to develop vaccines to prevent HIV or lower the
viral set point through the generation of effector
T cells [1,2] and ideally antibodies [3,4] are some-
what unidirectional. While these approaches,
especially antibody-based immunizations, are
powerful vaccines for the majority of infectious
diseases, their usefulness remains to be proven
in the HIV arena. Recent evidence from vac-
cine trials, where in some cases even increased
acquisition of infection was noted [5,6] and in
others only little success was seen , supports
the notion that a conventional approach to this
problem is at the very least very difficult. While
the reasons for these vaccine trial failures could
© 2012 Expert Reviews Ltd
The groundwork of vaccine discovery is to study
nature’s examples as there are usually individuals
that spontaneously eliminate a given pathogen.
Unraveling the phenotype of such an effective
immune response has, historically, been the key
to a successful vaccine . Unfortunately, in
HIV, nature does not provide such proof of prin-
ciple: we have no reliable proof of spontaneous
immune-mediated clearance of HIV, neither
in an animal model or in humans. Elite con-
trollers, who mount a broad and multispecific
immune response and control HIV well, still
cannot eliminate the virus. In addition, it has
not been so far possible to elicit an elite-control
type of immunity in nonelite controller indi-
viduals, to substantially improve viral control.
Consequently, we do not have a robust example
of what an effective, preventive immune response
to HIV could look like. Yet, current approaches
be manifold, the notions that immune activation
correlates well with disease progression and that
HIV replicates well in activated T cells, espe-
cially HIV-specific T cells , might be key chal-
lenges in designing a successful vaccine. Thus,
the dilemma in HIV infection is that, while
antiviral immunity by CD4 T cells could help
to eradicate the virus , such T cells may also be
supporters of viral replication (Figure 1).
Indeed, a multitude of reports have high-
lighted the detrimental role of immune cell acti-
vation in HIV-infection [10–13]. At the same time,
there is increasing evidence that anti-inflamma-
tory stimuli can protect from productive infec-
tion but also slow down disease progression in
infected individuals [14,15]. In this article, we will
outline some of these findings and discuss why
we believe that curbing the immune response
might be a promising alternative in HIV vaccine
discovery – an alternative that, in our opinion,
has not been considered sufficiently in current
efforts to design HIV vaccines.
HIV prevention & intervention trials
Active and passive immunization protocols
have been tested in nonhuman primate models
of HIV infection in proof-of-concept studies.
Vaccination regimens with recombinant viral
vectors that induced T-cell-mediated immu-
nity were shown to reduce replication or even
decrease the incidence of acquisition of SIV
in nonhuman primates [16,17]. Administration
of human neutralizing monoclonal antibodies
Edecio Cunha Neto2,
Jorge Kalil2 and
Matthias von Herrath*1
1Division of Developmental
Immunology at the La Jolla Institute for
Allergy & Immunology, 9420 Athena
Circle, La Jolla, CA 92037, USA
2Division of Clinical Immunology &
Allergy, School of Medicine, University
of São Paulo, São Paulo, Brazil
*Author for correspondence:
Tel.: +1 858 752 6500
Fax: +1 858 752 6993
Developing vaccines to prevent the establishment of HIV infection has been fraught with
difficulties. It might therefore be important to consider other new strategies. Since several studies
suggest that anti-inflammatory stimuli can protect from HIV infection and because HIV replicates
preferably in activated T cells, we suggest here that the reduction of immune activation through
a HIV-specific regulatory T-cell vaccine might thwart early viral replication. Thus, because immune
activation is a good predictor of disease progression and the immune activation set point has
been shown to be an early event during HIV infection, vaccinating to achieve control of early
virus-specific immune activation might be advantageous.
Keywords: HIV • immune regulation • T cells • vaccine
Can an immune-regulatory
vaccine prevent HIV infection?
