mechanisms of hiv-1 escape from immune responses and antiretroviral drugs
TRANSCRIPT
Mechanisms of HIV-1 escape from immune responses andantiretroviral drugsJustin Bailey, Joel N Blankson, Megan Wind-Rotolo and Robert F Siliciano�
Despite the fact that HIV-1 induces vigorous antiviral immune
responses, viral replication is never completely controlled in
infected individuals. Recent studies have provided insight
into the mechanisms by which focused immune pressure
directed at particular B or T cell epitopes leads to the rapid
appearance of escape mutations. Even if anti-HIV-1 immune
responses could be enhanced to the point where they inhibit
viral replication to the same extent as certain combinations
of antiretroviral drugs, eradication would be unlikely because
of the persistence of the virus in an extremely stable latent
reservoir in resting memory CD4þ T cells.
AddressesDepartment of Medicine, Johns Hopkins University School of Medicine,
Baltimore, MD 21204, USA�e-mail: [email protected]
Current Opinion in Immunology 2004, 16:470–476
This review comes from a themed issue on
Host–pathogen interactions
Edited by Tom Ottenhoff and Michael Bevan
Available online 15th June 2004
0952-7915/$ – see front matter
� 2004 Elsevier Ltd. All rights reserved.
DOI 10.1016/j.coi.2004.05.005
AbbreviationsAIDS acquired immunodeficiency syndrome
CTL cytotoxic T lymphocyte
env HIV-1 envelope
HAART highly active antiretroviral therapy
HIV human immunodeficiency virus
IjB inhibitor of kB
MHC major histocompatibility complex
nAb neutralizing antibody
SIV simian immunodeficiency virus
IntroductionHIV-1 persists in infected individuals despite robust
immune responses. Within weeks of exposure, rapid viral
replication produces high level viremia [1], which is
partially controlled by cytotoxic T lymphocyte (CTL)
responses [2,3]. Antibody responses develop soon there-
after, but viremia is not reduced to zero. Rather, it falls to
a ‘set point’, typically 104 �105 copies of HIV-1 RNA per
milliliter of plasma. This level is maintained throughout a
prolonged asymptomatic period, during which continuous
viral replication drives a progressive depletion of CD4þ
T cells, leading eventually to a collapse of immune
responses against the virus and other pathogens, and
the development of AIDS. There are also functional
abnormalities in the CD4þ T-cell compartment, includ-
ing an early defect in the anti-HIV-1 response [4]. How-
ever, the CD4þ T-cell defects do not prevent the
emergence of vigorous and sustained B-cell and CD8þ
T-cell responses to HIV-1.
This review will discuss recent work on how HIV-1 avoids
eradication by these responses. Interested readers are
referred to excellent reviews of earlier work in this area
[5,6]. Recent work [7] on intrinsic host factors that restrict
retroviral replication non-specifically will not be dis-
cussed further here.
Lessons from the response to antiretroviraltherapyInsight into how HIV-1 evades immune responses has
come from studies of viral persistence in the face of the
much stronger selective pressure exerted by antiretroviral
drugs. Following the initiation of highly active antiretro-
viral therapy (HAART), plasma virus levels decay rapidly
with multiphasic exponential kinetics [8–11]. This decay
occurs because HAART almost completely stops the new
infection of susceptible cells [8,9], thereby perturbing the
set point equilibrium between virus production and virus
clearance, and revealing the decay rates for free virus
(t1/2 ¼ minutes), for the CD4þ lymphoblasts that produce
most of the plasma virus (t1/2 ¼ 1 day), and for a minor
population of infected cells that turns over slowly (t1/2 ¼ 2
weeks). These decay processes bring plasma virus levels
down below the limit of detection of ultrasensitive clin-
ical assays (50 copies per milliliter of plasma).
The short t1/2 of most productively infected cells means
that the set point viremia is maintained by the infection of
large numbers of new cells per day to balance those that
die. According to the classic model of viral dynamics
[11,12], the number of new cells infected per day is given
by the equation:
dT� ¼ cV
N
where T* is the total body number of productively
infected cells, d and c are decay constants for productively
infected cells and free virus, respectively, V is the level of
viremia, and N is the burst size. Using recently revised
estimates of d and c [13] and a conservatively large
estimate of the burst size (50 000 virions/cell), the number
of newly infected cells arising per day for a patient with
typical levels of viremia is minimally 105. In each newly
Current Opinion in Immunology 2004, 16:470–476 www.sciencedirect.com
infected cell, the 10 kb viral genome is copied by reverse
transcriptase, which introduces errors at a rate of �3 �10�5/nucleotide [14]. Thus �1/3 of the 105 newly copied
viral genomes carry a new mutation. This number is
roughly equal to the total number of possible single point
mutations in the genome. Therefore, every possible point
mutation in the HIV-1 genome arises on a daily basis, a
result that explains the propensity of HIV-1 for escape
from immune selective pressure.
