The quasispecies immunity hypothesis: how vaccination can protect from AIDS
2. Infection in the naive host
3. Infection in the non-naive host
4. Quasispecies immunity
5. QI tests
6. Implications for vaccination and treatment
8. Copyright notice and disclaimer
Speed of deployment matters for protective immunity, as indicated by the
evolutionary selection of non-adaptive (fast, but non-specific) and
adaptive (slow, but antigen-specific) immune defenses. However, the immune
system is vulnerable to rapidly proliferating and mutating pathogens that
can: 1) elude non-adaptive responses; and 2) exploit the lag time of T cell
or antibody-mediated immunity. Genomic instability is a feature shared to
varying extent by many RNA viruses, and is prominent in human
immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV).
I speculate that early establishment of virus quasispecies reservoirs is
the basis for the inability of man's immune system to clear HIV infection.
I also propose that this explains the efficient protection provided by live
attenuated vaccines in the macaque/SIV model of acquired immunodeficiency
syndrome (AIDS), and sets a ceiling for the extent of protection obtainable
2. Infection in the naive host
Many pathogens avoid immune responses by antigenic variation. HIV exists
as a quasispecies with a very high mutation rate [1-3]. It varies among
individuals and considerable genetic heterogeneity occurs both at different
times  and anatomic locations  within a single infected host.
After transmission, HIV proliferates extensively in activated CD4+ T cells
 (and less in other susceptible cells). HIV isolates early after
transmission appear remarkably homogenous . This may reflect
transmission bottlenecks, the dramatic change of selective pressure upon
entering a new host, or the insensitivity of detection techniques. However,
low frequency variants *have* to be present, because of the error proneness
of retrovirus replication. At 1-10 mutations per new genome copy [8,9], HIV
is already sampling the potential epitope space before specific T cell and
antibody responses develop.
Primary viremia disseminates variant genomes throughout the body, mainly
in lymphoid tissues . By the time specific T cell responses and
antibodies appear and viremia decreases , at least three types of virus
reservoirs that are outside the reach of immune effector mechanisms will
have been established:
1. latent viral genomes in quiescent CD4+ T cells ; these will
generate new virus upon activation;
2. antibody- and complement-coated virions trapped in the follicular
dendritic cell network in lymph nodes [13,14]; although recognized by
antibodies, these virions are not neutralized; they are highly infectious
and concentrated at a site where contact with CD4+ T cells can easily
3. escape variants that have lost antigenic epitopes ; these do not
necessarily become dominant - possibly because of reduced replicative
fitness - but can hinder CTL function in several ways [16-18]; particularly
important in my view is the possibility that, because of the high mutation
rate of HIV, escape variants can also act as a 'dynamic' reservoir of
revertant virus, preventing clearance, but causing continuing
immunopathology and cytopathic effect.
Primary viremia is followed by an asymptomatic phase, during which both
viral quasispecies and infected CD4+ T cells turn over at a high rate
[19-21] in the presence of considerable cytotoxic T cell (CTL) activity
 and neutralizing antibodies (NA), as detectable in in vitro assays.
However these responses fail to clear completely the infection, and slow,
relentless depletion of CD4+ T cell clones and damage to the antigen
presenting function occur . It is possible that CTL activity may
actually be detrimental through incessant lysis of infected CD4 T cells and
antigen presenting cells, while new virus keeps emerging from
immunologically invisible reservoirs.
Cell mediated immunity is generally quite effective in controlling viral
infection, even when complete clearance is not achieved. A good example are
herpesviruses (DNA genome) that establish life-long latent infections and
are widespread in human populations. However, in comparison with HIV,
variation is limited, and, after primary infection is controlled, specific
effector CTL frequencies settle down on lower levels than in HIV infected
individuals. The size and diversity of virus reservoirs established after
infection could influence the very different outcomes of these virus-host
Closer examination of CTL clones  or T cell receptor V segment
families in CD8+ T cells reveals phases of expansion and contraction ,
while virus variants also fluctuate in time . Oscillation of CTL clones
and virus variants in time have been interpreted in terms of
immunodominance shifts in multi-epitope systems , implying a driving
role for the non-linear dynamics of antigenic stimulation and competition
among CTL responses. The view proposed here is that clonal expansions of
CTL might be driven by the random egress of virus variants from reservoirs
inaccessible to immune effectors.
