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Immune response to HIV

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REVIEW

CURRENT
OPINION Immune response to HIV
Matthieu Perreau a, Yves Levy c, and Giuseppe Pantaleo a,b

Purpose of review
Major advances have been made in the delineation of HIV-specific immune response and in the
mechanisms of virus escape. The kinetics of the immunological and virological events occurring during
primary HIV infection indicate that the establishment of the latent HIV reservoir, the major obstacle to HIV
eradication likely occurs during the very early stages of primary infection, that is, the ‘eclipse phase’, prior
to the development of the HIV-specific immune response which has limited efficacy in the control of the
early events of infection. Therefore, the window of opportunity to develop effective interventions either to
clear HIV during primary infection or to prevent rebound of HIV in patients successfully treated who stop
antiretroviral therapy is very narrow.
Recent findings
Genetic factors most strongly associated with nonprogressive infection are human leukocyte antigen (HLA)
class I alleles and particularly HLA-B
5701. CD4 and CD8 T-cell responses with polyfunctional profile are
associated with nonprogressive infection. Broader neutralizing antibodies are detected 3–4 years after
infection, generated only in 20% of individuals but show no efficacy in the control of HIV replication.
Summary
In the present review, we shall discuss the different components of the HIV-specific immune response
elicited by the infection, the kinetics of these responses during primary infection and the changes following
transition to the chronic phase of infection, and the functional profile of ‘effective’ versus ‘noneffective’
HIV-specific immune responses.
Keywords
antibodies, HIV, immune response, T cells

INTRODUCTION immunologically driven, clearance of HIV following

Primary HIV infection (PHI) is characterized by a
transient symptomatic illness (in 40–90% of cases)
associated with high levels of virus replication. In
the large majority (>80%) of infected individuals,
the transmitted virus results from the infection of a
single virus variant as revealed by genome analysis
of viral RNA isolated during PHI [1]. Symptoms are
not specific to HIV but typical of an acute viral
syndrome and may include fever, fatigue, rash,
headache, lymphadenopathy, pharyngitis, myalgia,
arthralgia, aseptic meningitis, retrorbital pain,
weight loss, depression, gastrointestinal distress
night sweats, and oral or genital ulcers [2]. The
symptomatic phase generally lasts for 2–4 weeks
in individuals with ‘normal’ rate of diseases pro-
gression, whereas severe and prolonged symptoms
are associated with rapid disease progression [3,4].
Once chronic HIV infection is established, the
course of HIV disease and progression may be influ-
enced substantially by host (genetic and immuno-
logical) and virological factors [5]. At present, there
have not been reports of spontaneous, that is,
infection. However, a small percentage (1–5% based
on case definition) of HIV-infected individuals
experience stable disease, that is, lack of decline of
CD4 T-cell counts, and control of virus replication
below 1000 HIV RNA copies/ml for an extended
period of time (at least 7–10 years) in the absence
of antiretroviral therapy (ART) [6]. These individuals
are called long-term nonprogressors (LTNPs) [7].
Furthermore, an even smaller percentage (<1%) of
individuals show control of virus replication below
a
Division of Immunology and Allergy, bSwiss Vaccine Research Institute,
Centre Hospitalier Universitaire Vaudois, University of Lausanne,
Lausanne, Switzerland and cINSERM U955, Université Paris Est Créteil,
Faculté de Médecine, Groupe Henri-Mondor Albert-Chenevier, Immuno-
logie Clinique, Vaccine Research Institute, Creteil, France
Correspondence to Matthieu Perreau, Division of Immunology and
Allergy, Centre Hospitalier Universitaire Vaudois, Rue Bugnon 46,
1011 Lausanne, Switzerland. Tel: +41 2 131 41073; e-mail: matthieu.
perreau@chuv.ch
Curr Opin HIV AIDS 2013, 8:333–340
DOI:10.1097/COH.0b013e328361faf4

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 Thirty years of HIV and AIDS
KEY POINTS
 HIV-specific immune response lacks efficacy during
the early stages of HIV spreading during
primary infection.