Escape from antibody-mediatedneutralizationAlthough antibodies effectively control many viral infec-
tions [15], HIV-1 replicates continuously in the face of a
strong antibody response. The mechanisms that allow the
virus to do so are best understood by considering the
structural features that the virus has evolved to avoid
neutralization. Neutralizing antibodies (nAbs) are direc-
ted at the HIV-1 envelope (env) protein, a heterodimer
consisting of an extensively glycosylated CD4-binding
subunit (gp120) and an associated transmembrane protein
(gp41). The env proteins are present on the virion surface
as ‘spikes’ composed of trimers of three gp120–gp41
complexes [16–18]. Although exposed on the surface,
these spikes resist neutralization through occlusion of
epitopes within the oligomer, extensive glycosylation,
extension of variable loops from the surface of the com-
plex, and steric and conformational blocking of receptor
binding sites [5,17].
Some antibodies bind monomeric gp120 or gp41 but do
not neutralize because they recognize epitopes buried
within the trimeric complex [18]. The HIV-1 env com-
plex is extensively glycosylated, with 50% of the mass of
its extracellular portion made up of N-linked glycans [19].
Glycosylation blocks access to the conserved core of the
protein while itself stimulating relatively little immune
response [20]. The removal of N-linked glycans near
the CD4 and coreceptor binding sites renders HIV-1 more
sensitive to neutralization [21]. The protection afforded
by glycosylation is not static, however. The precise pat-
tern of N-linked glycosylation varies widely between
isolates. Glycosylation sites can be shifted by mutation,
blocking or altering epitopes and allowing escape from
nAbs [22��]. Moreover, addition or loss of glycosylation at
a particular site may affect distant epitopes [23].
Gp120 has five variable regions (V1–V5), four of which
form loops on the surface, shielding the conserved core of
the protein. When nAbs against the variable loops
develop, escape mutants can usually be selected without
extreme loss of viral fitness [24]. Other structural ele-
ments also protect critical receptor binding sites from
nAbs. Access to the conserved coreceptor binding site is
sterically restricted. Gp120 undergoes a conformational
change when it binds CD4, exposing this site. Access is
limited even after this conformational change, as the
neutralizing activity of many antibodies to this site is
greater with Fab fragments than with intact antibodies
[25]. In addition, some antibodies against the CD4 bind-
ing site induce a conformational change in gp120, making
binding thermodynamically unfavorable [26].
The structural features of gp120, particularly its variable
loops, allow it to tolerate a vast array of mutations. This
permits repeated selection of neutralization escape var-
iants, as has been previously demonstrated in culture
assays, animal models, and in infected humans [5]. Even
cocktails of nAbs against highly conserved env epitopes
were shown to exert little control on established HIV-1
infection in a severe combined immunodeficiency (SCID)
mouse model [27]. Using single round infectivity assays
with reporter viruses, two groups have recently tracked
the development of nAbs and the evolution of virus in
individuals with acute HIV-1 infection [22��,28��]. Neu-
tralizing antibodies against autologous plasma virus devel-
oped within two months of seroconversion. Although
these nAbs ultimately reached high titers, escape was
extremely rapid, occurring while titers were still relatively
low. As new variants arose, nAbs against those variants
developed within three months, but by this time new viral
variants resistant to neutralization by those antibodies had
already arisen. Thus, the combination of structural fea-
tures limiting the formation of nAbs together with the
rapid selection of escape mutations explains the inability
of the nAb response to completely suppress viremia.
Escape from HIV-1-specific cytotoxicT lymphocytesA high frequency of HIV-1-specific CD8þ T cells can be
found in infected individuals, even those with advanced
disease [29]. That these cells reduce viral replication has
been convincingly demonstrated by experimental deple-
tion of CD8þ T cells in simian immunodeficiency virus
(SIV)-infected macaques, which results in a marked and
immediate increase in viral load [3,30]. The partial control
that CD8þ T cells exert over viral replication is observed
despite the downregulation of some class I MHC mole-
cules by HIV-1 Nef [31] and functional defects observed
in the CD8þ T-cell response [32]. Nevertheless, readily
measurable viral replication occurs throughout the course
of the infection in most patients.
