The Absence of CD4 + T Cell Count Recovery Despite Receipt of Virologically Suppressive Highly...

328 • CID 2009:48 (1 February) • HIV/AIDS

H I V / A I D S I N V I T E D A R T I C L EKenneth H. Mayer, Section Editor

The Absence of CD4+ T Cell Count Recovery DespiteReceipt of Virologically Suppressive Highly ActiveAntiretroviral Therapy: Clinical Risk, Immunological Gaps,and Therapeutic Options

Lidia Gazzola, Camilla Tincati, Giusi Maria Bellistrı, Antonella d’Arminio Monforte, and Giulia MarchettiDepartment of Medicine, Surgery, and Dentistry, Clinic of Infectious Diseases, “San Paolo” Hospital, University of Milan, Milan, Italy

Up to 30% of human immunodeficiency virus (HIV)–infected patients who are receiving long-term highly active antiretroviraltherapy do not exhibit a marked increase in the CD4+ T cell count, despite achieving complete suppression of the HIV load.These patients are referred to as “immunological nonresponders.” When treating immunological nonresponders, the practicingclinician has several questions, including questions about the clinical risk associated with persistent immunodeficiency andabout possible approaches to treatment that would provide clinical and immunological benefits. However, tentative answersto these questions require investigations of the mechanisms that underlie the lack of immune recovery, because only thedeepest comprehension of the immunological gaps underlying functional defects will allow administration of highly targetedand efficacious treatment strategies. The aim of our review is to provide a thorough assessment of the clinical implicationsof a lack of increase in the CD4+ T cell count in immunological nonresponders, to examine the immunological gaps limitingrecovery of the CD4+ T cell count, and to note possible therapeutic avenues, which may offer clinicians guidance regardinghow to most efficaciously treat these critical patients.

IMMUNOLOGICAL FAILURE AND HAART

In the era of HAART, HIV/AIDS clinicians have observed a

remarkable reduction in AIDS-related morbidity and mortality

rates. In fact, HAART has been shown to improve survival rates

among HIV-infected individuals through its ability to reduce

the HIV load to undetectable levels and to increase the CD4+

lymphocyte count in peripheral blood (defined as a full re-

sponse) [1, 2]. However, 15%–30% of patients have discordant

responses to long-term HAART consisting of a lack of increase

in the CD4+ T cell count but full suppression of HIV replication;

these people are referred to as “immunological nonresponders”

(INRs) [3, 4]. From a clinical standpoint, lack of CD4+ immune

reconstitution during receipt of effective HAART represents an

everyday issue in the clinical management of HIV/AIDS. In

Received 28 May 2008; accepted 16 September 2008; electronically published 5 January2009.

Reprints or correspondence: Dr. Giulia Marchetti, Dept. of Medicine, Surgery, and Dentistry,Clinic of Infectious Diseases, “San Paolo” Hospital, University of Milan, Via A. Di Rudinı, 8,20142 Milan, Italy ([email protected]).

Clinical Infectious Diseases 2009; 48:328–37� 2009 by the Infectious Diseases Society of America. All rights reserved.1058-4838/2009/4803-0010$15.00DOI: 10.1086/595851

particular, clinicians question whether INRs have an increased

risk of clinical progression to AIDS and whether it is possible

to identify early predictive factors of immunological failure

during HAART.

From a therapeutic standpoint, failure of CD4+ cell recon-

stitution during receipt of virologically suppressive HAART in-

dicates the need for alternative treatment strategies. However,

the essential premise of studies of therapeutic options in this

clinical context is the deep comprehension of the pathogenetic

mechanisms that underlie immunological failure. We assessed

the clinical implications of a lack of a recovery in the CD4+

cell count among INRs, the immunological gaps limiting CD4+

cell count recovery, and the possible therapeutic avenues that

may offer clinicians guidance regarding the most effective treat-

ments for these critical patients.

INVESTIGATING THE CLINICAL CORRELATESOF IMMUNOLOGICAL FAILURE DURINGHAART: ARE INRS AT INCREASED RISK OF HIV/AIDS DISEASE PROGRESSION AND DEATH?