After a median time of about 10 years a catastrophic transition to AIDS
occurs in most HIV infected individuals [26-28, 83]. Circulating CD4+ T
cells drop below a critical threshhold, CTL  and antibodies become
depleted and important viremia reappears. The host eventually succumbs to
opportunistic infections or AIDS related malignancies.
In about 5-10% of HIV infected individuals (long term non progressors -
LTNP), transition to AIDS does not occur by this time . The reasons are
not clear, and could include so far unidentified protective immune
responses, 'weak' infectious inoculum, non-immune host factors, or simply
be the tail end of a distribution of progression times. See  for a
recent review of this subject.
For most cases of HIV infection, massive virus replication and very strong
activation of virus specific immune responses co-exist during long periods.
I propose that the immune system of a naive individual simply cannot cope
with a strategy of viral persistence based on the combination of reservoirs
of virus that are 'invisible' to the immune system, quasispecies population
structure and high mutation rate. Under these conditions the specificity
and timing of immune responses is bound to be out of phase with
quasispecies variation. The immunological battle against HIV is lost by the
time primary viremia occurs.
3. Infection in the non-naive host
By pre-emptive induction of a primary response and immune memory, vaccines
shorten the delay between contact with pathogen and intervention of immune
effectors. Therefore vaccination is a logical approach to control HIV.
Vaccination induced effector mechanisms could completely prevent virus
dissemination, or reduce virus load and prolong the asymptomatic phase.
HIV vaccine candidates are still to prove themselves in man, while the
failure of antibodies induced by recombinant HIV gp120 vaccines to
neutralize primary HIV isolates has caused pessimism about their chances of
success in efficacy trials . However, epidemiological data on natural
resistance to HIV-1 exist and support a beneficial effect of pre-existing
Both HIV-1 and HIV-2 can cause AIDS in humans, although HIV-1 is more
transmissible, more virulent and has a shorter pre-symptomatic period than
the related HIV-2 . In a 9-year study of populations exposed to both
HIV-1 and HIV-2, it was found that previous HIV-2 infection provided about
70% protection against HIV-1 infection, although some double infections did
Since HIV-2 infection also eventually progresses to AIDS, the pathogenetic
role of relative kinetics of virus replication versus immune response
appears supported. In other words, the specific response to HIV-2 antigens
is ineffective against HIV-2, but the same response, which is only
cross-reactive against HIV-1, has a protective effect against the latter,
more virulent pathogen. The crucial factor appears to be the timing of the
response: too late for HIV-2, pre-emptive for HIV-1.
Several reports (reviewed in [33,34]) have described HIV-specific cellular
responses in HIV-exposed, seronegative individuals, although it has been
difficult to show that clearance of a virulent HIV inoculum had indeed
occurred. Maybe cell mediated immune responses controlled a putative small
infectious or attenuated inoculum without ever allowing primary viremia to
develop to the point of triggering antibody production. Confirmation of
natural immunity to HIV would give impulse to the search for protective
mechanisms and why they do not work in every infected individual.
HIV can infect chimpanzees, and the initial events following infection
(including cytopathic effect on CD4+ T cells) resemble those in humans.
However they are transient, virus burden is lower than in man and AIDS does
not develop . Chimpanzees can be protected from infection by
vaccination with recombinant envelope glycoprotein and neutralizing
antibody titers correlate with protection [36,37]. The high titers required
for sterile protection are difficult to achieve and to sustain without
frequent boosts, but these results clearly show the susceptibility of HIV
to immune effector mechanisms. Comparative studies of HIV pathogenesis in
man and chimpanzees could help identify the basis of long term non
Simian immunodeficiency virus (SIV) is related to HIV and causes in macaque
monkeys a disease that resembles HIV infection in man, induces similar
immune responses including NA and CTL and results in AIDS, as the immune
system in naive macaques generally fails to control the infection [38,39].