Expert Rev. Anti Infect. Ther. 10(3), 1–xxx (2012)
certainly not explain why the incidence in the vaccinated group
(at least in some countries) was actually higher than in the con-
trol group. By contrast, in the recent RV144 Thailand trial, the
vaccine contained ALVAC vCP1531 (recombinant canarypox vec-
tor encoding four doses) in combination with AIDSVAX B/E
(Recombinant gp120) and showed low-level efficacy in reducing
HIV-1 acquisition . While the most frequent vaccine-induced
immune responses were CD4+ T-cell proliferation, antibodies
against HIV-1 gp120, ADCC and low-titer neutralizing antibody
activities, vaccine-induced CD8 T-cell responses have not been
Thus, for preventive vaccines, the initial belief in the benefits
of inducing a stronger immune response is fading. While several
vaccines have demonstrated immunogenicity, efficacy was a much
Expert Rev. Anti Infect. Ther. 10(3), (2012)
protected macaques from Simian-HIV infection , but so far
it has been impossible to make an immunogen that elicits such
antibodies. Of the 150 vaccine regimens entering clinical trials
over the past two decades, only four have undergone evaluation
in larger-scale, test-of-concept (Phase IIb) or efficacy (Phase III)
trials. We will briefly comment on the two most recent trials, from
which the most immunological data has been collected.
While the lack of protection from HIV of the Adenovirus 5
HIV-1 gag/pol/nef trivalent vaccine, tested in the recent STEP
trial  may have been related to the narrowness of the induced
T-cell response (on average, only one epitope was recognized per
HIV-1 gene product in each vaccinee ), this notion would
harder target to achieve. Taken together,
preventive vaccine concepts that were
designed to boost HIV-specific immune
responses, could not live up to expecta-
tions. Consequently, one has to consider
alternative approaches to tackle HIV.
The role of immune activation to
It is widely accepted that chronic
immune activation in HIV infected
patients is associated with faster dis-
ease progression [10–13,20]. Indeed, it
has been shown that progressive HIV
infection and pathogenic SIV infection
in nonhuman primates are associated
with increased levels of lipopolysaccha-
ride, due to a leaky gut and microbial
translocation , which trigger immune
activation that is linked to HIV mortal-
ity . Strikingly, patients with elevated
signs of immune activation even before
seroconversion have reduced AIDS-
free survival rates compared with those
patients with reduced signs of immune
activation [10,12,20] and the degree of
immune activation that determines the
rate of disease progression is an early
event in HIV infection . However,
rather than preventing immune activation, the current strategy to
develop vaccines to prevent HIV is to optimize the generation of
effector T cells [1,2] using better vectors for immunization. Thus,
this strategy has the flip-side that HIV will be propagated more
readily once it infects the increased number of activated CD4
T cells elicited by the vaccine. Yet, the rationale for these efforts
has been based on solid grounds: in a small subset of patients,
termed ‘elite controllers’, control of viral replication was indeed
associated with a strong and multispecific antiviral T-cell response
. However, it is not clear, whether such a broad response can be
extended via vaccination to other infected individuals, for whom
the alternate approach of an immune regulatory vaccine proposed
here might be potentially of more benefit.
Indeed, nature provides other examples of how productive
HIV-infection can be prevented: HIV-exposed individuals that
remained HIV-negative. While the strongest association with
HIV-protection in those individuals has been shown to be the
genetic variation of the HIV coreceptor CCR5 that prevents viral
entry into the cells, several studies strongly suggest that low lev-
els of immune activation and the presence of anti-inflammatory
stimuli might contribute to protection in these individuals [23–27].
Individuals that produce higher levels of the anti-inflammatory
cytokine IL-10 due to a polymorphism in the IL-10 promoter
region are less susceptible for HIV infection [14,15] and interestingly,
treatment with recombinant IL-10 has been shown to prevent
HIV infection in a humanized mouse model . However, once
CD8 T cells and
HIV-specific CD4 cell becomes
activated by antigen-presenting
cells through TCR/MHC and
Expansion of activated
effectors provides the
for HIV replication
Figure 1. The two faces of CD4 T-cell activation in HIV infection. While antiviral
immunity by CD4 T cells could help to eradicate the virus by providing T-cell help and
through direct effects (Upper panel), the activated CD4 T cells are more susceptible to
becoming infected and thus, providing an optimal environment for HIV replication
TCR: T-cell receptor.