An essential premise in the assessment of clinical correlates of

insufficient immunological response to long-term HAART is

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HIV/AIDS • CID 2009:48 (1 February) • 329

the definition of immunological response itself. There is no

clear-cut agreement on how to assess an insufficient immune

response to HAART, with particular regard to the adequate

time to evaluation of immune response after the commence-

ment of HAART. Although an interval of 12 months may be

too premature to evaluate immune response to HAART [5], it

is our opinion that the broadly used criteria of an increase in

the CD4+ T cell count of !30% and an absolute CD4+ T cell

count �200 cells/mL during the first 6–12 months of HIV-

suppressive HAART identifies immunological nonresponse [6],

because immune response after 3–6 months of HAART is pre-

dictive of both immune reconstitution and HIV-related mor-

bidity and mortality in the long term [7, 8]. However, this

definition may identify an overly heterogeneous population and

fail to discriminate between a real long-term nonresponse and

a delayed response.

Kaufmann et al. [7] demonstrated that an incomplete im-

mune response in the short term led to an elevated risk of

Centers for Disease Control and Prevention category B and C

events in the long term, indicating an augmented risk of disease

progression in INRs. Additional observational studies have de-

fined an approximately doubled relative risk of clinical pro-

gression to AIDS and an increased risk of mortality in INRs,

compared with patients who had a complete response [9–13].

In addition, a new clinical concern was recently raised by

Gutierrez et al. [12], who showed that, despite having similar

proportions of new AIDS-defining events, INRs had an overall

higher rate of non–AIDS-related mortality, compared with pa-

tients who had a complete response, causing additional clinical

concern about the long-term risks of subclinical immunode-

ficiency. Accordingly, guidelines of the Department of Health

and Human Services (DHHS) prefer to define immunological

failure as the lack of an increase in the CD4+ T cell count to

more than 350–500 cells/mL after receipt of 4–7 years of effective

HAART [14], given recent data linking these immunological

thresholds with the risk of non-AIDS clinical events [15].

INVESTIGATION OF FACTORS ASSOCIATEDWITH IMMUNOLOGICAL FAILURE DURINGLONG-TERM HAART: WHICH FACTORSPREDICT IMMUNOLOGICAL NONRESPONSE?

Having defined an overall increased risk of HIV/AIDS disease

progression in INRs, we still need to assess whether the clinician

can depend on specific factors for early identification of which

patients are most likely to experience insufficient immune re-

covery while receiving HAART. As illustrated in table 1, several

factors have been individually associated with immunological

failure during HAART, and yet only those below have been

invariably proven to predict immunological nonresponse.

Age has been reported to have a significant impact on im-

mune recovery: the older the patient is, the more likely that

he or she will experience delayed immune reconstitution [18].

Indeed, older age has been associated with a decrease of thymic

function and other regenerative mechanisms, thus explaining

its role as an independent predictive factor of impaired immune

recovery [7, 10, 11, 16, 19]. In addition, recent data from cohort

studies suggest that immune recovery in older patients may

hide a more profound functional impairment, as evidenced by

a persistent increased risk of AIDS-related events in these pa-

tients, even after adjustment for CD4+ T cell counts [20, 21].

Another factor presumed to affect immune recovery during

HAART is concurrent viral hepatitis. In a recent meta-analysis,

Miller et al. [22] showed that increases in the CD4+ T cell count

during HAART are significantly lower in the course of hepatitis

C virus (HCV) coinfection. The biological rationale posits that

there are higher levels of T cell activation and death in HIV-

HCV–coinfected patients and that there is a possible direct

negative effect of HCV infection and replication inside lym-

phocyte subpopulations [23, 24]. However, the actual impact

of HCV infection on immune recovery in HIV-infected patients

still remains a matter of controversy, given the numerous con-

founding factors often present in the HCV-infected population,

such as a history of injection drug use, poor adherence to

therapy, and decreased access to health care [25–28]. Of these

factors, adherence to antiretroviral therapy has been proven to

be a strong independent predictor of recovery in the CD4+ T

cell count and the ultimate cause of impaired immune recovery

in injection drug users [29, 30].