 Establishment of the latent HIV reservoir occurs prior to
the development of operational immune responses.
 HIV-specific neutralizing antibodies appear to have
limited efficacy in the control of virus replication during
chronic infection.
50 HIV RNA copies/ml regardless of the length of the
time of control and are called elite controllers [6].
Rarely, the control of virus replication in LTNPs can
be explained by the presence of defective virus [8],
and most of them are infected with replication-
competent virus, thus indicating that host factors
predominantly contribute to virus control and pre-
vention of disease progression.
KINETICS OF IMMUNE RESPONSE DURING
PRIMARY INFECTION
In order to discuss the kinetics of the different
components of the immune response elicited by
HIV infection, we will use as a reference the Stages
defined by Fiebig on the basis of the kinetics of HIV
viral RNA and the appearance of an HIV-specific
antibody response [9,10].
Of particular importance is the initial period of
infection defined by the so-called ‘eclipse phase’.
This phase last for 10 days and defines the period
when the virus is not detectable in the plasma [1,11].
Studies performed in rhesus macaques infected with
simian immunodeficiency virus (SIV) [12,13] have
been instrumental to delineate the events occurring
in the ‘eclipse phase’. Virus-infected cells cannot be
detected in the mucosa until 1–3 days after infec-
tion and the first infected cells are resting memory
CD4 T cells expressing CCR5. In addition, submu-
cosal dendritic cells and Langerhans cells uptake the
virus from the mucosa through C-type lectins such
as DC-SIGN [14,15], which binds HIV gp120 with
high affinity [14,15] and internalizes virions and
subsequently expresses them on the cell surface after
the dendritic cells have matured and migrated to
draining lymph nodes where they encounter T cells
[14,16–18]. At 1 week postinfection, that is versus
the end of the ‘eclipse period’, the virus becomes
detectable in the draining lymph nodes where virus
production may be amplified as result of spreading
of infection among activated T cells that have
come in contact with dendritic cells [19,20]. The
environment of the lymphoid tissue is ideal for virus
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replication and spreading due to the large concen-
tration of activated T cells, to the trapping of virions
on the extracellular surface of follicular dendritic
cells [21–23], and to the abundant production of
pro-inflammatory cytokines such as interleukin-1
(IL-1), IL-6, or tumor necrosis factor a (TNF-a) that
highly support HIV replication [24]. The immune
response to HIV at the end of the ‘eclipse phase’ is
stimulated as indicated by the detection of proteins
of the acute phase, by the initial detection of inflam-
matory cytokines resulting from the activation of
the innate immune response [24–26], and likely by
the stimulation of HIV-specific CD4 T cells. During
the ‘eclipse phase’, no effector components of the
immune response to HIV capable of containing
the initial spreading of infection appear to be
operational and after the amplification of the infec-
tion in the draining lymph nodes, HIV viral RNA
becomes detectable in the plasma (Feibig Stage I)
and spreading of the infection to other anatomic
compartments such as the gut-associated lymphoid
tissues (GALTs) occurs [27]. At the end of the ‘eclipse
phase’, HIV begins to spread to the GALT that is
predominantly populated of CD4 CCR5þ memory
T cells. This results in an exponential expansion of
infection, with up to 20% of gut resident CD4 T cells
being infected and 80% depleted [27–31]. The
large depletion of CD4 T cells occurring in the
lymphoid tissues during this stage is indicated by
the detection of a number of markers of apoptosis
such as TRAIL, microparticles containing CCR5,
TNFR2, and soluble FAS ligand as viremia increases
[32]. By week 3–4, the levels of viremia peak (gener-
ally >107 virus particles per ml of plasma) [9] and it
is just at this time that antibody response becomes
detectable.