Boettler, Neto, Kalil & von Herrath
• Treg cells decrease HIV replication in activated CD4 T cells .
• Higher numbers of Tregs are associated with decreased signs of immune activation (CD69) in uninfected high-risk sex workers .
• Treg numbers appear to decline at slower rates when compared with other CD4 T cells .
• Preserved high numbers of circulating Tregs are associated with decreased immune activation in elite controllers .
• High numbers of Treg cells are associated with decreased signs of immune activation and reduced risk for vertical transmission in
• The increase of Treg cells over time due to the disruption of the mucosal Th17/Treg balance is a characteristic of pathogenic SIV and
possibly progressive HIV infection [57,58].
• FoxP3+ Treg cell accumulation in lymphoid tissues from humans and nonhuman primates is associated with disease progression,
independent  or dependent  from immune activation status.
• FoxP3+ CD4+ Treg cells are susceptible to HIV infection .
• Treg cells inhibit HIV-specific CD4 and CD8 T-cell responses in vitro [59,60].
infected, these high IL-10 producing individuals display higher
viral loads in the acute phase of infection , display reduced CD8
T-cell-responses and loose CD4 T cells more rapidly than lower
IL-10 producing individuals . On the other hand, high IL-10
producers ultimately have decreased viral titers in the chronic phase
of infection, progress significantly slower to AIDS  and survival
rates are doubled in these patients . In addition, elevated IL-10
mRNA levels are associated with a slower progression to AIDS in
HIV-infected children . Similarly, prevention of mucosal SIV-
infection could be achieved in a nonhuman primate model by local
administration of an anti-inflammatory compound that prevented
immune activation . These observations are also in agreement
with the notion that an anti-inflammatory cytokine milieu and the
absence of chronic immune activation have been repeatedly found
in nonpathogenic SIV infections in natural host primates. In these
animals, SIV replicates well and establishes persistence without
causing clinical disease [33–35]. This outcome is associated with
rapid termination of the initial type 1 interferon response in the
presence of anti-inflammatory cytokines, whereas disease-prone
macaques display a sustained type 1 interferon response in the pres-
ence of proinflammatory cytokines and activated effector T cells
[36,37]. Collectively, these findings suggest a nonredundant role
for anti-inflammatory stimuli in preventing an establishment of
productive infection but also harnessing the pathogenicity of HIV.
The role of Tregs
Tregs comprise a subset of T cells with suppressor activity capable
of blocking the activation (proliferation and cytokine produc-
tion) of effector T cells . Thus, the question whether Tregs are
capable of reducing immune activation during HIV infection has
attracted much attention. However, despite several years of intense
research and a multitude of publications on this topic, we are still
lacking a clear concept on how Treg cells influence HIV infec-
tion. On the one hand, Tregs have been associated with protec-
tion from productive infection and pathogenic disease in humans
and nonhuman primates [25,36,39,40]; but, on the other hand, Treg
cells have been shown to be important for the establishment of
HIV infection in humanized mice  and were associated with
increased immune activation in humans (Box 2) [42,43].
The major caveat in studying Treg cell function and a possi-
ble explanation for such diverging results is arguably the hetero-
geneity of this population, not exclusive to HIV-infection . The
majority of reports characterize Treg cells based on their expres-
sion pattern of defined surface markers (CD4+CD25+CD127-)
Box 1. Selected evidence for protective properties of anti-inflammatory stimuli in HIV (excluding Treg
• Individuals with an IL-10 promoter polymorphism that results in higher levels of IL-10 are less likely to become infected and progress
significantly slower to AIDS [14,15].