SIV infection results in a peak of viremia, which subsides in coincidence
with the appearance of anti-SIV CTL and antibodies [40,41,79-82].
Reservoirs of replicating SIV in lymph nodes have been correlated with
disease progression . Thus SIV infection in macaques is a good model
for HIV infection in humans.
Several vaccine trials in the SIV model system in macaques have yielded
protection against infection or disease  and I would like to speculate
how the scenario of early dissemination of virus quasispecies proposed
above might fit with macaque vaccination results obtained in experimental
systems widely differing in immunization, challenge virus, route of
infection and protection criteria.
Recombinant protein vaccines. Recombinant gp160 of SIV (priming by live
recombinant vaccinia virus, and boosting with gp160 expressed by
baculovirus) protected against infection with related cloned SIVmne ,
but failed against uncloned SIVmne . This key result shows the
possibility of protection and at the same time highlights the limitations.
The divergence present in uncloned SIVmne is already too much to be
contained by the relatively narrow-focused, vaccine induced effectors.
Protection thus could depend on the quasispecies divergence of the
Recombinant env or gag proteins of SIV generally failed to protect against
infection by SIV , although suppressive effects on virus load after
infection have been demonstrated . Presumably, effector mechanisms
induced by the vaccine could clear the quasispecies components that most
closely matched their specificity and reduce the viremic burst. However
sufficient virus dissemination occured to create reservoirs capable of
sustaining the pathogenetic process, albeit at lower virus load levels.
Whole inactivated virus vaccines. Several research groups achieved
protection of macaques against SIV infection using inactivated SIV vaccines
[48-57]. Both vaccine and challenge virus were grown in human cells, and it
was found that protection was due to an immune response against HLA and
possibly other human cell components incorporated in the virions [58-61].
Macaques immunized with whole inactivated SIV grown in human cells became
infected upon challenge with SIV grown in macaque cells . Only partial
protection could be attributed to immune responses against SIV components
The effectiveness of xenogeneic antibody responses against HLA antigens
incorporated in SIV virions - sterile immunity against uncloned
heterologous virus, cell associated virus and challenge by the rectal route
- suggests that allogeneic antibody responses might also protect humans
against HIV. Indeed findings in multiparous women support a possible
protective effect of allogeneic antibodies .
Concerning the role of quasispecies reservoirs in pathogenesis, protection
results by whole inactivated SIV highlight two key points: 1) when
quasispecies divergence of the challenge virus is 'short-circuited' by
including a constant component in all virions, and the same component is
present on the membrane of virus-infected cells in the inoculum,
antibodies against that component can clear the whole inoculum, including
cell-associated virus; 2) clearance must be happening before replication in
the cells of the new host, as the human antigen would be lost in the next
virus generation. Partial protection afforded by bona fide anti-SIV
responses appears consistent with quasispecies divergence.
Live attenuated vaccines. Powerful protection against infection with
virulent SIV was first achieved using live attenuated SIV (la-SIV) clones
having nef gene deletions [64-66]. Animals were protected against challenge
with cloned or uncloned homologous virulent SIVmac administered as late as
2.25 years after a single dose of live attenuated vaccine. Similar results
[67,68] were obtained with paired isogenic clones of SIVmac, where the
attenuated clone had mutations and deletions in the nef gene. Vaccinated
animals resisted high dose homologous challenge, and even virus-infected
cells. Partial protection against SIVsm was also achieved. The
immunological correlates of protection have not been identified.
Neutralizing antibody levels in protected animals are lower than those
achieved in unprotected animals immunized with whole inactivated virus or
recombinant proteins. T cell mediated immunity could be involved. In fact,
it has been reported that exposure of macaques to sub-infectious doses of
live SIV conferred long term protection against later challenge with
infectious doses. Protected animals had T cell responses in the absence of
antibody responses .
