Human Vaccines & Immunotherapeutics

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Therapeutic vaccines against HIV infection

Felipe Garca, Agathe Len, Josep M. Gatell, Montserrat Plana & Teresa
Gallart

To cite this article: Felipe Garca, Agathe Len, Josep M. Gatell, Montserrat Plana &
Teresa Gallart (2012) Therapeutic vaccines against HIV infection, Human Vaccines &
Immunotherapeutics, 8:5, 569-581, DOI: 10.4161/hv.19555

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Published online: 01 May 2012.

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Human Vaccines & Immunotherapeutics 8:5, 569581; May 2012;
Therapeutic vaccines against HIV infection
Felipe Garca,* Agathe Len, Josep M. Gatell, Montserrat Plana and Teresa Gallart
Hospital Clinic-HIVACAT; IDIBAPS; University of Barcelona; Barcelona, Spain
Keywords: therapeutic vaccine, dendritic cell, HIV, functional cure, recombinant virus, DNA
Resistance to medication, adverse effects in the medium-to-
long-term and cost all place important limitations on lifelong
adherence to combined antiretroviral therapy (cART). In this
context, new therapeutic alternatives to cART for life in HIV-
infected patients merit investigation. Some data suggest that
strong T cell-mediated immunity to HIV can indeed limit virus
replication and protect against CD4 depletion and disease
progression. The combination of cART with immune therapy
to restore and/or boost immune-specific responses to HIV has
2012 Landes Bioscience.
been proposed, the ultimate aim being to achieve a functional
cure. In this scenario, new, induced, HIV-specific immune
responses would be able to control viral replication to
undetectable levels, mimicking the situation of the minority
of patients who control viral replication without treatment and
do not progress to AIDS. Classical approaches such as whole
inactivated virus or recombinant protein initially proved useful
Do not distribute.
as therapeutic vaccines. Overall, however, the ability of these
early vaccines to increase HIV-specific responses was very
limited and study results were discouraging, as no consistent
immunogenicity was demonstrated and there was no clear
impact on viral load. Recent years have seen the development
of new approaches based on more innovative vectors such as
DNA, recombinant virus or dendritic cells. Most clinical trials
of these new vectors have demonstrated their ability to
induce HIV-specific immune responses, although they show
very limited efficacy in terms of controlling viral replication.
However, some preliminary results suggest that dendritic cell-
based vaccines are the most promising candidates. To improve
the effectiveness of these vaccines, a better understanding of
the mechanisms of protection, virological control and immune
deterioration is required; without this knowledge, an effi-
cacious therapeutic vaccine will remain elusive.
Introduction
Combined antiretroviral therapy (cART) has become one the best
tools to control HIV infection at both the individual1 and social
level.2,3 Indeed, cART has achieved impressive reductions in
morbidity and mortality among patients with advanced human
immunodeficiency virus (HIV).1 However, despite these advances
in infection control, the cost of medication, the mandatory high
*Correspondence to: Felipe Garca; Email: fgarcia@clinic.ub.es
Submitted: 11/17/11; Revised: 01/21/12; Accepted: 02/01/12
http://dx.doi.org/10.4161/hv.19555
www.landesbioscience.com Human Vaccines & Immunotherapeutics
REVIEW
G 2012 Landes Bioscience
adherence to medication for life, side effects4 and the risk of
development of resistance remain unsolved problems. Further-
more, the HIV epidemic has severely hampered economic growth
in developing countries. Although the number of HIV-infected
patients under treatment in these countries has increased steadily
in recent years, and although the number of new HIV infections
has fallen, the demand for treatment continues to rise.5 In fact, the
number of new infections is still higher than the number of new
patients on treatment. For economic, social, cultural and political
reasons, widespread treatment is difficult to implement in these
countries. Given this situation, there is a need for new therapeutic
alternatives to cART for life in HIV-infected patients.6
Two such alternatives which have been proposed are eradica-
tion and functional cure.7 There is one report of an HIV-infected
patient in whom viral replication remained absent, despite dis-
continuation of antiretroviral therapy, after transplantation with
CCR5D32/D32 stem cells.8 Recently published follow-ups of this
patient strongly suggest that cure of HIV has been achieved.9
Intensification of cART,10 stem cell therapy,11 gene therapy12 and
the elimination of latently infected cells are other alternatives to
eradication which are currently being assessed.7 However, it is
unlikely that therapeutic strategies leading to eradication will
emerge as a valid alternative to cART, and in fact, there are no
biological models to support this approach. Conversely, the con-
cept of functional cure, defined as control of HIV replication
without cART, is based on the observation that a small propor-
tion of HIV-infected patients (referred to as long-term non-
progressors or elite controllers) are able to control HIV replication
to below detectable levels, and without abnormalities in CD4 T-
cell counts, for more than 25 y. It has been proposed that the
strong HIV-specific immune responses observed in these patients
could account for this natural functional cure. Specifically,
control of viral replication has been associated with HLA types
B*57:01, B*27:05 and B*14, and it has been proposed that the
viral peptides presented by these HLA molecules induce strong
HIV-specific CD8 T-cell responses which are responsible for viral
control.13,14 These findings prompted the development of new
strategies based on the use of anti-HIV vaccines to induce high
frequencies and breadth of response of HIV-specific CD8 cyto-
toxic T lymphocytes (CTLs), together with strong CD4 T-cell
help, in HIV-infected patients.15,16 Recent reports suggest that
a strong T cell-mediated immunity to HIV can indeed limit
virus replication and protect against CD4 depletion and disease
progression.17 Here we will review the basis of the therapeutic
vaccine strategy and the different candidates tested in human
clinical trials.