• Elevated IL-10 mRNA levels are associated with a slower progression to AIDS in HIV-infected children .
• Antiretroviral treatment of HIV-infected pregnant women increases production of IL-10 in plasma and in vitro, which negatively
correlates with viral loads .
• Anti-inflammatory cytokine profiles and reduced immune activation is associated with nonpathogenic SIV infection in African green
monkeys compared with pathogenic infection in Rhesus macaques that develop AIDS .
• Early disruption of the innate immune response is associated with nonpathogenic infection in African green monkeys .
• IL-10 pretreatment prevents HIV infection in humanized mice .
Box 2. Protective and detrimental findings associated with Tregs.
Can an immune-regulatory vaccine prevent HIV infection?
Expert Rev. Anti Infect. Ther. 10(3), (2012)
and the transcription factor FoxP3. However, in HIV a purely
phenotypic characterization is particularly problematic, as differ-
ent CD4 subsets become infected with different kinetics [45,46].
To what extend this affects the expression of surface markers,
CD4 T cell plasticity and FoxP3 stability has not been addressed
In summary, these considerations argue for a more functional
definition of regulatory T cells than a merely phenotypic charac-
terization. Recent findings that IL-10 producing, FoxP3- negative
cells, so called type 1 regulatory T cells, can effectively suppress
effector T-cell functions support this notion .
A major setback in studying the protective role of anti-inflamma-
tory agents was the failed clinical trial with recombinant IL-10
nearly 10 years ago . In a clinical pilot study where chronically
infected patients received one dose of IL-10, a transient decline of
HIV-RNA was observed . However, these results could not be
confirmed in a randomized Phase II trial . IL-10 treatment of
chronically infected patients did not affect the clinical end points
of this trial including HIV-RNA levels and CD4 T-cell counts.
The reason for this failure could be manifold and include the small
study size (n = 10 per study group) and the short treatment period
(4 weeks). More importantly, however, in our opinion, a promising
concept was buried altogether after only one trial. Considering
the enormous effort that has been put into designing protective
vaccines that aim to establish an elite controller-like immune phe-
notype in vaccinees . This appears to be premature and we
believe that it is time to revisit approaches that induce regulatory
immunity rather than effector T cells to tackle HIV infection.
Several observations discussed above would argue that it might
indeed be possible to slow down disease progression in established
infection with a regulatory vaccine; however, public health consid-
erations would argue against such an approach, which might even
promote viral replication. Indeed, dampening the antiviral immu-
nity during established infection might result in uncontrolled viral
replication with an increased risk of HIV-transmission. Therefore,
an immune-regulatory vaccine would best be deployed to prevent
establishment of productive infection. The proof-of-principle in
this case would be the observation that high levels of IL-10 have
been shown to prevent HIV-infection in humans and mice. While
systemically elevated levels of IL-10 in order to prevent immune
activation would be a rather blunt tool on a population level, we
would argue that an HIV-specific vaccine approach could be a
promising alternative to current vaccination strategies.
The lack of in-depth studies focusing on therapeutic implica-
tions of the protective properties of such regulatory stimuli in
HIV is obviously the major caveat in designing such approaches
for HIV infection. However, in a first step,
observations from other disease models
could be used to define strategies with the
goal to induce a distinct HIV-specific cell
type with regulatory properties, which in
this case needs to be defined by its ability
to produce anti-inflammatory cytokines,
most importantly IL-10, and the capability
to migrate and accumulate at sites of viral
infection. It has been shown that dendritic
cells with regulatory properties are able to
suppress effector T cells in various disease
models through direct IL-10 secretion or
the induction of other regulatory cell types
[51,52]. Importantly, such regulatory den-
dritic cells induce not only CD4 regulatory
cells but also CD8 Treg cells, which could
be particularly useful in HIV as these cells
would not become infected. Secondly,
the induction of type 1 regulatory T cells
cells, which are strong IL-10 producers
 could be a promising approach. These
cells develop extrathymically and can be
efficiently expanded in vitro for proof-of-
concept studies. Thirdly, a DNA vaccine
that induces a regulatory T-cell response
with a distinct cytokine profile, in this
case IL-4 and IL-10 production, has been
shown to reduce the incidence of diabetes
through bystander suppression of autoreac-
tive T cells and has shown initial promise in
Figure 2. Possible way to induce a tolerogenic or regulatory antiviral response.