An intriguing feature of protection afforded by live attenuated vaccines
is that it develops after a time that is considerably longer than is
necessary for humoral and cellular responses to appear after virulent SIV
infection . Maybe a critical virus load (which would be reached slowly)
is necessary to induce immune protection. Alternatively, as discussed
below, it is the divergence of the quasispecies which primes the protective
4. Quasispecies immunity
I proposed above that early establishment of reservoirs of virus
quasispecies is the key pathogenetic mechanism in HIV and SIV infection. In
the 'quasispecies reservoir' scenario, it would appear nearly impossible
for the naive immune system to control HIV, and immunity induced by most
conventional vaccines has several pitfalls.
NA and T cells specific for a single antigen variant are unlikely to
control a heterogeneous quasispecies. 'True' in vivo NA can clear a free
virus inoculum on the first pass, provided all virions contain the
epitope(s) that they recognize. If this line of defense is leaky and host
cells become infected, NA will still be able to clear newly released free
virions that retain the recognized epitopes, but will miss escape variants
and virus transmitted by direct cell-cell contact. NA specific for viral
antigens - as opposed to cell antigens - will not prevent infection by an
inoculum of cells containing latent virus. In addition, the presence of
enhancing antibodies could establish reservoirs of infectious virions on
follicular dendritic cells, or facilitate uptake of virions by Fc positive
First-pass protection by T cells is unlikely because 1) T cells recognize
infected autologous cells, not virions; 2) the chances of contact between
initially rare infected cells and specific T cells are low. T cell mediated
protection thus will kick in only after a certain amount of virus
replication has occurred. The new viral crop will contain variants that
might escape immune recognition.
Thus the chances of vaccine protection will decrease with each round of
How can we then explain HIV infected LNTP and vaccine mediated protection
in the SIV/macaque model system? LTNP are difficult to interpret, since
information on the inoculum is often unavailable. I will not speculate on
various possibilities, and only refer to a report where the inoculum could
be defined, and which documented nef-U3 region defects in the attenuated
HIV quasispecies present in a blood donor and a cohort of recipients .
On the basis of protection results with la-SIV in macaques I propose an
interpretative hypothesis (which I refer to as 'quasispecies immunity'
(QI)) which addresses the generation of genetic heterogeneity in vivo.
According to the QI hypothesis, la-SIV differs from wild type SIV in its
reduced speed of replication in the adult macaque, but under host selective
pressures will generate the same variants as wild type SIV (and will even
be pathogenic in hosts that complement its replication speed defect ).
However, the immune system can cope with *slow* quasispecies divergence and
makes humoral and cell mediated responses to successive variants,
eventually controlling the infection. The point is that the virulent SIV
quasispecies, exposed to that particular host's selective pressures, would
have generated an essentially similar set of variants in fast succession,
outpacing the immune response. Thus, la-SIV will prime a broader spectrum
of specific antibodies and T cells than invariant recombinant proteins or
even whole inactivated vaccines.
Challenge with wild type SIV would then be met early on by multiple
'layers' of variant-specific effectors, improving resistance to
'breakthrough' virus replication, viremia and establishment of virus
reservoirs. It would be as if the first-pass protection window had been
The QI hypothesis assumes that the key pathogenetic mechanism of virulent
SIV is rapid replication and mutation, that la-SIV replication and mutation
do occur in the adult, and that the immune system responds to a
'sufficient' proportion of variants. The actual effector mechanism of
protection is not specified, and it could be any one or a combination of
those adaptive responses which have been described (NA, ADCC, CTL, cytokine
secreting T cells [73,74]).
Vaccination results in macaques appear compatible with this mechanism: 1)
protection requires early prevention of virus replication; 2) protection is
related to the overlap between diversity and multiplicity of pathogen
epitopes present in the vaccine and diversity of quasispecies that the
challenge inoculum can generate; (recombinant protein vaccines are
essentially monoclonal, WIV reflects some quasispecies diversity generated
during in vitro growth, and la-SIV can diverge as a quasispecies (albeit
'in slow motion'); 3)la-SIV vaccinated macaques become protected after a
time interval which allows for serial responses to different variants.