The first wave of antibody response is predom-
inantly composed of anti-gp41 IgG antibodies,
which form immune complexes with HIV virions
[33]. Immune complexes have been found in the
large majority of individuals (90%) during PHI, but
only a minority (about 20%) of virions was opson-
ised by anti-gp41 antibodies and forming immune
complexes [33]. The anti-gp41 antibodies bind
both infectious and noninfectious virions and lack
neutralizing activity [33]. Anti-gp120 antibodies
represent a minor component of the antibody
response during PHI while become the dominant
anti-Env antibody response after the transition to
the chronic phase of infection. As viremia peaks and
following initial decline, antibodies specific to the
other HIV proteins such as Gag are detected by week
3–4 of infection (Feibig Stages III/IV). Taken
together, the above observations indicate that the
antibody response during PHI has no efficacy in the
containment of HIV replication and spreading.
Volume 8  Number 4  July 2013

HIV-specific CD8 T-cell response is detected
during the increase in viremia levels and generally
peaks 1–2 weeks after viremia peak and the peak in
CD8 T-cell response coincides with the decline in
viremia levels [34,35]. The first wave of CD8 T-cell
response is directed predominantly against Env and
Nef HIV proteins. The initial CD8 T-cell response
appears to have limited or no effect on HIV repli-
cation as indicated by the persistence of a homo-
geneous founder virus without evidence of
immune-driven selection of virus escape mutants
[36]. It is only at the time of the peak CD8 T-cell
response and the decline of viremia that numerous
amino acid mutations occur in epitopes of the
founder virus recognized by CD8 T cells [36]. No
mutations are observed in the escape mutants [36].
The initial CD8 T-cell response is associated with a
massive expansion of HIV-specific CD8 T cells [37].
Despite the massive expansion, the initial CD8
T-cell response has likely limited efficacy in the
control of virus replication because of the rapid
emergence of virus escape mutants and of the rapid
disappearance of the responding CD8 T-cell clones
due to the lack of recognition of the escape mutants
or of exhaustion resulting from high virus/Ag load
[36,38].
In the absence of ART, the levels of viremia start
to decline around week 4 after infection in order to
reach the ‘virologic’ set point generally 12–16 weeks
after infection, which marks the transition of the
infection to the chronic phase [39]. The contri-
bution of the immune response to the decline of
viremia is only partial and predominantly mediated
by HIV-specific cytotoxic CD8 T cells that may kill
HIV-infected CD4 T cells. However, a major mech-
anism of the decline may be the lack of cell targets,
that is, CD4 T cells, for HIV due to the large
depletion of CD4 T cells through direct virus cytho-
pathic effect, killing by CD8 T cells and activation-
induced cell death. There is no evidence that the
antibody response plays any role in the partial sup-
pression of the decline of viremia and establishment
of the ‘virologic’ set point.
ANTIBODY RESPONSE
Neutralizing antibodies against autologous virus are
detected in a large proportion of HIV-infected indi-
viduals about 3 months after infection [40] and their
appearance is associated with the emergence of
mutations in the Env region [41,42]. Neutralizing
antibodies with broad neutralizing activity are
generated only in a minority (about 20%) of indi-
viduals and appear 2–4 years after infection, but
there is no evidence of their efficacy in the control of
viremia [43–45]. The number of human antibodies
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Immune response to HIV Perreau et al.
with a broad neutralizing activity against a wide
range of virus isolates [46–53] remains limited
and the majority of neutralizing antibodies has
narrow breadth [54].
Numerous phenotypical and functional abnor-
malities of the B-cell compartment have been
described in HIV-infected individuals [55]. These
abnormalities include abnormal B-cell activation
[56], appearance of transitional immature B cells
and exhausted B cells [57,58], and progressive loss
of recall responses to vaccination [59].
Passive administration of neutralizing anti-
bodies in nonhuman primates showed protection
against SIV challenge, but was dependent upon the
titer and the quality of the antibodies [60,61]. In
particular, the injection of a cocktail of neutralizing
antibodies was able to prevent SIV infection after
mucosal virus challenge [62–67]. However, B-cell
depletion in monkeys with chronic SIV infection
does not influence the levels of plasma viremia [68],
thus suggesting that B cells have limited protective
role during chronic infection.
