d )
virus-encodedantagonist
time
primate speciesphylogeny
lentiviralantagonist
non-lentiviralantagonists
time
***
** ***
***
***
***
Figure 2. Virus-driven evolution fuels a genetic conflict. (a) Depicted is a cycle of host – virus coevolution initiated when an antagonist encoded by a pathogenicvirus counteracts a host restriction factor. Host factor variants are drawn in solid black, and viral antagonists are drawn in white. Selection of host factor variants thatsuccessfully evade antagonism is followed by counter-selection of viral variants that re-establish the host – virus interaction, applying selective pressure on the hostonce again, resulting in a cycle of coevolution. Note that the ‘direction’ of the arms race can be reversed, such that host antiviral effectors ‘chase’ their viral targets.(b) The age of host genetic adaptations, and consequently of the causal pathogenic viruses, can be estimated when superimposed onto the primate species phy-logeny. For instance, the origins of positive selection on primate SAMHD1 appear to coincide with the birth of SAMHD1-degrading activity specific to somelentiviruses. (c) In cases where a particular restriction factor can be generally antagonized by a variety of different antagonists, information about binding sitescan nevertheless delineate those amino acid changes that occurred on account of lentiviruses rather than due to antagonists encoded by other viruses (grey shading).(d ) By tracing these lentiviral-specific changes on the primate phylogeny, one can infer whether one or several branches in primate phylogeny underwent selectionon account of pathogenic lentiviruses. For instance, despite being antagonized by several viruses, changes in APOBEC3G required to evade lentiviral Vif can be usedto calibrate Vif-escaping adaptive episodes in primate APOBEC3G. (Online version in colour.)
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to this purpose [32]. Vif binds A3G directly and links it to a
cellular E3 ubiquitin ligase to accelerate its turnover at the
proteasome [33–36]. Vif originated early during lentivirus
evolution and has been retained by every member of Lentivir-idae except equine infectious anaemia virus [18,37]. Therefore,
antagonism of primate A3G and its homologues in mammals
may be crucial for long-term lentivirus persistence, making it
an ideal candidate for studies of lentivirus-driven evolution.
An initial analysis of A3G evolution in primates exposed sig-
nals of selection throughout its length, suggesting that many
surfaces of the enzyme have been engaged by viral antagon-
ists of unknown origin [38]. However, a subsequent study of
A3G orthologues from a broad panel of Old World monkeys
(OWMs), including African green monkey (AGM) and sev-
eral other species comprising the SIV reservoir, revealed
recurrent selection at residues involved in the interaction
with the lentiviral Vif protein [39,40]. Single amino acid sub-
stitutions that allow evasion of Vif-mediated degradation
independently emerged on several occasions during primate
evolution, the oldest of which appeared at least 5 Ma in the
common ancestor of the guenon species. An even older Vif-
blocking adaptation in A3G, a multi-residue insertion event,
arose at least 12 Ma in a subset of OWMs (Colobinae) [39].
These findings suggest that, millions of years ago, lentiviruses
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left footprints of selection stamped in the A3G locus of simian
primates. Therefore, an examination of virus-driven evolution
of host immunity enables the inference of past lentivirus
infections in much deeper time-scales.
Similar inferences can be made from the evolution of the
newly discovered restriction factor SAMHD1, which imposes
a block to the viral reverse transcription in myeloid-derived
blood cells and resting CD4þ T cells [41]. Evolutionary analysis
of primate SAMHD1 revealed residues evolving under positive
selection that underlie interaction with and sensitivity to the
lentiviral-encoded antagonists Vpr and Vpx [42,43]. Interest-
ingly, mapping these signatures onto the primate phylogeny
found that the selection is most pronounced in members of
the Cercopithecinae lineage (figure 1), the OWM subfamily that
includes a large component of natural host species including
AGMs and sooty mangabeys. Taken together with functional
analyses demonstrating that SAMHD1-antagonizing activity
first arose in Vpr/Vpx from lentiviruses that infect the Cerco-pithecinae lineage, these results suggest that lentiviral pressure
led to both the origin and persistence of rapid evolution in pri-
mate SAMHD1. Dating this origin of positive selection using the
host species tree suggests that lentiviruses with the ability to
degrade SAMHD1 are at least 10 Myr old within primates.
