Download AIDS pathogenesis: a tale of two monkeys

J Med Primatol doi:10.1111/j.1600-0684.2008.00328.x
ORIGINAL ARTICLE
AIDS pathogenesis: a tale of two monkeys
Guido Silvestri
Departments of Pathology and Laboratory Medicine, and Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA,
USA, and Yerkes National Primate Research Center of Emory University, Atlanta, GA, USA
Keywords
AIDS – macaques – mangabeys – SIV
Correspondence
Guido Silvestri, University of Pennsylvania
School of Medicine, 705 Stellar Chance
Laboratories, 422 Curie Boulevard,
Philadelphia, PA 19143, USA.
Tel.: +1 215 5735363;
fax: +1 215 5735369;
e-mail: [email protected]
Despite many years of intense scientific effort, the pathogenic mechanisms
underlying the immunodeficiency that follows human immunodeficiency
virus (HIV) infection are still poorly understood. This lack of understanding is likely the main reason why at present there is neither a cure nor a
vaccine for AIDS. Important clues on the immunopathogenesis of primate
lentiviral infections have been provided by comparative studies of two simian models of SIV infection: the non-pathogenic SIV infection of sooty
mangabey, an African natural host species, and the pathogenic SIV-infection of non-natural host rhesus macaques, that develop a disease that closely resembles AIDS in humans. While the final mechanisms underlying the
difference in infection outcome between these two species are still incompletely understood, a series of recent studies has allowed the identification
of key similarities and differences between the two models of infection. In
this article we summarize these findings and review the main implications
in terms of HIV pathogenesis, therapy, and vaccines.
AIDS pathogenesis: a tale of two monkeys
With several million deaths per year, the AIDS pandemic represents without any question one of the
worst medical tragedies of modern times. As such, the
etiologic agent of this disease, the human immunodeficiency virus (HIV), is correctly considered a highly
pathogenic microbe. Since 1983, the year when the
virus was discovered, a great deal of progress has been
made in terms of understanding the genetic and molecular structure of the virus, elucidating its life cycle,
and designing compounds able to inhibit HIV replication. The practical result of these conceptual advances
is the availability of highly effective antiretroviral regimens whose widespread usage had a dramatic effect
on reducing mortality, morbidity, and transmission of
the infection, particularly in developed countries.
Unfortunately, the mechanisms linking the replication
of HIV with the development of a progressive and
eventually life-threatening immunodeficiency have not
yet been fully elucidated. In my opinion, this lack of
6
understanding of the interaction between the virus and
the host immune system is the reason why we are
unable to eradicate the infection and do not have an
effective AIDS vaccine.
Historically, the field of HIV immunology has by
and large adapted a basic working model – in part
derived from real or perceived analogies with murine
models of viral infections – which postulates that antiHIV adaptive immune responses, both humoral or cellular, are inherently ‘good’ as they have the potential
of suppressing virus replication, either via antibodymediated neutralization or cytotoxic T-lymphocyte
(CTL)-based lysis of infected cells. While plenty of evidence indicates that the adaptive immune system may
control HIV/SIV replication under certain circumstances [24], the reality of the interaction between HIV
and the host immune system is much more complex.
The well-known observation that HIV preferentially
infects and kills activated CD4+ T cells indicates
that every adaptive immune response to this virus –
which will involve the activation of CD4+ T helper
J Med Primatol 37 (Suppl 2) (2008) 6–12 ª 2008 The Author
Journal compilation ª 2008 Blackwell Munksgaard
Silvestri
cells – inevitably result in the generation of new fuel
for HIV replication. As such, any attempt to artificially
strengthen the in vivo immune responses to HIV with
the intent of inhibiting virus replication is complicated
by the potential, paradoxical risk of inducing more
target cells for the virus. Furthermore, the tremendous
ability of HIV to mutate and escape the host adaptive
immune responses often delineates a scenario wherein
vigorous but largely ineffective antiviral responses
result in more damage than help to the overall function of the host immune system. This latter point is
most eloquently revealed by the fact that during HIV
infection the level of CD8+ T cell activation appears
to predict disease progression even better than the level
of virus replication itself [10, 11]. In keeping with this
observation, several authors proposed that the state of
chronic, generalized immune activation that is associated with HIV infection is a key determinant of AIDS
pathogenesis [15, 17, 27, 43, 47].