Slow progression of HIV disease has been found
to be associated with high titers of anti-p24 anti-
bodies [69], with neutralizing antibodies directed
against autologous virus [70], or with antibodies
against certain gp120 epitopes [71]. Antibodies with
broader neutralizing activity have been found more
frequently in LTNPs [72–76]. However, it is unclear
whether these antibody responses reflect mechan-
isms of protection or rather the integrity of the
immune system in LTNPs.
Finally, mucosal HIV-specific immunoglobulin
A (IgA) response has been detected in HIV-exposed
uninfected individuals [77]. These IgA may prevent
potentially HIV transcytosis through the epithelium
[78]. IgA antibodies specific for the gp120-CD4-
binding site have also been detected in LTNPs [79].
THE ROLE OF CD8 T-CELLS IN VIRUS
CONTROL
CD8 T cells play a critical role in antiviral immunity
[34,35,80–84]. There are a number of observations
underscoring the importance of HIV-specific CD8
T cells in the control of virus replication and preven-
tion of disease progression in HIV-infected indivi-
duals. These include the rapid loss of control of virus
replication after CD8 T-cell depletion in SIV-infected
monkeys [80,81,85], the decline of viremia during
PHI coinciding with the peak of CD8 T-cell response
[35], the presence of CD8 T-cell responses in exposed
uninfected individuals [86–89], and the association
between protection and HIV-specific CD8 T-cell
responses restricted by certain human leukocyte
antigen (HLA) class I alleles [90,91].
www.co-hivandaids.com 335
 Thirty years of HIV and AIDS
CD8 T-cell responses from elite controllers
compared to progressors have superior capacity to
secrete multiple cytokines and chemokines (poly-
functionality), particularly IL-2 [92], to proliferate
[93], to inhibit HIV replication in vitro and kill target
cells [83,94], to express perforin and degranulate
upon HIV-specific stimulation [95–98], and to tar-
get Gag epitopes [99,100]. CD8 T-cell responses from
elite controllers also inhibited HIV replication with-
out prior activation in vitro, thus suggesting the
presence of a pool of CD8 T cells with immediate
or rapidly inducible antiviral effector function
[92,101–105]. Efficient viral suppression in vitro
is predominantly mediated by CD8 T cells specific
to Gag rather than Env or Nef [106,107], consist-
ently with the observed protection associated with
Gag-specific CD8 T-cell responses detected ex vivo
[99].
THE ROLE OF CD4 T-CELLS IN VIRUS
CONTROL
Memory CD4 T cells are the primary targets of HIV
[108], and massive depletion of CD4 T cells, particu-
larly of HIV-specific CD4 T cells [109], occurs during
PHI. Long-term ART only partially restores the pool
of total and HIV-specific memory CD4 T cells
[27,28,110,111].
HIV-specific CD4 T cells harbor a skewed func-
tional profile associated with a reduced IL-2 pro-
duction and proliferation capacity [95,112,113].
This functional impairment was later associated
with the expression of coinhibitory molecules [pro-
grammed death 1 [114–116], cytotoxic T lympho-
cyte antigen 4 (CTLA-4) [117]]. Interestingly, a
recent study highlighted the functional impairment
of follicular helper T cells (Tfh) as responsible for
inadequate B-cell help, which may explain some of
the functional abnormalities in the B-cell functions
&&
observed in HIV infection [118 ]. In this regard, it
has been recently shown that Tfh serve as the major
cell reservoir for HIV, which, in turn, may be respon-
&&
sible for their functional impairment [119 ].
Several evidence underscore the importance of
CD4 T-cell responses in the control HIV [120]. These
include the enrichment in LTNPs and elite con-
trollers of polyfunctional HIV-specific CD4 T cells
and preservation of proliferation capacity [84,121–
125], the greater production of IL-21 by HIV-specific
CD4 T cells in HIV controllers [126,127], the presence
of HIV-specific CD4 T cells with higher functional
avidity and T-cell receptor-binding affinity in LTNPs
[128], the association of some HLA class II alleles with
lower viral loads [129,130], and the lower expression
of CTLA-4 and other exhaustion markers in HIV-
specific CD4 T cells in LTNPs [117].