5. QI Tests
Replication and mutation of la-SIV are essential features of the QI
hypothesis. The QI hypothesis would be definitely invalidated by the
demonstration that la-SIV variants do not appear in vivo.
Also, abolishing or limiting mutation of la-SIV epitopes should impair
protection. The hypothesis predicts that expressing all epitopes of cloned
la-SIV by suitable recombinant vaccinia viruses or similar vectors, or DNA
immunization, which do not have the mutation rate of lentivirus genomes,
should only induce partial protection.
Likewise, if whole inactivated vaccines based on the la-SIV strain could
be made, one would expect protection only up to the extent of diversity
generated during in vitro growth. Clearly other factors (e.g. different
antigen processing and presentation) might impair protection, but finding
equivalent protection would weaken the hypothesis.
Conversely, the QI hypothesis predicts that use of challenge virus which
has been multiply passaged in autologous cells would eventually result in
enough quasispecies divergence to get around immunity induced by an
originally matched isogenic la-SIV. Protection in this system would be a
function of the overlap between the induced QI and the diversity of the
challenge quasispecies, making it likely that vaccination may fail.
Too rapid clearance of la-SIV by a powerful immune response or antiviral
treatment should impair protection. Envisage an experiment comparing la-SIV
grown in macaque and human cells. Both la-SIVs should protect naive
macaques equally, but protection should fail when la-SIV grown in human
cells is used in macaques immunized with fixed human cells . For the
same reason simultaneous treatment of la-SIV immunized macaques with PMPA
 should impair protection.
Conversely, if carefully adjusted antiviral treatment slowed down the
replication of wild type SIV simultaneously introduced into macaques, it
should be possible to induce protection against a second dose of wild type
virus in the absence of antiviral drugs. This would be analogous to results
with Rauscher murine leukaemia virus in mice. A similar view was expressed
by Baba et al. , although their model is based on virus load rather
than the divergence of the quasispecies. Macaques were also protected by
immunization with subinfectious doses of live SIV . Since mutation
requires replication, it is difficult to distinguish the roles of raw virus
burden and quasispecies divergence.
Viral antigens expressed by la-SIV will be presented to the immune system
in their native conformation and through the same antigen processing
pathways followed by virulent SIV.
If protection afforded by la-SIV is simply due to improved immunogenicity
(native conformation of antigen and appropriate processing and
presentation) then protection would be expected to correlate with the late
appearance of a crucial protective response to a conserved epitope, which
would clear la-SIV.
Instead, the QI hypothesis predicts the serial expansion of effectors with
epitope specificities matching and clearing each virus variant, until
la-SIV control is eventually achieved. Therefore, measurements of the
frequency of specific T cell clones by limiting dilution analysis and
titers of epitope specific antibodies in the period between la-SIV
vaccination and establishment of protection should distinguish between the
The QI hypothesis predicts that protection by attenuated SIV will
correlate with induction of immune responses to multiple variant epitopes
*before* exposure to wild type SIV. Responses developing *after* challenge
with virulent SIV should be unable to catch up with virus replication and
mutation, and fail to prevent the establishment of WT virus reservoirs in
6. Implications for vaccination and treatment
There are many approaches to AIDS vaccines. Purified recombinant protein
vaccines are less immunogenic, but safer, than live attenuated vaccines and
considerable work goes on to develop non-toxic adjuvants that might
compensate the low or inappropriate immunogenicity of non-replicating
vaccines. However, if the QI hypothesis is true, there is a sense in which
live attenuated vaccines would be inherently superior to non-replicating
immunogens, or even to live vector recombinant vaccines based on DNA
viruses such as vaccinia or adenovirus. Only live attenuated vaccines would
dynamically mimic the appearance of variants and quasispecies divergence
that follows infection, and elicit the corresponding responses. One hundred
per cent protection is never achieved by existing vaccines, among other
reasons because of pathogen variation. The problem is acute when a pathogen
quasispecies contains a variant genome per virion. Inasmuch as a live
attenuated quasispecies would prime multiple variant specific responses, it
would represent a theoretical maximum for protection achievable through
immunization with a single entity.