569
 Pathogenic Basis for a Therapeutic Vaccine Design
HIV-specific responses against HIV infection in antiretroviral
naive patients. The main question to be answered here is whether
the immune system can contain viral replication without cART,
even if only for limited periods. One major problem is that the
types of immunological responses which are able to control viral
replication are not known, although it does seem that the
relevance of the different response types changes with the stage of
HIV infection. Barouch et al. recently published the results of a
preventive vaccine which suggest that protection against infection
is mediated mainly by antibodies against env, whereas post-
infection control of viral replication is associated with cellular
responses against gag.18 Recent data reported by Pickers group in
relation to SIV-infected rhesus macaques suggest that the induc-
tion of effector memory T-cell responses (and not central memory
T-cell responses) with a CMV-vectored vaccine is essential for
control of viral replication.19
Anti-HIV-1 CTL responses have been detected in all studied
2012 Landes Bioscience.
cases of acute HIV infection, and it is believed that they reduce
the peak plasma viral load (PVL) to the stabilization level (set-
point) of PVL which is reached at the end of the acute phase.20,21
It has therefore been hypothesized that CTL play an essential role
in controlling viral replication during acute infection. However,
it is not clear that neutralizing antibodies contribute to the con-
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trol of viral replication during acute infection, since a delay in
the development of these antibodies is observed which is not
associated with changes in viral replication.22 Finally, and in
contrast to CTL and neutralizing antibodies, a clonal depletion
of HIV-specific CD4+ T cells occurs during acute HIV infection.
It has been suggested that the lack of response of these cells is
key to explaining the failure to control viral replication during
this phase.20,21 In fact, massive infection and loss of memory
CD4+ T cells occur in multiple tissues during acute infection,23
and HIV mainly infects HIV-specific CD4+ T cells.24 These
findings may provide a basis for explaining why a therapeutic
vaccine-induced transient activation of HIV-specific CD4but
not CD8T cells might have a detrimental effect on HIV
replication,25 and could offer important clues for the future design
of therapeutic vaccines.
Some data suggest that strong T cell-mediated immunity to
HIV can indeed limit virus replication and protect against CD4
depletion and disease progression in chronic HIV-infected
patients. Although in most infected patients replication leads to
the progressive destruction of the immune system and evolves
inevitably toward AIDS, a small number of immunologically
privileged individuals, or long-term non-progressors (LTNP),
have a potent and sustained response of anti-HIV-1 CTL, Th
cells and neutralizing HIV-1 antibodies. This is associated with
control of viral replication and the presence of very low or
undetectable viral concentrations in plasma in the absence of
cART.20 Direct data on the critical role of the CTL response
in controlling viral replication have been obtained in both the
infection model with macaques devoid of CD8+ T lympho-
cytes,26,27 and in the immunodeficient murine model.28 In addi-
tion, there is clear evidence from both human17,29 and animal
570 Human Vaccines & Immunotherapeutics
models30 that a specific helper T response against HIV is crucial in
obtaining an optimal, specific CTL response which can control
viral replication. This is consistent with other reported data on
chronic viral infections in murine models.31 Finally, studies in
animal models have shown that high levels of neutralizing anti-
bodies can block infection regardless of the route of exposure
to the virus.32 It has also been reported that plasma virus con-
tinually and rapidly evolves to escape neutralization, indicating
that neutralizing antibodies exert a level of selective pressure. It is
probable that neutralizing antibody responses account for the
extensive variation in the envelope gene observed in the early
months after primary HIV infection.33
Despite the relevance of HIV-specific immune responses in
both the acute and chronic stages of infection these responses
are not, in most patients, able to control viral replication to
undetectable levels and prevent the infection from progressing to
AIDS. Many authors hypothesize that selective escape from CD8+
T-cell and other immune responses is the main reason for the
failure to control HIV replication.34-42 Some studies suggest that
selective escape from CD8+ T-cell responses represents a major
driving force of HIV-1 sequence diversity. Allen et al.35 assessed
the relationship between viral evolution and adaptive CD8+ T-cell
responses in four HIV-infected patients who were studied for five
years after acute infection. Nearly two-thirds of the amino acid
mutations identified in non-envelope antigens were attributable
to CD8+ T-cell selective pressures. The preferential selection of
individual residues for mutation and the repeated selection for
identical mutations observed in this study suggest that there are
significant biochemical constraints on viral evolution. In addi-
tion, some mutations induced by immune-mediated selective
pressures have an impact on viral replication capacity.39,43 These
findings help to decide which epitopes should be used in a
therapeutic vaccine in order to avoid or limit the viral escape to
HIV CTL response.
In addition to viral escape, the lack of control of viral replica-
tion in HIV infection could be secondary to functional defects
of immune responses, which may be explained in terms of
alterations to the immune system. Although CD4+ and CD8+
cells capable of secreting interferon gamma (IFN-gamma) can
be found in most HIV-infected patients, proliferative CD4
responses are normally absent29,44,45 and CD8+ cells have defective
cytolytic activity.46,47,48 One explanation for these functional
deficits of CD4 and CD8 responses could be that the antigen-
presenting functions of the dendritic cells have deteriorated in
these patients, which may contribute to the functional defects
observed in the Th1 and CTL cellular responses.49,50 The absence
of a correct proliferation and expansion of CD4+ responses may,
in turn, influence the lack of cytolytic activity of CD8+ cells.44,51
In animal models there is a clear deficit in the secretion of
cytokines by CD4+ cells, which starts when PVL peaks in primary
infection.52 Lastly, the selective infection of HIV-specific CD4+
cells in infected patients may explain why these responses are
quickly lost in HIV infection.24
In summary, it seems clear that both cellular and humoral
immune responses are critical for correct control of HIV infection.