Earlier work suggesting that the virus generates escape
mutations to avoid the CTL response, summarized in
reference [5], was confirmed in an elegant study by Allen
and colleagues [33] in SIV-infected macaques. Following
infection with cloned SIV, viruses with mutations in an
immunodominant epitope in the Tat protein completely
replaced the wild-type virus one week after the peak CTL
response. Interestingly, the viral load did not increase.
Thus, the virus had escaped from the dominant CD8þ
T-cell response but not from the entire immune response.
This finding could be explained by a broadening of the
HIV-1 escape from immune responses Bailey et al. 471
www.sciencedirect.com Current Opinion in Immunology 2004, 16:470–476
SIV-specific immune response and/or the reduced fitness
of escape mutants.
Several case reports have shown that when the CTL
response is focused on a single immunodominant epitope
the appearance of escape mutants leads to an increase in
viral replication [34–36]. A highly focused response, how-
ever, may be the exception rather than the rule. An
important recent advance is the development of methods
for assessing the CTL response in a global fashion, so that
Figure 1
Thymicproduction
Thymicproduction
†
†
Ag
†††
†
†
Response of naïve T cellsto antigen generation of
effector and memory cells
Ag
††††
†
†
Response of memoryT cells to antigen
Proliferative renewal
Naï
veM
emor
yN
aïve
Mem
ory
†
†
Ag
††††
†
†
Generation of latentlyinfected cells
Ag HIV
†
Infectionand death ofactivated CD4+ T cells
HIV
Ag†
Intrinsic stability
Proliferative renewal
Reactivation of latent HIV
(a) Homeostasis of naïve and memory T cells
(b) Establishment and maintenance of a latent reservoir
Immunological memory and HIV-1 latency. (a) Normal T-cell homeostasis. Most of the CD4þ T cells in the body are small resting cells that
circulate throughout the lymphoid tissues poised to respond to a specific antigen (Ag). Approximately half are naı̈ve cells (blue) that have not
encountered an Ag since emerging from the thymus. The remainder are memory cells (green) that have previously responded to Ag. Following
encounter with Ag, resting cells undergo blast transformation and begin to proliferate. These lymphoblasts (red) undergo several rounds of cell
division, giving rising to effector cells. Most effector cells eventually die, but a fraction revert to a resting memory state. The memory pool ismaintained by the long lifespan of the cells and a gradual process of proliferative renewal. (b) Establishment of a latent reservoir in resting
memory CD4þ T cells. CD4þ lymphoblasts (red cells) are highly susceptible to productive infection and usually die within a few days after infection.
Latently infected cells with integrated HIV-1 DNA may be generated when lymphoblasts that are in the process of reverting to a resting state become
infected. When latently infected cells subsequently encounter the relevant Ag, they become permissive for virus gene expression and virus
production. Latently infected cells may be maintained by intrinsic stability, and by the process of proliferative renewal if they do not become
susceptible to HIV-1-induced cytopathic effects or host cytolytic mechanisms during this process. Reproduced with permission from [63].
472 Host–pathogen interactions
Current Opinion in Immunology 2004, 16:470–476 www.sciencedirect.com
responses to the relevant forms of all viral proteins are
detected [37,38�]. A recent comprehensive study demon-
strated that HIV-1-infected patients targeted a median of
14 distinct viral epitopes [38�]. Thus, complete escape
from the CTL response may require mutations in multi-
ple epitopes. Recent work has also suggested that escape
mutations may result in reduced fitness [39��,40��].Transmission of escape mutants to hosts that do not
generate an immune response to the epitope (due to
the lack of the relevant MHC molecule) results in even-
tual reversion to wild-type sequence. These two factors
may explain why escape mutations do not commonly lead
to the complete loss of control of viral replication in most
individuals.
HIV-1 latencyAlthough HAART can suppress detectable viremia for
prolonged periods, eradication has not been achieved
due, in part, to a latent form of the virus that persists
in resting memory CD4þ T cells [41,42�]. This latent
reservoir may be generated through infection of activated
CD4þ T cells, with integration of viral DNA into the host
genome. If the cell survives long enough to revert back to
a resting state, then the integrated viral DNA persists in
the resulting memory cell for the lifetime of the cell
(Figure 1). During this time, viral gene expression is
limited by several mechanisms (see below). Thus, latent
infection allows the virus to survive free from the selec-
tive pressure exerted by antiretroviral drugs or the
immune response. Evidence for this model comes from
studies of viral persistence in patients on HAART who
have no detectable free virus in the plasma. Resting
CD4þ T cells from the peripheral blood of these patients
do not release virus [43�], but they can be induced to do so
by cellular activation [41,42�,44–46]. The size of the pool
of latently infected resting CD4þ T cells does not decline
substantially even in patients who have had suppression
of measurable viremia for as long as seven years [42�].Analysis of the persistence of wild-type and drug-resistant
viruses supports the notion that at least a fraction of the
latent pool is extremely stable [47,48].