The possibility that the replication of a cytopathic
primate lentivirus which targets mainly activated
CD4+ T cells does not necessarily leads to AIDS is
illustrated by the well known observation that SIV
infection of natural hosts African non-human primate
species (including chimpanzees, sooty mangabeys, African green monkeys, mandrills, and several others) is
typically non-pathogenic despite levels of viremia similar to those observed in HIV infection [7, 18, 36, 39,
46, 49]. While the exact mechanisms by which natural
SIV hosts remain healthy are still relatively poorly
understood, a number of key observations have been
made over the past few years that have clarified several
important immunological and virological aspects of
these infections (reviewed in 14). In this article I will
summarize these advances by reviewing what aspects
of natural, non-pathogenic SIV infection of sooty
mangabeys (SMs, a paradigmatic model of natural
SIV infection) are either similar or different from what
has been observed in the non-natural, pathogenic
model of SIVmac infection of Indian rhesus macaques
(RMs). I wish to emphasize that natural SIV infection
of SMs is particularly relevant because SIVsmm, the
virus infecting SMs, is the origin of HIV-2 epidemics
in humans and the progenitor of the various RMadapted SIVmac viruses (i.e., SIVmac239, SIVmac251)
that are commonly used for studies of AIDS pathogenesis and vaccines [16, 19]. The main postulate of this
‘tale of two monkeys’ is that any feature of the infection that is similar in SMs and RMs is unlikely to be a
key determinant of the striking different outcomes
observed in these two species. On the contrary, the
identification of species-specific differences between
SIV-infected SMs and RMs may provide useful
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AIDS pathogenesis: a tale of two monkeys
information with respect to the molecular and cellular
mechanisms ultimately responsible for progression to
AIDS.
Common features of non-pathogenic
SIV-infection of SMs and pathogenic SIV
infection of RMs
Perhaps surprisingly, in the backdrop of the clear difference of outcomes (i.e., pathogenic in RMs and nonpathogenic in SMs) there are actually numerous
similarities in the immunological and virological
features of SIV infection in these two monkey species.
In both RMs and SMs, the acute infection is characterized by a peak of virus replication occurring
between one and two weeks post-inoculation [12, 31,
45]. This peak is followed by a relatively rapid decline
to levels ranging around 104–106 in SMs and 105–107
in SIVmac-infected RMs. While set-point viremia in
SIVmac239- or SIVmac251-infected RMs is usually
higher than in SMs, relatively lower levels of viremia
are observed in RMs infected with uncloned SIVsmm
who can still progress to AIDS [45]. The fact that the
viremia of SIV-infected SMs is at least as high – or
perhaps even higher – than that observed in untreated
HIV-infected individuals (and in SIVsmm-infected
RMs) indicates very clearly that the non-progressing
phenotype of SMs cannot be simply attributed to
lower levels of virus replication. In addition, if that
were the case, one would expect some signs of disease
progression in the animals with higher viremia – in
analogy to what has been observed in HIV-infected
humans [28, 29]. However, several studies have shown
that there is no tendency to develop AIDS even in the
SMs with highest viral load [44, 48]. Interestingly, in
both SMs and RMs the transition from the acute to
the chronic phase of infection results in a (quasi)
steady state of virus replication and CD4+ T cell
homeostasis – with the important difference, however,
that CD4+ T cell counts progressively decline overtime in the vast majority of RMs but only in a small
minority of SMs.