Viral escape and functional defects in these immune responses are
Volume 8 Issue 5
likely to be the main causes of sustained viral replication in
HIV infection, and constitute the two main problems that a
therapeutic vaccine should solve.
Influence of cART on HIV-specific immune responses. The
benefit of cART on the immune system is obtained through
an increase in the absolute number of circulating naive CD4
T lymphocytes, a concomitant reduction in the number of T
lymphocytes with activation markers, and restoration of the
response to memory antigens.53 However, despite the clinical
efficacy of cART54,55 this treatment by itself is unable to eradicate
the infection, even if it were administered for more than 60 y.56,57
This is mainly due to the fact that therapy cannot eliminate latent
HIV-1 in the form of integrated proviral DNA, as well as to the
existence of low levels of viral replication, which makes even
cell-to-cell infection possible.58,59 Furthermore, cART is incapable
of restoring the immune-specific response to HIV,17,45 and, in
fact, it leads to a fall in the specific CTL response due to the
lack of antigenic exposure.60 Some reports have shown that the
helper proliferative response to HIV p24 Ag presented by some
2012 Landes Bioscience.
cART patients does not reflect an improvement in the immune
phenotype or function of CD4 or CD8 cells, but in fact is
secondary to the small increases in viremia typically observed in
patients taking cART.61 This would explain the rapid rebound
of viral load that occurs within days or weeks of suspending
cART, even after several years of effective therapy.62,63 This
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rebound occurs even if cART is initiated in very early-stage HIV-
infected patients, in whom the immune system is theoretically
still well preserved (circulating CD4+ T lymphocytes above
500 cells/mL; PVL: 5,00010,000 copies/ml). Similarly, these
viral dynamics occur even when immune restoration is practically
complete in terms of the homeostasis of T lymphocytes and their
subpopulations, as well as in terms of the capacity for response
to polyclonal stimuli and memory antigens with cART.62,64
Taken together these data suggest that the first challenge for a
therapeutic vaccine is to demonstrate that it is possible to induce
de novo HIV-specific responses that are able to control viral
replication, albeit only partially. If this is the case, it would be
a proof of concept that would justify further investigation of
different immunotherapies.
Therapeutic Vaccines
Objectives of a therapeutic vaccine. The main objective of a
therapeutic vaccine is to induce or increase immune responses
against HIV infection using a planned exposure to HIV viral
antigens. In the ideal scenario, these responses would control viral
replication to an undetectable level, mimicking the situation of
the minority of patients who control viral replication without
treatment and do not progress to AIDS. This has been termed
functional cure and it is observed in most other infections (e.g.,
herpes or tuberculosis). Previous research has suggested that
partial control of viral replication could be enough to delay the
initiation of cART in antiretroviral naive patients or to offer
drug holidays in already-treated patients. However, the current
knowledge of HIV pathogenesis precludes this partial remission
of infection from being a conceivable clinical objective. Even
www.landesbioscience.com Human Vaccines & Immunotherapeutics
antiretroviral naive patients with a normal CD4 T-cell count
could be at higher risk of suffering non-AIDS events (cancer,
cardiovascular or neurological events) than the general popu-
lation.65-67 In addition, it seems that the early initiation of
antiretroviral therapy significantly improves survival, as compared
with deferred therapy.68 Furthermore, the discontinuation of
antiretroviral therapy in order to reduce drug-related adverse
effects and to improve the patients quality of life has been
shown to be associated with increased morbidity and mortality.69
It has been suggested that immune activation due to viral load
rebound after ART interruption would explain this increase in
the rates of AIDS-defining and non-AIDS-defining malignancies
or cardiovascular events among patients who discontinued
cART. Untreated HIV infection is characterized by a profound
and continuous state of immune activation manifested by an
increased turnover of B and T lymphocytes, natural killer cells
and a high level of pro-inflammatory cytokines such as IL-7 and
TNF-a.70 Another relevant feature is the elevation of activated
CD8+ T-cells expressing the DR+/CD38+ phenotype, which is
considered as a surrogate marker of disease progression.71,72
Systemic immune activation could lead, first, to exhaustion of
the immune system, including lymph node fibrosis,73,74 retention
of effector T cells in lymph nodes,75,76 clonal exhaustion and
thymic dysfunction. In addition, it could contribute to the
spreading of HIV infection by generating more targets for HIV,
thereby allowing ongoing HIV replication.24 In summary, partial
control of viral replication remains deleterious for HIV-infected
patients, and the objective of a therapeutic vaccine should be
complete remission of infection. Nonetheless, if a therapeutic
vaccine were shown to be capable of partially controlling viral
load this would be a proof of concept justifying further
investigation of new candidates.
A second objective has recently been proposed for therapeutic
vaccines.7 Based on data related to the eradication of HIV in the
Berlin patient8,9 it has been suggested that the combination
of cART intensification with a vaccine able to induce effective
HIV-specific responses could purge the HIV reservoir. This
strategy, together with others using different drugs or gene
therapy, is already being assessed in clinical trials.7
Types of therapeutic vaccines. Most of the therapeutic vac-
cines tested have previously been used as preventive candidates.
Classical approaches such as whole inactivated virus (REMUNE)
or recombinant protein (gp120) were initially shown to be useful.
In general, however, the capacity of these early vaccines to increase
HIV-specific responses was very limited and study results were
discouraging, as no consistent immunogenicity was demonstrated
and there was no clear impact on viral load.77,78-81,82-89 Recent
years have seen the development of new approaches based on
more innovative vectors such as DNA, recombinant virus or
dendritic cells. Most of the clinical trials involving these new
vectors have been exploratory and with a low number of patients.