With regard to immunovirological factors, nadir CD4+ T cell

count is the most common and most reliable determinant of

suboptimal immune recovery during HAART [7, 16, 17, 31,

32]. From a mechanistic standpoint, differences in CD4+ T cell

nadir are indicators of differences in immunological regulatory

functions over T cell homeostasis that might affect immune

recovery competence [33]. However, the sole quantification of

nadir CD4+ T cell count may fail to qualitatively estimate the

immunological mechanism(s) that hinder CD4+ T cell count

rescue, indicating a need for a more detailed assessment of

immunological gaps associated with nadir-driven T cell

homeostasis.

The identification of immunopathogenetic models behind

the negative impact of age, HCV coinfection, and nadir CD4+

cell count on immune recovery raises an additional clinical

question: are there immunological, virological, or genetic mark-

ers that can be directly exploited, from bench to bedside, to

predict immunological failure during HAART in at-risk pa-

tients? Although Spritzler et al. [34] demonstrate that peripheral

immunophenotype has a limited ability to predict HAART re-

sponse, only the most thorough investigation of immunovi-

rological correlates of discordant responses will allow for a

targeted immune-based treatment approach.



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Figure 1. Differences in CD4+ T cell dynamics between persons who experienced a full immunological response (FRs; A) and immunologicalnonresponders (INRs; B). Compared with FRs, INRs are notable for reduced bone marrow and thymic output of naive T cells in peripheral circulation,greater HIV- and antigen-driven T cell activation, and reduced content of T regulatory cells, ultimately leading to increase cellular death by apoptosis.Despite significantly lower CD4+ T cell counts in the periphery, a similar stimulation of the IL-7 compensatory loop is displayed by INRs and FRs.However, compared with FRs, INRs are characterized by reduced IL-7R expression on different T cell populations, thus potentially limiting the compensatoryeffect of IL-7. Different T cell pools are represented: recent thymic emigrants, naive T cells, resting memory T cells, activated T cells, T regulatorycells, and hematopoietic stem cell precursors (HSCPs). The size of the boxes and the number of cells represent the relative amount of each cell pooland are not to scale. IL-7R is represented on T cell surface according to its expression, not to scale. Ag, antigen.

INVESTIGATION OF THE PATHOGENETICCORRELATES OF INRS: WHICHIMMUNOVIROLOGICAL AND GENETICMECHANISMS LIMIT IMMUNE RECOVERYDURING LONG-TERM HAART?

Failure in De Novo CD4+ T Cell Production

The pathogenesis of immunological nonresponse may be sec-

ondary to specific failure of the T cell armamentarium ma-

chinery (i.e., failure of the bone marrow to produce hemato-

poietic stem cells) or to a deficiency in thymic output (figure

1) [35].

The role of bone marrow. Decreased bone marrow pro-

genitor cell growth and abnormal stromal microenvironment

have been described in patients with HIV/AIDS [36] and have

been partly restored after the commencement of HAART [37,

38]. Recent observations support the hypothesis that the lack

of immune recovery in INRs may be due, at least in part, to

persistent bone marrow impairment, despite receipt of HAART,

that is possibly characterized by altered clonogenic capability

and stromal cell function (figure 1) [39–41].

The role of thymic output. The failure to restore circulating

CD4+ T cells during HAART may partially be caused by de-

ficiencies in thymopoietin [42–45]. Indeed, several studies have

demonstrated a trend toward smaller thymuses and lower thy-

mopoietin levels in INRs (figure 1) [35, 46–48]. Given that a

hypofunctional thymus may account for the immunological

failure in INRs, a question remains whether the thymus itself

is unable to respond to thymopoietic signals (e.g., IL-7) or

whether the latter are insufficient to drive thymic-dependent

immune reconstitution.

The role of IL-7. IL-7, which is mainly produced by thymic

and bone marrow stromal cells, is a vital cytokine for thymocyte

development for which production is up-regulated in lympho-

penic conditions [49, 50]. A relative deficiency in IL-7 pro-

duction or function may occur in INRs. Studies have found

that plasma IL-7 levels in INRs are comparable to those in

patients who had complete responses, suggesting maintenance

of the IL-7 compensatory loop [47, 48]. Marziali et al. [47]

reported a reduction in IL-7R expression on CD4+ T cells ob-

tained from INRs, compared with CD4+ T cells obtained from

persons who had complete responses, as well as a positive cor-

relation between peripheral percentage of CD4+ T cells and

those expressing IL-7R, leading to speculation about defective

IL-7R expression. Additional studies are needed to aid com-



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prehension about the role of thymopoiesis and IL-7 signaling

in INRs [50, 51].