The determinants of the level of set-point viremia are
still poorly understood in both species, with the relative
contribution of immune control versus target cell availability remaining still unknown. Interestingly, the effect
of CD8+ T cell deletion seem to be more dramatic in
RMs than in SMs, thus suggesting that CTLs may be
more important in these animals in determining the setpoint viremia [1, 20, 25, 26, 42]. A caveat of these experiments is that the mechanisms by which CD8+ cell
depletion is followed by increased viral load are complex
and not well understood, particularly as it has become
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AIDS pathogenesis: a tale of two monkeys
clear that CD8 depletion results in a change of the activation state of CD4+ T cells which may have a direct
effect on virus replication [1; Picker personal communication]. Interestingly, the level of SIV-specific CD8+
T cell responses measured by intracellular cytokine
staining in response to ex vivo stimulation with SIV peptides appears to be similar in SMs and RMs [8, 51] and,
for both species, lower than what has been observed in
HIV-infected humans [2]. The lack of any evidence that
the AIDS-resistant naturally SIV-infected SMs have
‘better’ or ‘stronger’ SIV-specific adaptive immune
responses when compared to HIV-infected humans or
SIV-infected RMs has profound theoretical implications, as it indicates that natural SIV hosts have evolved
to a non-pathogenic type of infection independent of
immune control of virus replication. From a more practical point of view, this observation emphasizes the tremendous challenge of artificially inducing, with an
AIDS vaccine, a type of protective immunity that has
not been selected for in many thousands of years of evolutionary pressure posed by lentiviruses on the primate
immune system.
In both SMs and RMs (as well as African green
monkeys), the main cell type supporting virus replication appears to be a population of short-lived, activated CD4+ T cells [13, 32, 38]. In SIV-infected SMs,
this conclusion is supported by at least four different
lines of evidence. First, histological studies where virus
replication is assessed by in situ hybridization in conjunction with staining for T cell markers indicate that
the majority of infected cells are CD3+CD4+ [Estes
and Silvestri, unpublished observations]. Second, the
kinetics of plasma viral load decline after treatment
with antiretroviral drugs indicates that 90%–99% of
virus replication in SMs occurs on short-lived cells,
thus compatible with activated CD4+ T cells [13].
Third, depletion of CD4+ T cells with an anti-CD4
monoclonal antibody that does not deplete macrophages is associated with marked decline in viral load
[22]. Fourth, CD4+ T cells are severely depleted in
mucosal tissues of SIV-infected SMs during the acute
phase of infection, likely due to direct cytopathic effect
of the virus [12]. Collectively these observations indicate that the nonpathogenic phenotype of SMs is not
related to differences in the spectrum of target cells for
virus replication. That SIV-infected SMs experience a
rapid and dramatic deletion of mucosal CD4+ T cells
whose kinetics is similar to that observed in SIVinfected RMs [12] is an observation of great interest,
and suggests that the differences in mucosal immune
function between pathogenic and non-pathogenic primate lentiviral infection develop during the chronic
phase of infection [33]. Consistent with this hypothesis
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Silvestri
is the observation that the level of mucosal CD4+
T cells remains stable in chronically SIV-infected SMs
while it progressively declines coincident with development of AIDS in SIV-infected RMs. The fact that
SMs are able to deal with a rapid and significant
depletion of mucosal CD4+ T cells is also consistent
with the possibility that these animals have evolved to
become less dependent on these cells to maintain an
intact mucosal immunity. An alternative – but not
mutually exclusive hypothesis – is that additional factors (i.e., lack of local immune activation, see next paragraph) may protect the CD4+ T cell-depleted
mucosal immune system of natural SIV hosts. In this
context, it is interesting to note that, in contrast to
SIV-infected RMs and HIV-infected humans, SIVinfected SMs do not show any signs of microbial
translocation from the intestinal lumen to the circulation [4]. As microbial translocation may be a key
determinant of the generalized immune activation that
is thought to cause systemic CD4+ T cell depletion
and progression to AIDS in HIV-infected individuals,
it is possible that, in SIV-infected SMs, a preserved
mucosal immune function explains the paradox of a
selective depletion of CD4+ T cells in the MALT but
not in the blood or lymph nodes.
Differences between non-pathogenic SIV
infection of SMs and pathogenic SIV infection of
RMs
There are three main and consistent immunological
differences between SIV-infected RMs and SMs, with
the latter typically showing:
(i) preservation of peripheral CD4+ T cell homeostasis;
(ii) lower levels of immune activation;
(iii) lower expression of CCR5 on CD4+ T cells
(reviewed in 14).