In fact, in randomized studies no therapeutic vaccine has yet to
demonstrate lasting and potent effectiveness in terms of con-
trolling viral load, improving CD4 T-cell count or delaying
clinical progression. These weak results have precluded further
development. Although a great number of candidates have been
571
Table 1. Therapeutic vaccine clinical trials
References Immunogen Virological responses Immunogenicity responses
Whole inactivated vaccine
8790 Remune: inactivated whole virus. No clinical benefits Induction of gag-specific helper responses
Subunit vaccines
91100 Recombinant envelope protein No clinical benefits Improvement in specific lymphocyte proliferation
101103 HIV p24-like peptides (Vacc-4x) No clinical benefits Induction of HIV-associated specific responses
in 90% of patients
104106 Tat protein Not assessed Induction of Tat-specific T helper cell responses
Consistent decrease in cellular and biochemical
activation markers
Persistent increases in regulatory T cells
Stable increases in the percentage and absolute
numbers of both CD4 T cells and B lymphocytes
Reduced percentage of CD8 T cells and NK
lymphocytes
107 A combination of Nef-Tat fusion protein and envelope Not assessed Induction of strong gp120-specific
glycoprotein gp120 formulated with AS02A adjuvant CD4+ T-cell responses.
Induction of HIV-1-specific CD4+ T cells and CD8+

2012 Landes Bioscience.

T-cell proliferation
Vaccines using DNA as a vector
111, 112 DNA constructs encoding the nef, No clinical benefits Induction of HIV-1-specific cellular responses
rev or tat regulatory genes of HIV-1
113 DNA encoding env/rev and gag/pol genes Reduction of viral blips Poor capacity to boost virus-specific CD4
and CD8 T-cell responses

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114 DNA encoding HIVA, an immunogen comprising
HIV-1 clade A p24/p17 fused to a string of cytotoxic
T-cell epitopes
115, 116 DermaVir, a single plasmid DNA (pDNA) immunogen
expressing 15 HIV antigens formulated in a
nanoparticle developed for topical application
Viral vector vaccines
124 ALVAC-HIV vCP1452 [expresses HIV-1 env and gag
gene products and nef and pol gene products
encompassing known human HLA-A2restricted
cytotoxic T cell (CTL) epitopes from these genes]
with Remune
77, 125 ALVAC-HIV vCP1452 and recombinant gp160
129 ALVAC-HIV vCP1452
25, 130 ALVAC vCP1452
131 ALVAC vCP1452 with Remune
126, 132 ALVAC-HIV vCP1433 (expresses several HIV genes
for gp120, gp41, 55 polyprotein, for a portion of pol lowered their viral set-point
encoding the protease and for genes expressing
cytotoxic T lymphocyte peptides from pol and nef)
with Lipo-6T vaccine (a mixture of the tetanus toxoid
TT-830843 class II-restricted universal CD4 epitope
combined with some peptides of Gag, Nef and Pol) and
followed by three cycles of subcutaneous interleukin-2
Not assessed
No clinical benefits
No clinical benefits
No clinical benefits
No clinical benefits
Increased virus production
following treatment interruption
Tended to delay viral load rebound
Associated with a longer time to
meet pre-set criteria to restart ART
24% of the Vac-IL-2 group
compared with 5% of controls
Poor capacity to boost virus-specific CD4
and CD8 T-cell responses
Induction of HIV-specific immune responses
Significantly increased HIV-1-specific CD4(+)
and CD8(+) T-cell responses
Significant increases in anti-gp120
or anti-p24 antibody titers,
Transient augmentation of T-cell
proliferation responses to gp160 and/or p24.
Increased HIV-1-specific CD8 T cells
Modest increases in the median
lymphoproliferative response
Weakly immunogenic, inducing activated
CD4 T-cell responses
Induction of HIV-specific cells,
not correlated with viral load rebound
Vaccine-elicited immunological responses
predictive of virological control

572 Human Vaccines & Immunotherapeutics Volume 8 Issue 5

Table 1. Therapeutic vaccine clinical trials (continued)
Viral vector vaccines
128 ALVAC-HIV vCP1433
133 Fowl pox vector containing gag/pol sequences or
fowl pox vector containing gag/pol sequences and
a gene which encodes human interferon gamma
140 HIV-1 nef-expressing MVA
141143 MVA expressing HIV-1 gag p24, p17
and a CD8+ T cell epitope string
144, 145 Recombinant adenovirus serotype 5 HIV-1 gag
Dendritic cell-based vaccines
162, Heterologous peptides or ALVAC-HIV-1 vCP1452167
2012 Landes Bioscience.
165168
163, 164, Autologous whole inactivated HIV or RNA encoding
169171 CD40L and autologous HIV-1 antigens169,171
used in clinical trials, this review will focus on those summarized
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in Table 1.
