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OpinionRates of HIV immune escape andreversion: implications for vaccination
Miles P. Davenport1, Liyen Loh2, Janka Petravic1 and Stephen J. Kent2
1
2

Centre for Vascular Research, University of NSW, Kensington, NSW 2052, Australia
Department of Microbiology and Immunology, University of Melbourne, VIC 3010, Australia

HIV-1 mutates extensively in vivo to escape immune
control by CD8+ T cells (CTLs). The CTL escape mutant
virus might also revert back to wild-type upon transmission to new hosts if significant fitness costs are
incurred by the mutation. Immune escape and reversion
can be extremely fast if they occur very early after infection, whereas they are much slower when they begin
later during infection. Immune escape presents a significant barrier to vaccination, because escape of vaccinemediated immune responses could neutralise any
benefits of vaccination. Here, we consider the dynamics
of immune escape and reversion in vivo in natural infection, and suggest how understanding of this can beused to predict optimal vaccine targets and design vaccination strategies that maximise immune control. We
predict that inducing synchronous, broad CTL by vaccination should limit the likelihood of viral escape from
immune control.
Studying the dynamics of immune escape and reversion
A confusing picture has emerged in recent years fromstudies of immune escape and reversion of HIV-1 inhumans and SIV in macaques. Some macaque studies
suggest fast rates of escape and reversion during or early
after acute infection. Fast escape, where escape mutant(EM) virus first arises and becomes the primary quasispecies within a few weeks, implies strong immune pressure from CD8+ T cells (CTLs). Similarly, fast reversion
from EM to wild-type (WT) virus over a few weeks indicateshigh fitness costs of the escape mutation [1,2]. By contrast,
several studies of HIV-1-infected people suggest muchslower rates of immune escape and reversion, where several months or longer is required to complete the change
from one viral phenotype to the other [3–7]. The differencein escape rates in humans and macaques has been used tosuggest that CTL pressure is lower in HIV than in SIV [4],whereas the difference in reversion rates was interpreted
as escape mutations in humans having lower fitness costs.
However, recent evidence indicates that transmission of
escape mutant virus and the maintenance of escapemutant virus are associated with reduced viral loads inHIV, implying significant fitness costs associated with the
CTL escape variants [8–10].
Understanding the differences in escape and reversion
rates between SIV and HIV requires studying the
dynamics of viral evolution within the host. Although
Corresponding author: Kent, S.J. (skent@unimelb.edu.au)

mutational escape from HIV-specific CTL responses has
been documented for over 15 years [11], sequencing technologies remain the primary method to follow escape. Bulk
sequencing is insensitive to variants <30% of the population and even cloning and sequencing cannot reliably
detect the presence of 10% of minor species unless massive numbers of clones are sequenced. A viral subpopulation comprising 10% of the total represents a large
amount of viremia where the total viral load exceeds 106
copies during early infection. This methodological limitation has made it difficult to perform detailed longitudinalstudies of escape and reversion dynamics. Quantitative
PCR-based methods have recently been developed andused to accurately measure the ‘viral load’ of both WT
and EM quasi-species [12–14]. Specific forward primers
modified with locked nucleic acids and minor-binding
groove bases allow detection of <0.1% minor quasi-species[13,14]. This permits tracking EM or WT virus over time,even where large quantitative differences between WT and
EM virus emerge as escape proceeds. These quantitative
PCR approaches have allowed a dynamic understanding of
immune escape, and have clarified the differences between
HIV and SIV. These data now suggest that a dynamic
interplay between viral mutation, host immune pressure,and the availability of host target (CD4+) T cells explains
the observed differences and has important implications
for vaccine design [3,4]This article assesses the reasons why rates of CTLdriven immune escape and reversion are variable during
the course of natural HIV infection of humans and SIV
infection of macaques, and how vaccination is likely toimpact rates of escape and reversion. These are topicalissues given the failure of a recent CTL-based vaccination
approach, which induced fairly narrow responses, to prevent or modify HIV infection of humans [15]. We predictthat some apparently ‘conserved’ epitopes in HIV might
escape slowly simply because immune responses to these
epitopes develop late. Targeting of such epitopes by vaccination could be counterproductive, because it will simply
drive early escape. However, we predict that inducing
broad CTL responses that simultaneously target multiple
epitopes in acute infection will reduce escape and facilitate
more effective virologic control.
Reversion of transmitted escape mutant virus
To understand the dynamics of escape and reversion invivo, it is easiest to first consider the dynamics of reversion;
EM virus is often at a replicative disadvantage compared0966-842X/$ – see front matter ß 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.tim.2008.09.001 Available online 27 October 2008