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The superior efficacy of CD8 T cells from elite
controllers might also reflect the preservation of the
CD4 TCM-cell compartment and of proliferation
capacity, which was observed in elite controllers
as compared to untreated and treated chronically
HIV-infected individuals [121,122,128,131].
In addition, CD4 T cells from elite controllers do
not show signs of immune exhaustion such as loss of
polyfunctionality and expression of coinhibitory
molecules [117,132]. Therefore, these cells are able
to secrete IL-2, IL-21, and possibly other cytokines
needed to help CD8 T cells in developing and main-
taining their effector functions as well as their pro-
liferation capacity and survival [101,121,122,133].
THE ROLE OF HLA ALLELES IN CONTROL
Whole-genome analysis has demonstrated that
the genetic factors most strongly associated with
nonprogressive infection are HLA class I alleles
and the activating killer cell Ig-like receptor (KIR)
allele KIR3DS [90,134–141]. In particular, the HLA-
B
5701, HLA-B
5801, and the HLA-B
2705 are
associated with slow disease progression, whereas
HLA-B
35 with faster disease progression [139,142].
Protective CD8 T-cell responses restricted by HLA-
B
5701 and HLA-
B27 recognize the following
immunodominant Gag epitopes: TSTLQEQIGW
(TW10), KAFSEPVIPMF (KF11), ISPRTLNAW (IW9)
restricted by HLA-B
5701, and KRWIILGLNK (KK10)
restricted by HLA-B
27 [138,143]. The low viremia is
associated with high rate of sequence mutation
(reflecting the immunological pressure exerted on
epitopes restricted by HLA-B
57), induction of virus
variants with reduced replication capacity, and the
ability to recognize epitopes with escape mutations
[144,145]. The effect of HLA-B on disease outcome
seems to be mediated in part by the amino acid
position located in the peptide-binding groove,
suggesting a difference in the conformation of the
peptide presentation [90]. Indeed, intrinsic differ-
ences in self-peptide binding among HLA molecules
are important during T-cell repertoire development.
As fewer self-peptides are able to bind to HLA-B
57
molecules, fewer CD8 T cells restricted by this HLA
will undergo negative selection. HLA-B
57-restricted
CD8 T cells have higher tolerability for epitope
mutations: several mutations in the peptide recog-
nized do not abrogate the recognition capacity by
T cells. These observations explain also the associ-
ation between HLA-B
57 and control of hepatitis C
virus (HCV) infection and the association between
HLA-B
57 and HLA-B
27 and enhanced risk of auto-
immunity [146–148]. Along the same line, KK10-
specific CD8 T-cell clones isolated from elite con-
trollers expressing HLA-B
27 were characterized by
Volume 8  Number 4  July 2013

complementarity determining regions 3 (CDR3)
sequences significantly closer to germline sequen-
ces, superior ability to control virus replication
in vitro, and superior cross-reactivity than KK10-
specific CD8 T-cell clones isolated from progressors
[105].
CONCLUSION
HIV-specific T-cell and antibody responses have
been extensively characterized in HIV infection.
Despite the fact that the magnitude of these
responses is orders of magnitude greater as com-
pared to those elicited by other viruses establishing
chronic infections, HIV-specific responses fail to
effectively control HIV replication and disease pro-
gression in the absence of ART in the large majority
(>95%) of HIV-infected individuals. Several genetic
factors and functional profile of the HIV-specific
immune response (particularly in the T-cell
response) are associated with protection in LTNPs
and elite controllers. These observations together
with the recent identification of Tfh cells as the
major cell reservoir for HIV infection may guide
the future development of therapeutic interven-
tions aimed at the development of strategies that
may either stimulate effective T-cell immunity or
efficiently target the major HIV cell reservoir, that is,
Tfh cells.
Acknowledgements
None.
Conflicts of interest
The authors declare no conflict of interest.
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