Remune. The Remune vaccine initially aroused considerable
expectation. This is a vaccine of an inactivated whole virus in
which the envelope protein has been removed during the process
of inactivation, which is performed by synthesis and formulated
with incomplete Freund adjuvant. The vaccine stems from a virus
originally obtained in Zaire and contains a type-A envelope and
type-G gag. It has been administered to more than 3,000 people
with an antiviral-controlled virus. The results showed that it was
able to induce gag-specific helper responses which were sometimes
very potent, but did not suggest a capacity for immunological
control of viral replication.87-90 The best and most extensive study
aimed to determine whether the addition of Remune would
confer added clinical efficacy to that achievable by cART. This
was a multicenter, double-blind, placebo-controlled, randomized
trial conducted at 77 centers in the United States, and involved
2527 cART-treated, HIV-infected patients with a CD4 T-cell
level between 300 106/L and 549 106/L. There were no
differences in HIV progression-free survival, changes in HIV
RNA or CD4 cell counts when comparing Remune and placebo
recipients.89
Subunit vaccines. Multiple strategies have been used to design
therapeutic HIV vaccines based on peptides or recombinant
proteins, including vaccination with a recombinant envelope
protein,91-100 HIV p24-like peptides (Vacc-4x),101-103 a Tat
protein104-106 and a combination of Nef-Tat fusion protein and
envelope glycoprotein gp120 formulated with AS02A adjuvant.107
The basis for the use of these candidates is that a therapeutic
HIV vaccine that induces HIV-1-specific CD4+ T-cell responses
could improve antiviral immunity, resulting in delayed disease
progression.
www.landesbioscience.com Human Vaccines & Immunotherapeutics
Prolongation of treatment Significantly increased HIV-p24-specific
discontinuation lymphoproliferative responses,
HIV-gag-specific CD8 T cells boosted
in 55% of patients tested
No clinical benefits No differences in anti-HIV-specific immune
responses between placebo and vaccine study arms
After interruption of cART viremia Recognition of new CTL epitopes
remained below the pre-cART
viral load in 9/14 patients
Not assessed Significantly increased the frequencies of
CD8+ and CD4+ T cells secreting IFN-gamma
Enhanced proliferative responses to gag peptides
Reduction of 0.5 log10 Induction of HIV-1 gag-specific CD4 cells correlated
of PVL after a 16-week ATI o with control of viral replication in vivo
No change in median VL Induced novel epitope-specific CD8 T cells
and/or CD4 T cells
Median VL drop 0.50.7 log, Increased HIV-specific CD8/CD4 (ELISPOT/ICS)
maintained 48 weeks and correlated with VL changes
A number of clinical trials using recombinant gp120 or gp160
as immunogens have been performed both in combination and
without antiretrovirals.91-100 Overall, these trials have not demon-
strated clinical benefit, although an improvement in specific
lymphocyte proliferation is observed in some of them.
Vacc-4x consists of four synthetic peptides corresponding to
conserved domains of the HIV-1 protein p24 that preferentially
include HLA-A2 restricted elements. To ensure optimal exposure
of the immunogen to antigen-presenting cells (APCs) the vaccine
was given intradermally together with granulocyte-macrophage
colony-stimulating factor (GM-CSF).101 Forty HIV-infected
patients on cART were vaccinated with either low-dose or high-
dose Vacc-4x over 26 weeks. HIV-associated specific responses
were safely induced in 90% of patients in a dose-dependent
manner and were influenced by the HLA haplotype.103 There-
after, cART was discontinued in patients for 14 weeks. Patients
with the strongest delayed-type hypersensitivity (DTH) responses
before treatment interruption tended to achieve lower actual
HIV RNA levels.101 Finally, long-term HIV-specific immune
responses and clinical outcomes were evaluated. Vacc-4x-induced
cellular immune responses were unchanged 1.5 y after completing
immunization, and 62% of patients were still off cART.102
Based on efficacy studies in animal models108 and those
suggesting that the presence of an anti-Tat immune response
correlates with a slower progression to disease,109 some authors have
proposed that a preventive and therapeutic Tat protein-based
vaccine deserves to be investigated. The first randomized, double
blind, placebo-controlled phase I vaccine trial based on the native
Tat protein was conducted in HIV-infected asymptomatic
individuals.106 The vaccine was well tolerated and induced and/or
maintained Tat-specific T helper cell responses in all subjects, with
a wide spectrum of functional anti-Tat antibodies. In addition,
573
2.5 y after the last immunization Tat-specific humoral and cellular
immune responses were still detectable in vaccinees.105 These data
provided the basis for a phase II study in 87 successfully-treated
HIV-infected patients, the results of which have recently been
reported.104 It was confirmed that immunization with Tat was safe
and immunogenic. In addition, there was a consistent decrease
in cellular and biochemical activation markers and persistent
increases in the number of regulatory T cells. This was associated
with stable increases in the percentage and absolute numbers of
both CD4 T cells and B lymphocytes, as well as with a reduction
in the percentage of CD8 T cells and NK lymphocytes. The
authors concluded that Tat immunization in patients on cART
could help to restore immune homeostasis. The improvement
in immune system function (as opposed to functional cure) is a
benefit that some other investigators have claimed as an alternative
primary end-point for therapeutic vaccines.90,110 However, the
clinical relevance of the recovery of these parameters is not clear.
Until this issue is clarified, functional cure remains the best objec-
tive for a therapeutic vaccine.
2012 Landes Bioscience.
A clinical trial of the gp120/NefTat/AS02A therapeutic
vaccine in chronically HIV-1-infected volunteers on suppressive
ART found the vaccine to be safe, well tolerated and able
to induce strong gp120-specific CD4+ T-cell responses, and a
higher number of vaccinees developed both HIV-1-specific
CD4+ T-cell responses and CD8+ T-cell proliferation.107
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Therapy interruption to determine whether these immunological
responses might lead to improved control of HIV-1viral load
was not performed.
Vaccines using DNA as a vector. DNA vaccines are based on
bacterial plasmids that express the desired antigen in situ, which
leads to induction of an immune response of the Th1 type. The
first trial, reported in 1998, included nine asymptomatic HIV-1-
infected patients who were immunized with DNA constructs
encoding the nef, rev or tat regulatory genes of HIV-1.111 The
vaccination induced HIV-1-specific cellular responses, but was
not able to control viral replication or change CD4+ T-cell counts.