Tetherin (also called BST-2) is a broadly acting antiviral
effector that ‘tethers’ virions to the cell surface to disallow
their release and spread. The non-specific antiviral mechan-
ism employed by Tetherin allows it to restrict a wide array
of enveloped virus families, including retroviruses, flavi-
viruses, herpesviruses and paramyxoviruses [26]. Despite
this apparent lack of specificity, a lentiviral-driven conflict
appears to have played a prominent role during the evo-
lutionary history of Tetherin in primates. Sequencing the
Tetherin locus from representatives of major primate clades
revealed that it is undergoing positive selection (adaptive
evolution) [44,45]. In particular, the most rapidly evolving
Tetherin residue in an analysis of OWM species maps pre-
cisely to one of the amino acids in the cytoplasmic tail of
Tetherin which confers species specificity to antagonism by
SIV Nef [45–48]. Nef downregulates Tetherin from the cell
surface [46], and presumably binds directly to these amino
acids in the cytoplasmic tail of Tetherin. This suggests that
the repeated amino acid substitutions at this single residue
were driven to allow escape from Nef antagonism [45]. How-
ever, because other viruses also encode Tetherin antagonists,
it is possible that another antagonist with the same specificity
as Nef was responsible for this host gene selection. Thus, a
caveat of using the host gene evolution to date paleoviruses
is that it may not be possible to determine which virus
family drove the ancient selection. However, when selection
converges on several antiviral factors inside the cell, as is
the case for the paleo-lentiviruses in primates, it increases
the confidence that an ancient virus that encoded Vif, Vpx/
Vpr and Nef was responsible for selection on multiple host
genes in a similar time period.
Finally, the analysis of the ‘birth’ of an antiviral gene
formed between the restriction factor TRIM5 and CypA,
called TRIM-CypA, supports the existence of an even older
lentivirus within primates [49]. Rhesus macaques (Macacamulatta) encode a TRIM-CypA fusion protein that emerged
in the ancestor of macaque species 5–6 Ma [50–52]. While
rhesus TRIM5a potently blocks HIV-1 replication, TRIM-
CypA exhibits specificity towards HIV-2 and SIVagm,
suggesting that it was selected millions of years ago in
response to a lentivirus with similar characteristics [53,54]. In
a remarkable demonstration of convergent evolution, a TRIM-
CypA fusion has evolved independently in owl monkeys
(Aotus), a genus endemic to South America, establishing that
the species of the New World may have been subjected to len-
tiviruses as well [55,56]. More recent analyses uncovered an
even older TRIM-CypA fusion protein, which was present in
the ancestor of all simian primates 43 Ma, and appears to
have been active for 10 Myr before undergoing decay and loss
of function [49]. If ‘birth’ of this older TRIM-CypA gene was
also driven by selective pressure by a lentivirus, then this
implies that lentiviruses have episodically infected simian pri-
mates for most of their evolutionary history. Thus, although
each method of detecting paleoviruses has its advantages and
shortcomings (reviewed in [15,21, 25,57]), the use of host gene
evolution to infer ancient viral infections has the potential to
identify past pathogenic challenges, where any direct traces of
the virus are long gone.
3. Host polymorphism as a readout for recentvirus-driven evolution
Most examples of lentivirus-driven selection we have discus-
sed so far examine interspecies divergence, presumably fixed
mutations that distinguish the antiviral gene of one species
from another. However, the selection can also manifest as vari-
ation (known as polymorphism) within a species or within very
closely related species, which provides a powerful means to
assess ongoing or very recent selective pressures. When applied
to the evolution of antiviral immunity, polymorphism may
result from relatively recent instances of virus-driven evolution
because the variation has not yet been purged or fixed within
the host population.
Analyses of gene diversity within AGMs (genus Chloro-cebus), a highly abundant natural host species of lentiviral
infections, have turned up polymorphisms in genes that
have relevance to ongoing and ancient virus–host evolution.
AGMs comprise four major subspecies known commonly as
vervet, tantalus, grivet and sabaeus monkeys, each occupying
distinct geographies in sub-Saharan Africa. Each AGM sub-
species harbours a distinct SIV strain (collectively referred
to as SIVagm). In two of those subspecies, single amino acid
changes in A3G emerged independently to allow evasion of
the lentiviral antagonist, Vif. Specifically, these adaptive
mutations prevent degradation by Vif from heterologous
SIVagm isolates (those found in the other populations),
suggesting that they are selected as a result of Vif-mediated
selective pressure [40].