Excessive CD4+ T Cell Destruction

As illustrated in figure 1, INRs may also be characterized by

augmented levels of CD4+ T cell loss in the periphery [35].

CD4+ T cell hyperactivation. CD4+ T cell hyperactivation

has been demonstrated to persist even after HAART virological

suppression occurs and to have a significant effect on recovery

of the CD4+ T cell count during HAART [52, 53]. Indeed,

despite complete suppression of the HIV load, INRs maintain

CD4+ T cell hyperactivation comparable to that in patients who

have not experienced viral suppression (figure 1) [48, 54].

Although highlighting the possible pathogenetic role of en-

hanced CD4+ T cell activation in insufficient CD4+ T cell count

recovery, these findings also raise questions on the driver(s) of

persistently elevated CD4+ T cell activation.

Ongoing viral replication. Even in the context of complete

viral suppression, INRs have been shown to have higher levels

of proviral DNA in total, memory, and naive CD4+ T cells,

reinforcing the role of increased HIV antigen–driven CD4+ T

cell activation as a driving force of continuous loss of CD4+ T

cells in INRs [48]. On the one hand, despite control of plasma

viral loads, the persistence of residual low-level viral replication

at levels less than the detection limit of the most-sensitive meth-

ods, either in blood or in other compartments, maintains the

HIV DNA burden in the reservoir; on the other hand, it rep-

resents a continuous trigger of immune activation [55, 56].

Persistent antigenic stimulation. CD4+ T cell hyperacti-

vation may also be secondary to ongoing chronic inflammatory

disease. Recently, a pathogenetic model of increased translo-

cation of microbial bioproducts from the gastrointestinal lumen

has been proposed as a continuous trigger of immune activation

in patients with HIV/AIDS [57, 58]. Brenchley et al. [59] el-

egantly demonstrated that high levels of plasma lipopolysac-

charide—an indicator of microbial translocation—in HIV-in-

fected patients correlate with immune hyperactivation and are

only partially restored by HAART. We reported a consistent

trend toward higher lipopolysaccharide levels in INRs, com-

pared with levels in persons who had a complete response, that

correlated with the proportion of activated Ki67+ CD4+ and

CD8+ cells. Taken together, these data allow speculation that

microbial translocation, by perpetuating peripheral CD4+ T cell

activation, may contribute to the inefficient recovery in the

CD4+ T cell count in INRs [60]. Consistent with this finding

is the fact that HIV-driven dysfunction of CD4+ T cell ho-

meostasis in the gut mucosa, with local immune activation, has

been shown to persist after commencement of HAART [61–

64]. However, a clear-cut correlation between mucosal immune

restoration and immunological and clinical outcome during

HAART is still missing [64, 65].

Immunoregulatory mechanisms. T regulatory cells are a

specialized T cell subpopulation with the ability to down-mod-

ulate immune activation and function [66]. Indeed, Marziali

et al. [47] reported a significant reduction in T regulatory cell

count in INRs, compared with patients who had complete re-

sponses, inversely correlating with activated CD4+ T cells, al-

lowing one to hypothesize that persistently low levels of T

regulatory cells, which are unable to turn off immune activa-

tion, could partly account for immune reconstitution failure

in INRs [47].

Genetic Influence

A role of genetic polymorphisms involved in CD4+ T cell ho-

meostasis has also been postulated in dictating the magnitude

of recovery in the CD4+ T cell count during HAART. In a

recent multivariate analysis, Haas et al. [67] found a significant

association between CD4+ T cell count recovery and polymor-

phisms in genes encoding TNF-related apoptosis-induced li-

gand, TNF-a, Bcl-2–interacting molecule, and IL-15/IL-15R.

Similarly, diverse polymorphisms in chemokine or chemokine

receptors and HLA genes have been associated with the re-

sponse to HAART, although different association patterns were

demonstrated by different authors [68–70]. In conclusion, it

seems reasonable that multiple genetic variants may be involved

in the pathogenesis of immunological nonresponse vis-a-vis

complex immune phenotypes in these individuals.