Vaccination with la-SIV in macaque models affords powerful protection
against virulent SIV, but the use of live attenuated HIV in humans might
involve considerable risks including cancer and mutation/recombination to
virulent forms. The potential liability issues make North American and
European market-oriented health companies reluctant to invest much effort
in developing live attenuated HIV vaccines, even if an acceptable
risk/benefit ratio might exist for use in countries with high infection
However, QI might be generated by other means. For instance, the use of
variant gp120 peptide cocktails to immunize against variant env gene
products was advocated , and this approach could be extended to other
epitopes. The practical aspects of producing such vaccines appear however
daunting, and powerful but safe adjuvants would be essential.
Alternatively, nucleic acid vaccination with DNA or RNA coding for
mixtures of epitopes might be envisaged, as long as in vivo re-assembly of
infectious genomes could be avoided. Nucleic acid technology has the
additional advantage of extra flexibility in generating variant epitopes
and inactivating biological protein function while retaining linear epitope
immunogenicity by cutting and splicing large chunks of coding sequences.
Live attenuated vaccines should match prevailing wild type quasispecies as
close as possible, in order to maximize protective cover. Given the
diversity of selective pressures stemming from human polymorphism, this is
a tall order. Consider how current influenza vaccine manufacturers cope
with the seasonal variation of the virus by switching to new strains
expected to cause pandemics. Even for a mixture of just three strains, this
approach requires extensive monitoring and vaccine production capability.
The mercurial variability of HIV quasispecies would probably make a direct
transfer of this approach impractical. However nucleic acid based
vaccination might allow more flexibility.
A conventional vaccine design approach to pathogen variation consists in
exploiting protective effector mechanisms triggered by recognition of a
conserved epitope. As for immunotherapy, an interesting model of
progression to AIDS in HIV infected individuals supports boosting CTL
responses to single conserved epitopes, rather than trying to stimulate
responses to all epitopes available in vivo . However, it is not
guaranteed that conserved epitopes may always be found. As for prophylaxis,
the identification of the correlates of protection in la-SIV vaccinated
macaques should show whether responses to a single conserved epitope
protect better than responses to multiple epitopes. Likewise, the
SIV/macaque animal model could provide an experimental test for the
mathematical model of immunodominance among CTL responses against different
An alternative approach to lentivirus variation stems from the realization
that host cell derived antigens incorporated into virions could become the
target of protective antibody responses in a xenogeneic host . The
extension of such findings to an allogeneic system would allow to use
allogeneic antibodies against HLA antigens to protect from HIV. This
approach would bypass virus quasispecies variation. In order to circumvent
allogeneic antibodies, HIV would have to lose altogether the ability to
incorporate host antigens in its envelope.
The issue of quasispecies reservoirs also affects chemotherapeutic
approaches to HIV control. Rapid emergence of variants resistent to
different classes of antiviral compounds has been documented in HIV
infected patients [20,21,77]. Although the immune repertoire of HIV
infected individuals becomes depleted as they progress to AIDS, potentially
useful immune responses are present initially, and could synergize with
antiviral therapy. Thus non-toxic *early* combination therapy would be
expected to have the biggest impact on virus burden. Recent reports of
infection prevention by co-administration of PMPA in monkeys given
infectious SIV  support early use of antivirals.
In co-evolving with their hosts, viruses have developed sophisticated
infection strategies, often exploiting the workings of the immune system
itself in order to maximize their survival. By using live attenuated HIV
vaccines to provide quasispecies immunity the human host would be just
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nec poterat quisquam reperiri, quem neque morbus nec mors nec luctus
temptaret tempore tali.
and no person could be found in those days, who was not touched by disease,
De Rerum Natura (circa 54 BC)