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Figure 1. Factors determining immune escape and reversion. Wild-type (WT) virus can outgrow escape mutant (EM) virus in a host that is unable to recognize the epitope
because of its higher replicative capacity, leading to ‘reversion’ from EM to WT (a, b). When the host is inoculated with pure EM virus, the WT must arise by mutation.
However, the optimal time for mutation (viral peak) coincides with the worst time for WT virus to compete because of the low number of target cells. Thus, reversion tends
to occur late and slowly after infection with pure EM virus. When WT virus is present in the initial inoculum, it outgrows EM during the first weeks of infection, when hightarget cell number favor its growth. Immune escape (c, d) can occur at different rates depending on whether the immune response is early (c) or late (d). Vaccination might
speed up ‘late responses,’ leading to rapid early escape. If both the EM virus and strong immune pressure are present early in infection, high immune pressure and low
fitness cost, due to the nadir in target cell numbers soon after the peak of virus, will lead to rapid escape. If the immune pressure (or mutation) is present only later in
infection, then higher steady-state target cell numbers will increase the effective fitness cost of escape, leading to slower selection of the escape variant.

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Opinionwith WT virus, owing to the ‘fitness cost’ of escape mutation[6–8]. Thus, in the absence of immune pressure (forexample in a host lacking the correct MHC to recognize
the WT epitope), a transmitted EM virus reverts to WT(Figure 1a,b). There are several prerequisites to successful
reversion: (i) the WT virus must have higher replicative
capacity (‘fitness’) than the EM; (ii) the WT virus needs tobe present (either in the initial inoculum, or generated
through mutation from EM virus); and (iii) there must be
sufficient available uninfected CD4 cells – ‘target cells’ – forthe WT virus to grow in and outcompete the EM [13].
Simplistically, if there are very few cells available for
infection, both WT and EM will grow slowly, and theWT virus will have difficulty ‘outgrowing’ the EM virus.
Thus, a critical driver of early ‘reversion’ is the presenceor absence of the WT virus in the infecting inoculum.
Where the WT virus is already present in the EM virus,
the fitter WT virus can rapidly outgrow the EM virus
during the early exponential phase of viral replication,
when target cell levels are at their highest (Figure 1b).
However, when infection occurs with pure EM virus, thenmutation of EM virus is required to generate the original
WT variant. Because mutation occurs only during infectionof new targets, it will be more likely to occur as the numberof infected cells increases. This first WT mutant to arise in
an infected cell must then avoid an early death before
infecting another cell, and then grow and compete with
the EM virus. However, WT revertants are most likely to
be generated by mutation around the peak of infection, andthis corresponds with the worst time for their growth andcompetition against EM virus because of the shortage of
uninfected target cells. Indeed, in many circumstances
there are predicted to be too few target cells for WT virus
to grow at this time [13]. As a result, if a WT mutant isgenerated at peak, it will either fail to grow, or compete
extremely poorly with EM and thus only slowly outgrow
EM virus. Thus, after infection with pure EM virus reversion might often not occur in acute infection and insteadarise during the chronic phase, where the daily probabilityof mutation is lower but the target cell availability in thechronic phase of infection is higher and will at least permit
moderate WT virus growth rates.
Recent analyses of viral variability during HIV-1 infection by analysing single genomes predict that approximately three-quarters of new HIV-1 infections are initiatedwith a single strain, whereas a quarter of subjects acquire
two or more variants [16,17]. In cases where WT and EM
are both transmitted, it is also possible that the WT virus
could outgrow the EM virus sufficiently rapidly that EM
virus might not be detected at all by sequencing techniquesby the time of the first sampling (usually 2–3 weeks after
infection). Thus in humans rapid reversion might not be
detected in acute infection, and those reversion events thatare observed will be late and slow [9,10] – not necessarily
because of the low fitness cost of escape, but due to infection
dynamics following clonal inoculation with EM virus. It isnoteworthy that where clonal EM virus has been used to
infect monkeys and thus mutation is required to produce
WT variants, slower reversion is also observed [2]. Recombination between WT and EM virus could further speed up
reversion [18].