INVESTIGATION OF THE THERAPEUTICOPTIONS FOR INRS: WHICH STRATEGIES MAYIMPROVE IMMUNE RECOVERY IN INRS?

Having assessed the clinical risk and the immunological defects

that may be potential targets for adjuvant approaches in INRs,

additional questions arise on the actual direction for an effective

therapeutic strategy. Should we aim at improving peripheral T

cell production and expansion or rather, should we seek im-

mune activation control, enhancing peripheral survival of CD4+

T cells?

MOLECULES THAT SUSTAIN THE CD4+ T CELLCOUNT IN THE PERIPHERY

IL-2. Thus far, several controlled studies have been conducted

to investigate the effect of IL-2 in INRs, concluding that IL-2

is safe and efficacious in inducing a rapid and significant re-

constitution of the CD4+ T cell compartment, with no signif-

icant impact on HIV load [71–73]. Most interestingly, data

showing no HIV-related events among IL-2–treated patients,

compared with recipients of HAART alone, suggest that the IL-

2–driven increases in the CD4+ T cell count may also be effective

in preserving an adequate cellular immunity [72, 74–76], even

though the ultimate evidence of IL-2 clinical impact is still being

sought [14, 77].



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Nonetheless, major constraints to the clinical use of IL-2 in

INRs include a time-limited immune benefit in sustaining CD4+

T cell counts and inefficacy in a minor group of nonresponding

patients. Although a possible way to overcome such limitations

has recently been proposed (consisting of induction mainte-

nance strategies of long-term IL-2 treatment [78]), it is clear

that IL-2 immunotherapy alone for the treatment of INRs failed

to meet the initial expectations. Given these controversies and

possible drug-associated adverse effects in IL-2 recipients,

DHHS guidelines recommend the use of IL-2 immunotherapy

only in the context of clinical trials [14].

IL-7. Two recent trials have demonstrated a sustained dose-

dependent increase in naive and memory CD4+ and CD8+ T

cells after administration of IL-7 to HIV-infected patients [79–

81]. However, the opportunity to use IL-7 as an immune ad-

juvant in INRs is still controversial, given evidence that en-

dogenous plasma IL-7 levels are already elevated in INRs. In

our opinion, a possible way to understand this controversy is

analysis of IL-7 production and signaling in INRs that would

yield evidence on the functional status of the IL-7 axis and,

thus, to the possible benefits of its exogenous administration.

However, DHHS guidelines recommend use of IL-7 immu-

notherapy only in the context of clinical trials [14].

Modulation of T regulatory cells. Although they are an

intriguing target for immune therapy, no clear-cut consensus

has been reached on whether and how to exogenously modulate

T regulatory cell function and/or activity [82]. Thus far, data

on the effects of IL-2 and IL-7 immunotherapy on T regulatory

cells have been discordant [83, 84], indicating the importance

of investigating the role of cytokine-based approaches to this

particular T cell population.

STRATEGIES AIMED AT TURNING OFF IMMUNEHYPERACTIVATION

Antiretroviral therapy strategies. Differences in CD4+ T cell

response may exist among different drug classes. Controversial

data on a greater immunological efficacy of protease inhibitor–

containing regimens have been generated [85]. Indeed, a recent

randomized clinical trial that compared first-line regimens in-

cluding nonnucleoside reverse-transcriptase inhibitors versus

protease inhibitor reported a superior immune response to the

latter regimen, but this occurred only in the long term, and

there was doubt about its clinical significance [86]. Further-

more, data on thymidine analogue–associated mitochondrial

toxicity and oxidative stress have accumulated recently. These

findings suggest a role for thymidine analogues—including nu-

cleoside reverse-transcriptase–based regimens—in cell dys-

function [87], possibly hampering recovery of the CD4+ T cell

count.