Normal or near normal levels of CD4+ T cells (i.e.,
>500/cm3) are observed in 85%–90% of naturally
SIV-infected SMs despite many years of infection with
a highly replicating virus [48]. It should be noted that
the disconnection between peripheral CD4+ T cell
counts (that are mostly normal) and mucosal CD4+ T
cell levels (that are decreased after infection) is a typical feature of SIV-infected SMs that is not found in
RMs or humans. Interestingly, moderate to severe systemic CD4+ T cell depletion is observed in 10%–15%
of naturally SIV-infected SMs as well as a subset of
experimentally SIV-infected SMs that developed a
dual-tropic (i.e., CCR5 and CXCR4-using) variant of
SIVsmm [30, 48]. The fact that even these animals
with a persistently severe CD4+ T-cell depletion
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Silvestri
(i.e., CD4+ T cell counts <50/cm3 for over five years)
do not progress to AIDS is a finding whose importance, in my opinion, is hard to overestimate, and
which raises fundamental questions on the nature of
lentivirus pathogenesis and the function of CD4+
T cells in primates. Does this observation indicate that
in absence of other factors (i.e., immune activation?
depletion of other cell types?) the immune system
can successfully cope with a massive and persistent
depletion of CD4+ T cells? Does it mean that CD4
depletion is more of a marker, rather than a cause, of
the HIV-induced immunodeficiency? It is my hope that
these unconventional and somewhat provocative
hypothesis be taken very seriously by the scientific
community as their testing might reveal previously
unappreciated but in fact highly significant aspects of
HIV/AIDS pathogenesis.
The fact that SIV-infected SMs show markedly
lower levels of immune activation when compared to
SIV-infected RMs or HIV-infected humans has been
shown in a fairly large number of studies [5, 6, 12, 21,
31, 44, 45, 48]. Consistent with their lower levels of
immune activation, naturally SIV-infected SMs show
low levels of bystander apoptosis and cell cycle dysregulation when compared to RMs [35]. While a previous study from our group suggested that differences in
T cell activation and proliferation are apparent since
the acute phase of infection [45], more recent studies
indicate that the main differences in the level of
immune activation between SMs and RMs are manifest during the chronic phase of infection [12]. The
observation that natural, non-pathogenic SIV infection
is characterized by low levels of immune activation has
also been made in other species such as chimpanzees,
AGMs and mandrills [5, 14, 23, 34, 36]. Collectively,
these studies led several authors to hypothesize that
attenuated immune activation protects natural SIV
hosts from progression to AIDS in the face of chronic
infection with a highly replicating cytopathic retrovirus
[46, 49]. This hypothesis is clearly consistent with the
finding that immune activation is a strong correlate of
diseases progression in HIV-infected humans (reviewed
in 8). The cellular and molecular mechanisms responsible for the low levels of immune activation in SIVinfected SMs are still poorly understood and likely
complex. As mentioned above, a preserved integrity
of the mucosal barrier with low levels of microbial
translocation may provide significant protection from
Toll-like receptor (TLR)-mediated activation of macrophages and dendritic cells with consequent downstream
bystander activation of T cells [3, 4]. Also, a better
ability of SIVsmm Nef to down-regulate CD3-TCR in
infected CD4+ T cells may be instrumental to reduce
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AIDS pathogenesis: a tale of two monkeys
T cell activation – particularly in comparison with
HIV-infected humans [41]. In addition, in SIV-infected
SMs a lower production of IFN-a by plasmacytoid
dendritic cells in response to certain viral TLR ligands
may also set the tone for a less vigorous T cell
response to SIV antigens [26]. At least in SIV-infected
African green monkeys, increased activity of regulatory T cells during acute infection may also contribute to the attenuated immune phenotype [23].