These results were confirmed with the same candidate in patients
on cART.112 A further two candidates have been tested in HIV-
infected patients on cART, the first encoding env/rev and gag/pol
genes113 and the second encoding HIVA, an immunogen com-
prising HIV-1 clade A p24/p17 fused to a string of cytotoxic
T-cell epitopes.114 These candidates were safe but their capacity
to boost virus-specific CD4 and CD8 T-cell responses was poor.
Given these results, novel means of vaccine delivery have been
proposed for further improvement of DNA vaccine potency.
DermaVir, a single plasmid DNA (pDNA) immunogen expres-
sing 15 HIV antigens, has been formulated in a nanoparticle
with polyethylenimine-mannose and glucose, and has been
developed for topical application to deliver DNA-encoded
antigens into Langerhans cells.115 This candidate has recently
been tested in the context of structured therapy interruption in a
pilot clinical trial.116 Although HIV DNA immunization induces
broader and higher magnitudes of HIV-specific immune res-
ponses compared with structured therapy interruptions alone,
this candidate did not have any effect on the dynamics of viral
rebound, set-point viral load or CD4 T-cell counts.
574 Human Vaccines & Immunotherapeutics
Viral vector vaccines. Given the poor results obtained with
Remune, subunit vaccines and vaccines using DNA as the vector
it has been proposed that outcomes could be improved by using
viral vectors as immunogens. Live recombinant vaccines are made
of a live viral or bacterial vector that is engineered to carry the
genes that encode HIV antigens. The antigens are presented on
the surface of the cell as externalized peptides in the context of
MHC class I molecules, thus priming for CD8+ T-cell responses.
The best studied vaccine vectors in humans are the pox viruses.117
Vaccinia virus engineered with HIV-1 genes has been shown to
induce virus-specific cellular and humoral immune responses in
immunized macaques, as well as protection against simian
immunodeficiency virus (SIV) infection when immunization
with such constructs has been followed with boosting by
recombinant proteins. However, due to the development of
life-threatening disseminated vaccinia infections in immuno-
suppressed individuals there is a reluctance to use replication-
competent vaccinia virus as a vector system in large human trials.
Particular attention has, however, been focused on pox viruses
with limited in vivo replicative capacity and which, therefore, are
non-pathogenic in animal models and humans118,119; examples
include MVA and NYVAC, which carry deletions of the genes
associated with pathogenicity, or avian pox viruses (canary pox
and fowl pox). These vectors are restricted to the early stages of
virus replication in human cells but initiate protein synthesis
and thus elicit specific immune responses to the recombinant
antigen.118,120-123
The best studied vector has been canary pox
(ALVAC).25,77,124-128,129-131 The international QUEST study124
was performed on patients who started treatment during the
acute phase. After a mean of two years of virological control,
79 patients were randomized to receive either immunization
with ALVAC-HIV vCP1452, with ALVAC-HIV vCP1452 plus
Remune, or placebo. ALVAC-HIV vCP1452 expresses HIV-1
env and gag gene products and nef and pol gene products
encompassing known human HLA-A2restricted cytotoxic T-cell
(CTL) epitopes from these genes. The choice of vaccine
candidates for this study was dictated by their safety records in
HIV-1-infected subjects and by immunogenicity. The combina-
tion of vaccines in a single treatment arm was selected for its
potential to enhance CD4 T helper cells (Remune) and CTLs
(ALVAC-HIV vCP1452). After 24 weeks immunization, cART
was interrupted. There was no difference between the groups
in terms of viral rebound dynamics or viral load figures. These
results confirm the findings of a previous small randomized
pilot study of HIV-infected patients treated with cART during
acute infection and who received ALVAC-HIV vCP1452 and
recombinant gp160.77,125
Similar results with ALVAC-HIV vCP1452 have been
obtained in chronic HIV-infected patients. The ACTG 5068
included 99 subjects receiving successful cART who were
randomized to undergo continued cART, structured therapy
interruptions (STIs), ALVAC-HIV vCP1452 immunization, or
STIs and ALVAC-HIV vCP1452 immunization. Subjects in the
two STI arms had significantly enhanced immunological control
of HIV replication compared with subjects in the two arms
Volume 8 Issue 5
without STIs. ALVAC-HIV vCP1452 did not affect viral load
measures.129 A separate placebo-controlled study conducted in
chronically-infected patients suggested that the immunogenicity
conferred by the ALVAC vCP1452 candidate vaccine alone could
be deleterious, since it was associated with higher virus production
following treatment interruption.130 Further research suggested
that ALVAC vCP1452 was only weakly immunogenic, it failing
to elicit significant HIV-specific CD8 T-cell responses and
inducing activated CD4 T-cell responses that could favor greater
viral rebound after treatment interruption.25 These results appear
to conflict with those of a clinical trial reported recently by
Angel et al.131 This was a randomized, placebo-controlled, double-
blind study in which effectively-treated HIV-infected individuals
with high CD4 T-cell counts were randomized to receive
ALVAC vCP1452 with Remune, ALVAC vCP1452 alone or
placebo over 20 weeks. At week 24, participants interrupted
cART. ALVAC with or without Remune did not lower the viral
load set-point, although it tended to delay viral load rebound
and was associated with a greater time to meet pre-set criteria to
2012 Landes Bioscience.
restart ART. In contrast to the findings reported by Autran
et al.130 and Papagno et al.25 the induction of helper CD4 T-cell
responses was not associated with a worse virological outcome.