The goal would be to induce a distinct HIV-specific cell type with regulatory properties.
DNA vaccination and peptide vaccination that induce a regulatory response but also
cell-transfer studies with regulatory DCs and Type 1 regulatory T helper cells have been
proven successful in animal models for autoimmune diseases or graft-versus-host
diseases. Naive DCs are thought to develop into rDCs upon contact with the regulatory
vaccine. In the lymphatic tissue, these rDCs present the antigen in a tolergonic fashion to
CD4 and CD8 T cells. Those T cells then acquire a regulatory phenotype. In HIV infection,
such cells might be able to prevent activation of HIV target cells, for example, in an IL 10
dependent fashion, which could prevent the establishment of productive infection.
DC: Dendritic cell; IDO: xxxx; PEG: xxx; RA: xxxx; rDC: Regulatory dendritic cell.
Data from [51–54,61].
Boettler, Neto, Kalil & von Herrath
Walker LM, Burton DR. Rational
antibody-based HIV-1 vaccine design:
current approaches and future directions.
Curr. Opin. Immunol. 22(3), 358–366
Buchbinder SP, Mehrotra DV, Duerr A
et al. Efficacy assessment of a cell-mediated
immunity HIV-1 vaccine (the step study):
a double-blind, randomised, placebo-
controlled, test-of-concept trial. Lancet
372(9653), 1881–1893 (2008).
HIV vaccine failure prompts Merck to halt
trial. Nature 449 (2007).
Rerks-Ngarm S, Pitisuttithum P,
Nitayaphan S et al. Vaccination with
immune activation in the pathogenesis of
clinical trials of autoimmune diabetes (Figure 2) . While none of
these approaches describe a comprehensively developed concept,
they might constitute first steps to elaborate on. Such approaches
may have the potential to prevent immune activation in response
to HIV infection and could thus prevent the establishment of a
fertile field where HIV can easily replicate. This could result in
the prevention of productive infection, as is suggested by lower
infection rates in high IL-10 producers [14,15] and the preventive
effect of IL-10 pretreatment in humanized mice .
Expert commentary & five-year view
It has become apparent that it is difficult to develop a preventive
vaccine for HIV. The reasons for this are manifold and, among
others, include the ability of the virus to mutate and evade anti-
body and/or T-cell recognition but also the intrinsic property
of HIV requiring activated CD4 T cells to replicate efficiently.
This unique aspect creates a dilemma, because we must weigh
the benefits of inducing a strong antiviral response with the risk
of helping the virus at the same time to find an even more fertile
ground for replication and possibly gaining an initial foothold
prior to sequestering into reservoirs from which it is difficult to
eradicate. We therefore discussed evidence indicating that damp-
ening the antiviral immune response prior to HIV mucosal expo-
sure could be beneficial in preventing productive infections. Less
antiviral immunity might in some cases be better, a concept that
deserves more exploration in our opinion.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.s
• Current approaches to develop vaccines to prevent HIV that aim at the generation of effector T cells have largely been unsuccessful.
• HIV replicates preferably in activated T cells and immune activation increases the risk of HIV-acquisition. Thus we face the dilemma that
antiviral immunity by CD4 T cells could help to eradicate the virus but such T cells may also be supporters of viral replication.
• There is an increasing body of evidence suggesting that anti-inflammatory stimuli can prevent HIV-acquisition.
• We discuss the possibility of an immune-regulatory vaccine to prevent productive HIV infection.
Papers of special note have been highlighted as:
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