Earlier findings of polymorphism in the chemokine
receptor gene CCR5 of AGM provide further evidence of lenti-
virus-driven selection in this natural host species. The CCR5 is
used by HIV/SIV as a co-receptor to enter host cells. Non-
synonymous mutations in CCR5 of AGM subspecies cluster
in regions targeted by the viral envelope glycoprotein; this
variation inhibits SIVagm infection in vitro [58]. Interestingly,
the primary receptor for lentivirus entry, CD4, is also poly-
morphic in AGM [13] and is undergoing adaptive evolution
in primates at positions that govern virus entry [59]. Together,
signatures of recent selection in AGM suggest that both host
factors with antiviral functions and host factors that are essen-
tial for virus replication are subjected to ongoing evolutionary
change during the course of host–virus coevolution.
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Whereas the variation between species allows us to infer
the presence of ancient, pathogenic lentiviruses among pri-
mate ancestors, selection resolved to the population level
hints that contemporary lentiviruses other than SIVcpz may
also impact the fitness of their respective hosts. Indeed,
cases of AIDS, while rare, have been documented in SIV-
infected AGMs and sooty mangabeys in captivity [60,61].
Furthermore, cross-species transmission of apparently non-
pathogenic SIV strains, both in the laboratory and in the
wild, can induce disease in the non-natural host [62,63].
Even in the absence of full-blown AIDS, SIV infections may
have subtler, unrecognized consequences that, nevertheless,
seriously impact host fitness. For example, infection may
affect either reproductive rate, as observed in SIV-infected
chimpanzees [4], or social behaviours such as mate choice.
Long-term field studies of SIV-infected natural hosts are
needed to better understand the impact of wild lentivirus
infections on these and other parameters of host fitness.
20120496 4. Protective polymorphism: tripping up a viralopponent that cannot be outrunThe lentivirus genome has a mutation rate that is one million
times faster than that of its host [64]; so, primate species must
overcome a severe handicap in order to survive. Nonetheless,
it has been suggested that the presence of multiple host geno-
types may insulate populations from invading viruses by
slowing the rate of viral adaptation [65]. In fact, immune
polymorphism will not only benefit populations but also
individuals [66]. A potential protective role for heterozygos-
ity at the A3G gene is made possible by examining SIV
evolution following experimental infection of AGMs with
differing A3G genotypes.
As described earlier, the sabaeus population of AGM
encodes a unique, derived allele of A3G (D130H) that is
resistant to Vif from SIVagm strains infecting other AGM
populations. Using plasma samples isolated from three
sabaeus monkeys experimentally infected with SIVagm.Ver
(a virus naturally found in vervets) [67], we monitored the
sequence evolution in vif. Vif readily counteracted A3G in
individuals homozygous for the ancestral A3G allele. In ani-
mals that were homozygous for the A3G (D130H) allele that
was resistant to Vif from the initial virus inoculum, the vifgene evolved within the animal in order to counter this
A3G polymorphism [40]. However, in a sabaeus monkey
that was heterozygous, encoding an ancestral A3G allele
and a derived A3G (D130H) allele, SIVagm.Ver vif failed to
evolve the capacity to antagonize both variants in vivo(figure 3a) [40]. These findings suggest that the virus adap-
tation is dramatically impeded when two variants of a host
factor are present inside the cell.
Upon closer examination, the mechanism of constraint
imposed by A3G heterozygosity becomes clear. Adaptive
mutations selected in vivo enabled Vif to antagonize derived
A3G, but as a result, Vif lost activity against the ancestral
form (figure 3b, compare parental Vif with adapted Vif ).
Reversion of just one amino acid selected in Vif (Y84C)
resulted in a protein with the opposite specificity (figure 3b,
compare adapted Vif with adapted Vif þ C84Y), demon-
strates that this residue toggles the substrate specificity of
Vif. Therefore, virus adaptation to A3G is an evolutionary
trade-off, because evolving to target a variant of the host
factor compromises its ability to target the other. These data
support the idea that heterozygosity can provide an adaptive
advantage to the host and shift the balance of power in a
host–virus genetic conflict, at least temporarily. We find that
the Vif protein from SIVagm.sab, the lentivirus naturally circu-
lating among sabaeus monkeys in the wild, has overcome this
challenge and learned to counteract both derived and ancestral
variants of A3G [40]. However, this likely required repeated
transmission cycles and more extensive bouts of virus adap-
tation, because SIVagm.sab Vif shares less than 40% amino
acid identity with Vif from other SIVagm strains. Thus, hetero-
zygosity in restriction factors may have the capacity to severely
limit the ability of viruses to successfully counter-adapt during
the early stages of virus emergence.