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Understanding the dynamics of reversion in vivo isessential to understand immune escape. The selection of
EM virus involves a balance of WT and EM advantages: theincreased replicative fitness of the WT virus means that it
is always trying to ‘revert’ and take over from EM, and thestrength of this selection for WT virus is determined bytarget cell availability, as discussed above. The advantageof the EM virus is that it escapes CTL killing, which mightalso fluctuate over time. The net effect of the WT ‘reversion
advantage’ and the EM ‘immune escape advantage’ determines the rate of immune escape, as discussed below.
Timing and rate of immune escapeThe strong selection pressure exerted by CTL induces early
and rapid escape at some epitopes in SIV [11]. Vaccination
can accelerate this by applying higher immune pressure[19]. By contrast, escape in HIV is often relatively slow.
Recently, it has been shown that the timing of immune
escape is a major determinant of its rate; escape at thesame epitope in macaques varies in rate depending on
when it occurs [20]. Evidence from studies of extremely
early infection in humans suggests rapid escape in early
infection here also [14,15].
Immune escape again requires several factors: (i) the
presence of EM virus (in inoculum, or generated bymutation); (ii) the presence of immune pressure on WT;(iii) sufficient number of target cells at the time of appearance of EM, so that it is able to grow when it emerges; andBox 1. Factors influencing reversion and escape rate
Selection of immune escape variants is driven by immune pressurefavouring unrecognized epitope variants. Thus, the higher the CTL
response, the higher the escape rate. However, escape mutation
usually also involves a ‘fitness cost’ because of the lower replicative
capacity of the escape mutant virus. The effective fitness costexperienced by the virus is influenced by the number of available
target cells for the viruses to grow in [13]. Early in infection, target
cell numbers are high and the immune response is weak (point A),
so the net balance favours reversion to wild-type virus [19].
However, just after the peak in virus the CTL response is at its
peak, and the target cell number is at its lowest point (point B). Thisset of factors promotes rapid escape. In chronic infection, CTL levels
have dropped and target cell numbers are partially recovered,leading to a slow rate of immune escape (point C) (Figure I).

Figure I. Factors influencing reversion and escape rate.

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Opinion(iv) that the fitness cost of escape is less than the immunepressure (Box 1). As described above, the fitness cost of
escape varies with the availability of target cells for infection. Early in infection the growth advantage of the WT
virus is maximised because of the large number of target
cells, and the selective pressure of CTL is low because of adelay in their activation [16,17]. The optimal time for the
EM to appear is just before the peak of viraemia; at thistime the probability of mutation is close to its highest level,
there is already some CTL response reducing the WT
fitness, and target cells are low enough to reduce theWT growth advantage, but not yet so low that the EM
virus is unable to grow, as might occur at maximum
depletion. If the EM emerges at this time, it is wellestablished just after the peak of total viral load. This
time represents the perfect combination of factors forpromoting escape (Figure 1c): a peak in CTL response(to many epitopes), and a nadir in CD4+ T cell numbers
leading to a low ‘fitness cost’ of escape. At this time there islittle growth of either EM or WT virus because of low target
cell numbers, but the rapid decay of WT virus due to CTL
control leads to the rapid selection of EM virus.
This rapid early escape in the first few weeks of infection
is often a predictable factor of early SIV/HIV infection.
Early escape occurs as a natural consequence of viral