While the hypothesis that low immune activation is
the key to maintaining a healthy immune system in
natural SIV hosts is supported by very strong correlative evidence, the ultimate proof of the ‘immune
activation’ hypothesis would come from in vivo
experiments wherein induction of AIDS in natural
hosts is achieved by increasing their level of immune
activation.
The third main difference between SMs and RMs
(and, more generally, between natural and non-natural
hosts for primate lentiviral infections) is in the expression of CCR5 by CD4+ T cells. In RMs and humans,
the fraction of CD4+ T cells expressing CCR5 is
approximately 10%–20% in blood and >50% in mucosal tissues [37]. The enrichment in CD4 + CCR5 +
T cells in the MALT is consistent with the known role
of CCR5 as a marker of effector/effector memory
T cell differentiation [40]. Intriguingly, the fraction of
CD4+CCR5+ T cells in SMs – both uninfected and
SIV-infected – is much lower, that is, in the range of
1%–5% in both blood and MALT [37, 50]. This low
expression of CCR5 in SMs is specific for CD4+
T cells as levels comparable to those observed in RMs
and humans are found in CD8+ T cells. While this
finding is absolutely unequivocal, its precise pathophysologic meaning – particularly in the context of
the non-pathogenicity of natural SIV infection – is
still unclear. Obviously, the low expression of CCR5
on CD4+ T cells does not protect SMs from either
horizontal transmission or virus replication in infected
animals. Similarly, this low CCR5 expression does not
protect CD4+ T cells from direct infection in vivo, as
several lines of evidence indicate that CD4+ T cells,
rather than macrophages or other non-CD4 cell types,
produce the bulk of virus in SIV-infected SMs. A more
likely possibility is that a restriction of CCR5 expression to more differentiated (i.e., effector/activated)
CD4+ T cells will limit SIV replication to a subset of
more ‘expendable’ CD4+ T cells – that is, cells that
are likely doomed to die of activation-induced apoptosis regardless of their being infected or not. In this
context, a significant beneficial effect in preserving
CD4+ T cell homeostasis may result from protecting
the pool of central memory CD4+ T cells from the
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AIDS pathogenesis: a tale of two monkeys
direct effect of virus replication [46]. An additional,
non-mutually exclusive possibility is that low CCR5
expression on CD4+ T cells may protect SIV-infected
SMs from immune activation, as CD4+CCR5+effector T cells may be less able to home to inflamed tissues
and thus provide less of a substrate for SIV replication
and further inflammation. This latter hypothesis is
consistent with recent work indicating that, in HIVinfected humans, specific CCR5 genotypes protect
from progression to AIDS independently of both viral
load and cellular immune responses to HIV [9].
Finally, it is possible that low CCR5 expression on
CD4+ T cells is involved in the resistance of SMs
(and natural SIV hosts in general) from vertical transmission of the infection [46].
Implications in terms of HIV pathogenesis,
therapy, and vaccines
Understanding how primates and their lentiviruses have
co-evolved to reach a pacific co-existence in nature will
continue to provide crucial insights into human AIDS
pathogenesis that, ultimately, may have important
implications for the therapy and prevention of HIV
infection and AIDS. In terms of therapeutic implications, I believe that defining the cellular and molecular
mechanisms that dictate the obvious differences in
immune activation and CCR5 expression between natural and non-natural hosts will aid in the design of new,
immune-based therapies to be used, in addition to
HAART, in the treatment of HIV infection. In terms of
AIDS vaccine, the first major conclusion that can be
drown from these studies of natural SIV infections is
that thousands of years of co-evolution of African
primates and their lentiviruses have resulted in a state
of apathogenicity wherein virus replication is not
controlled by the host immune system, thus emphasizing how daunting is the task of developing an AIDS
vaccine. The second major implication of these studies
is that the dissociation between virus replication and
disease progression typical of SIV-infected natural hosts
is an invitation to explore potential alternative strategy
of AIDS prevention that will result in delayed disease
progression without suppressing virus replication.
Conflicts of interest
The author has no conflict of interest.
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J Med Primatol 37 (Suppl 2) (2008) 6–12 ª 2008 The Author
Journal compilation ª 2008 Blackwell Munksgaard