5. Ebb and flow of the lentivirus reservoir: virusextinction and re-emergence
In addition to describing the immune adaptations of natural
host species that have resulted from, and possibly enabled,
long-term coexistence with lentiviruses, some features of pri-
mate immunity suggest that lentiviruses may have been
more widespread in the past than they are today. Species-
specific SIV strains have been defined in dozens of African
non-human primates, yet the relationship between lentiviruses
and some species is more ambiguous. Surveys of SIV in the
wild have identified ‘dead-end’ or ‘incidental’ hosts that are
not infected with unique versions of SIV but instead harbour
transient infections normally found in other species. Examples
include the yellow baboon, the chacma baboon and the white-
crowned mangabey, three species that, at low prevalence, carry
an SIVagm subtype usually confined to the autologous host
[68–70]. While clearly exposed to lentiviruses today, it is uncer-
tain whether such species were hosts to species-specific strains
in the past, although analyses of the genetics of their restriction
factors similar to that which has been done in AGMs [40] may
be able to discern between these two hypotheses.
Similarly, the first report of lentivirus infection in patas
monkeys, a species that is closely related to and sympatric
with sabaeus monkeys (AGM) in Senegal, showed that
approximately 5% of animals were cross infected with the
SIVagm.Sab subtype [71]. A later study showed that patas
monkeys share the immunophenotypic features of canonical
natural host species, namely the downregulation of the CD4
receptor from helper T cells, suggesting that a hypothetical
patas-specific SIV may have once existed [72]. This observa-
tion raises the possibility that adaptation of host immunity
(such as downregulation of lentivirus receptors or co-receptors)
may in fact mediate resistance to infection, thereby driving
the extinction of certain lentivirus strains. A similar conclusion
may be drawn for the white-crowned mangabey, which exhi-
bits a relatively low frequency of CD4þ T cells, a property
shared by other mangabey species that are known natural
hosts [73]. The prospect that genetic adaptations present in
these species may provide resistance to lentivirus infections
in the wild provides encouragement to gene therapeutic
approaches being developed to control the spread of HIV-1
in humans.
While it may be reasonable to suspect that most (if not all)
primate species in Africa have been infected by lentiviruses at
one time or another, primate habitats span the globe from the
New World to the Far East. Current surveillance efforts limit
10
100
A3G:
no Vif
0.1
derivedancestral
parental Vifadapted Vifadapted Vif + C84Y
infe
ctiv
ity (
%)
1
homozygous -ancestral
(a)
(b)
homozygous -derived
heterozygous
host A3Ggenotype:
viral vifadaptation status:
no adaptationnecessary
rapid adaptation toderived A3G variant
constraint imposed byancestral A3G impedes
adaptation to derived A3G
A3G Vif
Figure 3. Host heterozygosity may impede viral adaptation in the setting of cross-species transmission. (a) The outcome of experimental infection of three sabaeusAGMs that differ by A3G genotype is schematized. A3G variants are drawn as solid black bullets, whereas Vif variants are drawn as white crescents. The Vif-sensitive,ancestral A3G variant is readily antagonized by Vif. However, antagonism of the Vif-resistant, derived A3G variant requires counter-adaptation of the vif gene. Solidarrows signify in vivo evolution of vif in order to re-establish the interaction. In the ‘heterozygous’ monkey, expressing both the ancestral and derived A3G variant, vifcounter-evolution does not occur. (b) Single-round virus infections were performed using virions produced in the presence of Vif and A3G. Infectivity of viruses isreported as a percentage, relative to infectivity in the absence of A3G (100%). Error bars indicate standard deviation from the mean of three infection replicates.Residues found at the Vif-binding site of the ancestral and derived A3G variants are shown in grey boxes. Red bars correspond to the parental vif encoded by thevirus inoculum (SIVagm.Ver90). SIVagm.Ver90 Vif antagonizes the ancestral A3G variant, as illustrated by its ability to rescue virus infectivity (compare ‘no Vif ’ with‘parental Vif ’). By contrast, SIVagm.Ver90 cannot antagonize the derived A3G variant. Vif amplified following experimental infection of a monkey homozygous forthe derived A3G variant (‘adapted Vif ’) demonstrates elevated antagonism of derived A3G but a loss of activity against ancestral A3G (compare ‘adapted Vif ’ with‘parental Vif ’). Reversion of a cysteine residue selected in vivo (C84Y) results in Vif with the opposite specificity. (Online version in colour.)