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and immune dynamics, and might be hard to alter byvaccination. However, escape later in infection is morevariable in its timing and might not occur in all individuals. Understanding why early escape is often so stereotyped and delayed escape is often variable or absent atsome epitopes could provide insights into improved viral
control.
Understanding early versus late escape during naturalinfection
The discussion above indicates why we might often see
early, rapid escape. Why then is escape delayed at some
epitopes (Figure 2)? A simple explanation for this is thatthe mutation is rare, so that there are too few infected cells
during acute infection to guarantee production of theEM, and it instead tends to arise later in chronic infection(Box 2). In this case, many rounds of infection might berequired before the mutant arises. This is most likely thecase when multiple mutations are required to produce
escape [18]. An alternative mechanism is that the hostimmune response tends to arise late, after the peak ofviremia [18–20]. In this latter case, even though themutation might be produced during acute infection, theimmune pressure driving its selection might be absent or
minimal so it is likely to be lost. Once the immune response

Figure 2. Choosing epitopes where vaccination will reduce escape. Vaccination is predicted to have different effects on the rate of viral escape, depending on the dynamics
of escape in natural infection. (a) Epitopes that escape early do so because of a combination of early immune pressure and a ‘high probability’ escape mutation. Vaccination
might reduce the probability of mutation by reducing viral load and increase immune pressure, but will likely have little effect on escape at these epitopes unless the
reduction in viral load is very high. (b) Epitopes that escape late might do so because the mutation is a ‘low probability’ event, despite an early immune response, or
because of a late-arising immune response (c). In the case of a low-probability mutation, if vaccination reduces viral load it will further delay, and maybe even prevent,escape. However, if late escape occurs because of a late-arising immune response, vaccination will lead to an earlier ‘memory’ response to the epitope and simply
precipitate early escape.

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OpinionBox 2. Mutation rate and the expected time of appearanceof the escape mutant
HIV mutation occurs during the infection of new cells. The
probability of a mutation emerging is therefore determined simply
by the number of infected cells (and scales with viral load). The‘cumulative probability’ of a mutation having occurred before acertain time is thus proportional to the total number of cells infectedfrom the start of infection until this time and is proportional to thearea under the viral load curve.
The cumulative probability of mutation grows exponentially
until the peak of infection; the growth then slows down until thechronic phase, when it grows slowly and fairly linearly in time
(Figure I). If the probability that an infected cell will produce anescape mutant (EM) is m, then we can expect the EM to appear
after 1/m cells are infected. If we consider two possible escapescenarios, one with a high probability of mutation (m is high) andthe other with a low probability of mutation (m is low), they will
be expected to occur at different times. Here, the mutation rate
for the first mutant m1 is large, and in natural infection it appears
early, at t1 before the viral peak. The second mutant has a lower
probability m2 and would appear in the chronic phase of naturalinfection at t2.
Vaccination will act to reduce viral loads, and thus reduce theprobability of mutation (although the effect of vaccination is always
delayed for several days, during which the number of infected cells
grows in the same way in vaccinated and unvaccinated individuals[29]. The ‘easy’ escape mutation (m1) will still occur, and any slightdelays in its occurrence will have little effect. However, theemergence of the ‘difficult’ mutant (m2), that would have normallyappeared during the chronic phase, will be delayed till much later orcompletely suppressed.

Figure I. Mutation rate and the expected time of appearance of the escapemutant.