At all events, further research is required to determine whether
the best strategy to induce viral control in chronic HIV-infected
patients should be based on inducing robust and broad CD8
Do not distribute.
T-cell responses but only modestly activating CD4 T-cell
responses.
The best results for a viral vector have been reported with
ALVAC vCP1433 in combination with Lipo-6T vaccines,
followed by three cycles of subcutaneous interleukin-2.126,132
ALVAC-HIV vCP1433 expresses several HIV genes for gp120,
gp41, 55 polyprotein, for a portion of pol encoding the protease
and for genes expressing cytotoxic T-lymphocyte peptides from
pol and nef. The Lipo-6T vaccine is a mixture of the tetanus
toxoid TT-830843 class II-restricted universal CD4 epitope
combined with certain peptides of Gag, Nef and Pol. Chronic
HIV-infected patients were randomized to receive either cART
alone (n = 37) or four doses of ALVAC-HIV vCP1433 and Lipo-
6T followed by three cycles of IL-2 (n = 34). Vaccination
improved the proliferative response against p24 Ag, as well as
CD8 T-cell responses. After cART interruption, 24% of the
Vac-IL-2 group lowered their viral set-point, compared with 5%
of controls. Vaccine-elicited immunological responses were pre-
dictive of virological control. Vaccination with the same product
(ALVAC-HIV vCP1433) in a French clinical trial was safe,
immunogenic and associated with prolongation of treatment
discontinuation.128
A pilot clinical trial of a therapeutic vaccination based on a
fowl pox vector and involving patients with primary infection
has been reported by Emery et al.133 After a mean of four years
of cART, 35 patients with controlled viral replication were
randomized to be vaccinated with a fowl pox vector free of HIV
sequences, a vector containing gag/pol sequences, or a vector
containing gag/pol sequences and a gene which encodes human
interferon gamma. Surprisingly, there were few differences
between the groups in terms of the presence of CTL cells, as
www.landesbioscience.com Human Vaccines & Immunotherapeutics
measured by ELISPOT, or in cytolytic responses after vaccina-
tion and before interruption of treatment. Treatment was not
interrupted in ten patients. There were no differences in the
control of viral replication between the placebo group and the
group vaccinated with gag/pol. However, patients immunized
with gag/pol and interferon gamma had better control of viral
replication, with a mean viral load of 0.8 log10 less than the
other two groups, although the differences between groups were
not significant. The absence of immune responses in the two
vaccinated groups is disappointing, while the response in the
interferon group is surprising and merits further investigation.
The modified vaccinia virus Ankara (MVA) was developed
toward the end of the smallpox eradication campaign in the
1970s, the aim being to obtain a vaccine with a better safety
profile than the ones in use at that time. MVA was dereived
from vaccinia by over 570 passages in chicken embryo fibroblast
cells (CEF).134 The complete genomic sequence has been
sequenced and has a length of 178 kb. It consists of 193 open
reading frames (ORFs), corresponding to 177 genes, of which
25 are split and/or have suffered mutations resulting in truncated
proteins. These numerous mutations, affecting host interactive
proteins and some structural proteins, explain the attenuated
phenotype of MVA.119 There is clinical experience with MVA
as a vaccine against smallpox in over 120,000 people.118,120
During extensive field studies, including with high-risk patients,
no side effects were associated with the use of the MVA
vaccine.118,120 The combination of a very good safety profile and
the ability to deliver antigens in a highly immunogenic way
makes MVA suitable as a vaccine vector. It can stimulate anti-
body and T-cell responses even in the presence of pre-existing
antibodies,135 and it has been shown to be effective in primates
and humans for several viruses, including SIV and SHIV.121,136-139
Harrer et al.140 investigated the safety and immunogenicity of
an HIV-1 nef-expressing MVA in 14 cART-treated HIV-
infected patients. Vaccination with MVA-nef was safe, was
associated with recognition of new CTL epitopes, and after
interruption of cART viremia remained below the pre-cART viral
load in 9/14 patients. In another pilot study, vaccination of 16
HIV-1-infected cART-treated individuals with MVA expressing
HIV-1 gag p24, p17 and a CD8+ T-cell epitope string was
not only safe but also significantly increased the frequencies of
CD8+ and CD4+ T cells secreting IFN-gamma and enhanced
proliferative responses to gag peptides.141-143
Finally, in ACTG A5197, HIV-1-infected individuals who
received a recombinant adenovirus serotype 5 HIV-1 gag thera-
peutic vaccine had a 0.5 log10 lower PVL after a 16-week ATI,
compared with those who received placebo.144,145
In summary, although most viral vector vaccines have been
able to induce HIV-specific immune responses in clinical trials
they have shown very limited efficacy in terms of controlling viral
replication. New therapeutic strategies are therefore warranted.
Dendritic cell-based vaccines. Dendritic cells (DC) are the
most potent professional antigen-processing and presenting cells
(APC), with the unique ability to induce both primary and
secondary immune responses of CD4+ and CD8+ T lympho-
cytes.146,147 A wide variety of data in experimental in vivo and in
575
vitro systems have shown that DC are able to engulf exogenous
soluble proteins, tumor cell lysates, and inactivated virus and
virus-infected apoptotic cells, as well as presenting antigens
not only in the MHC-class II pathway to helper CD4+ T cells
(Th)146 but also in the MHC-class I pathway to cytotoxic
CD8+ T lymphocytes (CTL), a phenomenon also known as
cross-presentation or cross-priming148-150.
