Mechanisms of HIV-1 escape from immune responses and antiretroviral drugs

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


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



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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22.��

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37. Altfeld M, Addo MM, Shankarappa R, Lee PK, Allen TM, Yu XG,Rathod A, Harlow J, O’Sullivan K, Johnston MN et al.:Enhanced detection of human immunodeficiency virus type1-specific T-cell responses to highly variable regions by usingpeptides based on autologous virus sequences. J Virol 2003,77:7330-7340.

38.�

Addo MM, Yu XG, Rathod A, Cohen D, Eldridge RL, Strick D,Johnston MN, Corcoran C, Wurcel AG, Fitzpatrick CA et al.:Comprehensive epitope analysis of human immunodeficiencyvirus type 1 (HIV-1)-specific T-cell responses directed againstthe entire expressed HIV-1 genome demonstrate broadlydirected responses, but no correlation to viral load.J Virol 2003, 77:2081-2092.

This paper provides a good illustration of the power of comprehensiveapproaches to the analysis of HIV-1-specific immunity.

39.��

Leslie AJ, Pfafferott KJ, Chetty P, Draenert R, Addo MM, Feeney M,Tang Y, Holmes EC, Allen T, Prado JG et al.: HIV evolution: CTLescape mutation and reversion after transmission.Nat Med 2004, 10:282-289.

One of two recent studies showing the reversion to wild-type sequenceafter the transmission of CTL escape mutants into hosts not expressingthe relevant MHC molecules.

40.��

Friedrich TC, Dodds EJ, Yant LJ, Vojnov L, Rudersdorf R,Cullen C, Evans DT, Desrosiers RC, Mothe BR, Sidney J et al.:Reversion of CTL escape-variant immunodeficiency virusesin vivo. Nat Med 2004, 10:275-281.

See annotation to [39��].

41. Finzi D, Blankson J, Siliciano JD, Margolick JB, Chadwick K,Pierson T, Smith K, Lisziewicz J, Lori F, Flexner C et al.:Latent infection of CD4R T cells provides a mechanism forlifelong persistence of HIV-1, even in patients on effectivecombination therapy. Nat Med 1999, 5:512-517.

42.�

Siliciano JD, Kajdas J, Finzi D, Quinn TC, Chadwich K,Margolick JB, Kovacs C, Gange SJ, Siliciano RF: Long termfollow-up studies confirm the extraordinary stability of thelatent reservoir for HIV-1 in resting CD4R T cells. Nat Med 2003,9:727-728.

This study measured the t1/2 of the latent reservoir as 44 months, usinglong-term follow-up of patients receiving HAART with no detectableviremia for up to seven years.

43.�

Chun TW, Justement JS, Lempicki RA, Yang J, Dennis G Jr,Hallahan CW, Sanford C, Pandya P, Liu S, McLaughlin M et al.:Gene expression and viral prodution in latently infected, restingCD4R T cells in viremic versus aviremic HIV-infectedindividuals. Proc Natl Acad Sci USA 2003, 100:1908-1913.

This study compared the production of HIV-1 by infected resting CD4þ Tcells from viremic and aviremic patients, and showed that resting CD4þ Tcells from aviremic patients failed to produce HIV-1 without activation.Altered patterns of host gene expression in resting CD4þ T cells fromviremic versus aviremic patients were also defined.

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53.�

Ganesh L, Burstein E, Guha-Niyogi A, Louder MK, Mascola JR,Klomp LW, Wijmenga C, Duckett CS, Nabel GJ: The gene productMurr1 restricts HIV-1 replication in resting CD4R lymphocytes.Nature 2003, 426:853-857.

This report showed that Murr1 regulates IkB turnover and is expressed inCD4þ T cells, indicating a role for Murr1 in the inhibition of productiveinfection of resting CD4þ T cells.

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59.�

Han Y, Lassen K, Monie D, Sedaghat AR, Shimoji S, Liu X,Pierson TC, Margolick JB, Siliciano RF, Siliciano JD: RestingCD4R T cells from HIV-1-infected individuals carry integratedHIV-1 genomes within actively transcribed host genes.J Virol 2004, in press.

This study shows that HIV-1 is preferentially integrated into the introns ofactively transcribed genes in resting CD4þ T cells, indicating that the



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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61.��

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.

62.�

Swingler S, Brichacek B, Jacque JM, Ulich C, Zhou J, Stevenson M:HIV-1 Nef intersects the macrophage CD40L signallingpathway to promote resting-cell infection. Nature 2003,424:213-219.

In this report, macrophages that express Nef are shown to release a factorthat, through a complex mechanism involving B cells, stimulates restingCD4þ T cells to become susceptible to viral infection.

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Mechanisms of HIV-1 escape from immune responses and antiretroviral drugs

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