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develops in chronic infection, the rate at which mutantsarise is again low, and the fitness cost has risen because thenumber of target cells is higher than just after the peak, so
escape is slow and late (Figure 1d). Other immune factors
could also influence viral load and escape dynamics; forexample, during acute infection, innate immune responses
might reduce viral growth of both EM and WT strains.
Similarly, during chronic infection changes in T cell repertoire [21] or loss of CD4 T cell help might facilitate escape[22]. Overall, we expect a fundamental difference in escapetiming and rates between those epitopes that experiencehigh immune pressure early versus late.
Impact of vaccination on escape dynamics
Immune escape is a major mechanism by which the virus
could neutralise the impact of vaccination [23]. What is theeffect of vaccination on the rate of immune escape? Vaccination might act to reduce the escape rate by reducing theviral levels and the probability of generating a mutant, andby preserving CD4+ T cells, which increase the ‘fitness cost’of escape (Box 2). However, vaccination might also makeescape faster by increasing the immune selection pressure,particularly if this occurs in acute infection. The balance of
these forces will be strongly dependent on the timing andmechanisms of escape in natural infection.
For epitopes where escape occurs rapidly in natural infection, vaccination is likely to have relatively little effect.
The probability of mutation arising could be reduced, but
unless there is a large reduction in viral load, this might beinsufficient to prevent the mutant arising early. By contrast,
because the natural level of immune response is sufficient toproduce escape, boosting this by vaccination is unlikely to
produce more rapid escape because the escape is so fast that
this is of little consequence.
Where vaccination is likely to have the most impact is inepitopes that normally escape late. However, the result ofvaccination will be determined by the reason for the lateescape. If an epitope escapes late because of the low
probability of mutation, then anything that reduces viralload will delay escape in proportion to the cumulative viralload reduction (Box 2). Otherwise, if an epitope escapes latebecause of a delayed immune response, then vaccination
against that epitope will drive the immune response tooccur in acute infection. In this case, the phenotype ofescape after vaccination will be early and rapid during
acute infection and much faster than in natural infection.
This contention is supported by the observation that
although CTL responses restricted by HLA-B*27 provide
a benefit during chronic natural HIV infection with lateescape [24], in a vaccinated subject infected with HIV,
escape occurred early and the subject progressed rapidly[25].
Identifying epitopes that don’t escape until late in infection is one way of choosing immune targets for vaccination. However, we should first confirm that slow escapeoccurs despite immune pressure; that is, because of difficulties in producing the mutations rather than because of
the absence of early immune pressure [18–20]. If vaccination can reduce viral loads in acute infection it should
prevent early escape at these epitopes and facilitate sustained immune control.
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OpinionConcluding remarks and future directions
How does the foregoing help us design better potential
vaccination strategies for HIV? Immune escape from CTL
responses is indeed an Achilles heel for HIV vaccination,and understanding and controlling the forces that determine escape is an important aim. The timing and rate ofescape and reversion are determined by the complex interplay among viral load, target cell number, and immunepressure, and do not in themselves predict the fitness costat an epitope or the likely effectiveness of vaccination. A
significant issue clouding our understanding of escape isour ‘one epitope at a time’ approach to studying escape.
Because of the technical complexities of measuring andcomparing escape, we often tend to think about it ‘one
epitope at a time.’ It is likely that escape in vivo conforms
somewhat to this pattern, where a flurry of early escape
events is followed by a slow sequential escape in chronic
infection.
Targeting vaccination to epitopes that are stable andonly escape late in natural infection could either precipitate or slow immune escape. The major advantage oftargeting such ‘late escaping’ epitopes might come not fromthe effects on that epitope alone, but from bringing to beara large number of responses simultaneously rather thanhave them arising sequentially [18–20,26] and permitting‘one escape at a time.’ If we can synchronise multiple
responses to occur simultaneously early in infection andreduce the peak viral load and target cell depletion, thenwe could reduce the probability of mutation and increase
fitness cost at multiple epitopes. Moreover, the more epitopes that are simultaneously targeted, the more difficult it
becomes to produce EM virus with multiple mutations.
This presents significant challenges in overcoming thephenomenon of immunodominance and ‘clonal succession’[27]; There is a natural tendency for highly presented
epitopes or high-avidity T cell clones to dominate theresponse, and this might be exacerbated by vaccination[28]. Thus, the benefits of eliciting responses to multiple
epitopes might be undermined if there is a strong immunodominance hierarchy, leading to sequential escape fromsuccessive waves of immunodominant CTL responses todifferent epitopes. The diversity of the response in terms ofthe number of epitopes equally targeted in acute infection
rather than the total magnitude of the response could be
the key consideration.
Acknowledgements
Supported by Australian National Health and Medical Research Council
grants and a James S McDonnell Foundation Award. M.P.D. is a Sylvia
and Charles Viertel Senior Medical Research Fellow.

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