Several recent studies have addressed the mechanisms of
HIV-1 latency. Resting CD4þ T cells do not contain the
activated forms of host transcription factors required to
produce new virus from the integrated provirus [49–52].
The HIV-1 long terminal repeat (LTR) contains binding
sites for nuclear factor-kB (NF-kB), a cellular transcrip-
tion factor that is sequestered in the cytoplasm of resting
CD4þ T cells by virtue of its interaction with the inhibitor
of kB (IkB) complex. Activation-induced phosphorylation
and proteasomal degradation of IkB allows NF-kB to
translocate to the nucleus. The recently characterized
Murr1 protein inhibits proteasomal degradation of IkB
and may thereby restrict HIV-1 gene expression in
infected resting CD4þ T cells [53�]. Other studies sug-
gest that, in resting cells, HIV-1 transcription initiates but
terminates prematurely because of a lack of Tat and
Tat-associated host factors that promote transcriptional
elongation [54–57]. Although elegant in vitro studies
suggest that integration into regions of heterochromatin
is another potential mechanism of latency [58], a recent
study has shown that most of the HIV-1 DNA in resting
CD4þ T cells from patients on HAART is found within
the introns of genes that are actively expressed in resting
CD4þ T cells [59�].
Although latency prevents eradication in patients on
HAART, it is not clear if HIV-1 latency evolved to
promote viral persistence. Classical forms of viral latency,
such as the programmed latency of herpes simplex virus
(HSV), allow persistence when viral replication has been
arrested elsewhere in the host [60]. For individuals with
untreated HIV-1 infection, active viral replication con-
tinues throughout the course of the disease. The same is
true for the simian viruses from which HIV-1 evolved
[61��]. Thus, latency is not essential for HIV-1 persis-
tence. In addition, unlike HSV, HIV-1 does not have a
clear genetic program of latency. There is some evidence
that HIV-1 Nef might function to establish conditions
that allow the direct infection of resting CD4þ T cells
[62�], but whether this leads to latency in vivo remains
unclear. It remains possible that latency is an unfortunate
accident of the fact that HIV-1 is trophic for activated
CD4þ T cells, which can undergo a profound and rever-
sible change to a quiescent state which happens not to be
permissive for viral replication. In any event, latency
occurs and is likely to prevent immune-mediated clear-
ance should it become possible to enhance immune
responses to the point where they exert as strong an
antiviral effect as HAART.
ConclusionsIn the vast majority of infected individuals, active repli-
cation of the virus continues throughout the course of the
infection at a level that reflects a balance between immu-
nological control (through nAbs and CTLs) and viral
escape. Viral escape occurs through the evolution of
escape mutants with alterations in key regions of the
env protein and in CTL epitopes. Levels of viral replica-
tion in many untreated individuals are high enough that
every possible point mutation in the entire viral genome
arises on a daily basis. Structural features of the env
protein allow the accumulation of mutations at a rate
that permits the virus to become resistant to neutraliza-
tion by contemporaneous antibodies. Escape from CTL
responses is more difficult because the responses are
directed at epitopes in multiple viral proteins, some of
which cannot tolerate mutations without a significant loss
of viral fitness. Thus, pressure exerted by CTLs holds
levels of replication down.
Future approaches to the treatment HIV-1 infection
might include efforts to enhance anti-HIV-1 immune
HIV-1 escape from immune responses Bailey et al. 473
www.sciencedirect.com Current Opinion in Immunology 2004, 16:470–476
responses to the point where they can suppress viral
replication to levels low enough to halt viral evolution.
This degree of suppression can be achieved by anti-
retroviral drugs, but even in patients on combination
antiretroviral therapy, the virus can persist for life in a
stable latent reservoir in resting CD4þ T cells.
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38.�
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39.��
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40.��
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42.�
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43.�
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absence of virus production in these cells is not due to integration of theprovirus into areas of the genome repressive for transcription.
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Silvestri G, Sodora DL, Koup RA, Paiardini M, O’Neil SP,McClure HM, Staprans SI, Feinberg MB: Nonpathogenic SIVinfection of sooty mangabeys is characterized by limitedbystander immunopathology despite chronic high-levelviremia. Immunity 2003, 18:441-452.
This is an important study of differences between non-pathogenic andpathogenic SIV infection.
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476 Host–pathogen interactions
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