The negative impact of low-level residual HIV levels to less

than suppressive threshold during CD4+ immune recovery in

INRs led to the hypothesis that intensification of HAART may

improve immunological responses in INRs [88–92]. The avail-

ability of new drug classes, such as fusion and integrase inhib-

itors, which provide the strongest suppression of HIV loads

and HIV DNA burden and the greatest immunological efficacy

[93, 94], makes this issue more relevant and current. Recently,

CCR5 antagonists have been suggested to have the potential to

yield the greatest CD4+ T cell count gains, given their specific

effect in the suppression of immune activation [95]. Indeed, a

very recent meta-analysis investigated the differences in in-

creases in the CD4+ T cell count among patients enrolled in

phase II/III trials of new antiretrovirals and found an enhanced

CD4+ T cell response in recipients of CCR5 antagonist–con-

taining regimens, compared with recipients of other regimens,

that was independent of suppression of the HIV load [96].

Even if the durability and clinical meaning of this finding re-

main to be determined, these data support deeper investigation

of this approach in INRs.

In addition to identification of the “best” antiretroviral strat-

egy for INRs, a major challenge for clinicians is the identifi-

cation of the “best” CD4+ T cell range for initiation of HAART.

Indeed, given the persistence of different trajectories for the

recovery of the CD4+ T cell count based on different baseline

ranks, with some individuals barely achieving a protective CD4+

T cell count of !200 cells/mL after 5 years of HAART, the impact

of commencement of HAART should be evaluated in patients

with a high risk of becoming INRs, such as older patients

[21, 97].

Immunosuppressive agents. Because there has been inter-

est in “turning off” excessive immune activation, various im-

munosuppressive agents have been investigated [98–103]. In

addition to providing positive data on the efficacious control

of immune activation, these trials have also demonstrated an

immunological benefit in terms of increases in the CD4+ T cell

count [99, 101]. Unfortunately, trials assessing the benefit of

administration of immunosuppressive drugs to INRs are still

lacking, the major concern being the potential risk of admin-

istering immunosuppressive agents to patients with a highly

depleted CD4+ T cell compartment. In our opinion, a prom-

ising approach may be the identification of targeted interven-

tions to interact with pathways of immune activation that are

specific to INRs, thus allowing for a more efficacious and less

dangerous intervention.

CONCLUSIONS AND FUTURE DIRECTIONS

The absence of a recovery in the CD4+ T cell count during

long-term, virologically suppressive HAART is an unquestion-

able source of anxiety to HIV-infected patients and their treat-

ing clinicians, given the long-term risks of disease progression

and death, underscoring the need for means of identifying early

predictive factors and treatment options. Furthermore, INRs

may be viewed as a merging point between clinical practice

and basic science: while HIV/AIDS clinicians investigate which



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treatment most effectively sustains peripheral the CD4+ T cell

count, bench scientists, by investigating the immunovirological

pathways behind insufficient recovery of the CD4+ T cell count,

may provide tools both to forecast immunological failure and

to investigate new therapeutic strategies.

Unfortunately, even though several approaches have been

suggested and investigated, no consensus has been reached yet

on the most efficacious treatment for immunological nonre-

sponse. Thus, we are now facing a dichotomy, whereby the

ever-growing list of new-class antiretrovirals provides us with

the most potent weapons against HIV/AIDS, while we still lack

a full grasp on the most proper means of administering them

to INRs. However, even though such research has not yet pro-

vided a unique treatment protocol, research has revealed diverse

immunovirological and even genetic patterns behind impaired

CD4+ T cell count recovery, indicating the need for novel treat-

ment scenarios tailored to different INRs, possibly including

antiretrovirals and immunomodulants. Thus, with regard to

the frustrating lack of concrete therapeutic options, we strongly

advocate the continuous investigation of the correlates of the

failure of CD4+ T cell counts to recover during HAART to aid

HIV/AIDS clinicians who treat INRs today, to find the most

effective and timely therapeutic options in the future.

Acknowledgments

We thank Tiziana Formenti for providing invaluable proofreading andediting. We are particularly thankful to all the staff members of the Clinicof Infectious Diseases, “San Paolo” Hospital, University of Milan.

Financial support. Fondo Interno Ricerca Scientifica e Tecnologica2007–Universita degli Studi di Milano; Istituto Superiore di Sanita, “Na-tional research program on AIDS”; and Fondazione Romeo and EnricaInvernizzi.

Potential conflicts of interest. All authors: no conflicts.

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