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the range of SIV infections to the African continent, but a trail of
genetic evidence allows one to follow the spread of lentiviruses
out of Africa. For example, the Asian macaque species housed
in American primate centres recently acquired lentivirus infec-
tions via artificial cross-species transmission of SIV from sooty
mangabeys [74]. On the other hand, more recent hallmarks of
selection imprinted in other host factors strongly suggest the
possibility of a ‘natural’ rhesus-specific SIV strain in the
recent past. A high-frequency single nucleotide polymorphism
(SNP) in A3G of Indian-origin rhesus macaques, like those
identified in other members of the Cercopithecinae subfamily
of OWMs, encodes a unique charge-altering amino acid
change that affects susceptibility to the viral antagonist Vif
(figure 4) [39]. Likewise, there is an evidence of polymorphisms
in the TRIM5 gene in rhesus macaques [75], as well as the
presence of the TRIM5-CypA fusion gene in rhesus macaques
[50–52] that would provide protection against some lenti-
viruses. These polymorphisms may represent a vestigial
footprint of an extinct lentivirus that once circulated among
these primates. Thus, innovation in the innate immune
repertoire of the rhesus macaque may have been inspired by
encounters with lentiviruses in wild habitats.
Perhaps most striking of all, human evolutionary genetics
may allude to a lentiviral presence that preceded HIV-1. A
unique five amino acid deletion is fixed in the human ortho-
logue of Tetherin. As a broad acting antiviral effector, a
deletion in Tetherin could have been selected in response to
any number of enveloped viruses. However, this deletion
spans residues necessary for antagonism by the lentiviral
Nef protein used by many SIV strains, suggesting that it
may have been selected by a pathogenic, Nef-encoding lenti-
virus approximately 800 000 years ago (figure 4) [44,45,76].
Therefore, changes in innate immune genes of humans may
have been triggered by previous lentivirus infections in our
recent ancestors.
6. Looking backwards to move forwardThe evidence presented in this review for ancient lentiviral
infections of primate based on selections of host genes is
rhesus macaque – A3G D130N
humans –tetherin
deletion
lemurs – pSIV fossil
Colobinae – A3G insertion
guenons – A3G D130A
macaques – TRIM
-CypA
owl monkeys –
TRIM-CypA
time (ya)100 K1Myr10Myr40Myr 5Myr
AGM (sab) – A3G D130H
AGM (gri) – A3G K128E
moustached guenon – A3G K128E
simian ancestor
- TRIM
-CypA
SAMHD1-degrading activity
(Cercopithecinae)
Figure 4. An overview of host genetic adaptations used to infer past lentivirus infections in deep and shallow time. Adaptations are described by host species,followed by the gene name, protein fusion product, of lentivirus fossil. Those marked by a vertical flag are fixed adaptations and the minimum age is anchored inthe timeline. Mutations marked by a horizontal bracket are polymorphic in a single species of primate. The range of the bracket spans the minimum and maximumdate at which the mutation could have appeared. ya, years ago, Myr, million years, K, thousand years. (Online version in colour.)
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summarized in figure 4. An understanding of these virus origins
may allow us to better understand the host–virus interactions
that are pivotal to virus infection, transmission and long-term
persistence. While selected by virus infections of the past, the
strategies that primates have deployed to cope with lentiviruses,
and an understanding of how such adaptations constrain virus
fitness, may be exploited as novel therapeutic strategies to stem
modern pandemics in humans. For example, the introduction of
HIV-specific restriction factors into human cells is a burgeoning
avenue for antiviral gene therapy [77–79]. However, the vast
potential for viruses to counter-evolve in the face of genetic
innovations of their hosts means that a combinatorial approach
to gene therapy may prove most successful. That is, an enduring
blockade of host–virus interactions might only be achieved by
introducing multiple genetic changes in one or more antiviral
genes, like those naturally selected in hosts of SIV. Finally, an
appreciation for the size of the lentivirus reservoir, both past
and present, and for the pathogenic prowess of the many
species-specific virus strains contained therein, will help to
identify the human populations most at risk of zoonotic
infection and virus emergence.
Acknowledgements. We thank Lucie Etienne, Chelsea Spragg and PatrickMitchell for comments on the text.
Funding statement. A.A.C. was supported by a National Science Foun-dation Predoctoral Fellowship. This work was supported byNational Institutes of Health grant no. R01 AI30927 (to M.E.) and aNational Science Foundation CAREER award (to H.S.M.). H.S.M. isan Early Career Scientist of the Howard Hughes Medical Institute.
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