In vitro culture of human blood monocytes (MO) with GM-
CSF and IL-4 gives rise to myeloid DC.151,152 Some data suggest
that these human myeloid DC not only activate naive CD4+
T cells but also promote their differentiation into Th1 cells,
preventing the differentiation into Th2.153 In addition, antigen-
pulsed DC secrete antigen-presenting particles (termed exosomes)
which express functional MHC-class I and II and T-cell co-
stimulatory molecules, and they are able to prime CTL in vivo
and eradicate or suppress the growth of established murine
tumors.154 Autologous DC pulsed in vitro with a variety of
inactivated pathogens have also been shown to induce a potent
protective immunity in murine models of human infections.154-158
2012 Landes Bioscience.
All these data indicate that in vitro-generated DC may be the
most potent cellular adjuvant for a vaccine preparation designed
to induce effective Th1 and CTL responses to tumor antigens
and intracellular pathogens.
It has been reported that an inactivated SIV-pulsed therapeutic
dendritic-cell vaccine was able to elicit effective and lasting SIV-
Do not distribute.
specific cellular and humoral immunity. This study found that
after three immunizations administered at two-week intervals the
SIV cellular DNA and the SIV plasma RNA levels decreased by
50-fold and 1,000-fold, respectively. This decrease in viral load
was negatively correlated with SIV-specific T-cell responses.
Neutralizing antibody responses also increased significantly and
remained increased throughout the follow-up period.159 Finally,
two studies in a hu-PBL-SCID mouse model suggest that mice
immunized with inactivated virus-pulsed dendritic cells elicit a
potent immune response against HIV, which protects the animals
from virus challenge.160,161
There are at least ten published clinical trials of DC immuno-
therapy for HIV infection in humans.162-169,170,171 Most of them
found that DC immunotherapy elicited immunological res-
ponses, even though the design of the trials and the HIV antigens
used to pulse DC were very different. It should be noted,
however, that virological responses were only observed in four of
these trials.163,164,170,171
Two of these four trials were performed in untreated
patients. The first was a preliminary, non-controlled, non-
randomized study that showed striking results for a MD-DC-
based vaccine loaded with high doses of chemically-inactivated
(with aldrithiol-2) autologous virus in untreated HIV patients.163
Plasma viral load (PVL) decreased by 90% for at least one year
in eight of 18 patients. This decrease in PVL was associated
with strong and sustained HIV-1-specific cellular responses. The
second trial was a double-blind, placebo-controlled study using
the same schedule and immunizing the same type of patients
(HIV-1-infected patients off cART).170 Only a modest virological
response, which was maintained for at least 48 weeks in the
vaccinated group, was observed.170 This change in VL in the
576 Human Vaccines & Immunotherapeutics
immunized patients was small (ranging from 0.30 to 0.60 log10)
but clinically significant when compared with the placebo group,
and it was maintained up to week 48. However, this small
decrease in VL in immunized patients was inversely correlated
with a weak increase in HIV-1-specific CD8+ T-cell responses.
The other two trials involved antiretroviral-treated patients.
The first was an open, randomized (2:1) clinical trial using heat-
inactivated autologous virus in cART-treated HIV-1-infected
patients, and reported partial and transient control of viral
replication after interruption of antiretroviral therapy.164 In this
study, autologous DC vaccine pulsed ex vivo with heat-inactivated
autologous HIV-1 elicited only weak Th1- and HIV-1-specific
CD8+ T-cell responses. Recently, Routy et al.,171 in an uncon-
trolled study, reported the final results of an immunotherapy
regimen consisting of MD-DC electroporated with mRNA
encoding autologous HIV-1 antigens (Gag, Nef, Rev, Vpr); this
was administered monthly in 33 subjects in four intradermal
doses in combination with cART, followed by two more doses
during a 12-week cART interruption (STI). They found that
eight out of 24 subjects (33%) met the criteria for the primary
endpoint of three instances of viral load , 1,000 copies/mL,
while 11 out of 24 subjects (46%) met the criteria for the
secondary endpoint of three instances of viral load , 10,000
copies/mL. At week 12 of the STI, 16/24 subjects responded with
a mean reduction in viral load of 1.2 log compared with their
pre-cART viral load value. These data are impressive and are
similar to those reported by Lu et al.163 with HIV-1-infected
patients who were vaccinated when treated with cART. These
data need to be confirmed in a randomized, placebo-controlled
study. A review of DC-based vaccine clinical trials has recently
been published.172
Conclusions
Our knowledge of the immunological control of HIV viral
replication and the causes of cellular and humoral immune
deterioration is limited, and we lack immunological methods
able to demonstrate an efficacious immune control of HIV in
vivo. The efficacy of immune therapy and therapeutic vaccines
has been modest in the best of cases, although some pre-
liminary results with dendritic cell-based vaccines seem promis-
ing. Efforts must now be redoubled in order to improve our
understanding of the mechanisms of protection, virological
control and immune deterioration, as without this knowledge
an efficacious therapeutic vaccine remains a long way off. Given
the toxicity and long-term efficacy problems associated with
current drugs the search for therapeutic vaccines must be seen as
a priority line of investigation.
Acknowledgments
This study was partially supported by the following grants: FIS
PS09/01297, TRA-094, EC10153, FIS PI10/02984, SAF2006
26667-E, RIS*, HIVACAT**, ORVACS***. F.G. was recipient
of a research grant from IDIBAPS****, Barcelona, Spain. M.P.
was supported by contract FIS 03/0072 from the Fundaci
Privada Clnic per a la Recerca Biomdica, in collaboration with
Volume 8 Issue 5
the Spanish Department of Health. *Red Temtica Cooperativa
de Grupos de Investigacin en Sida del Fondo de Investigacin
Sanitaria (FIS). **HIVACAT: HIV development program in
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