Cytokine & Growth Factor Reviews 23 (2012) 207–214

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Cytokine & Growth Factor Reviews

journal homepage: www.elsevier.com/locate/cytogfr

The role of cytokines in the pathogenesis and treatment of HIV infection

Marta Catalfamo *, Cecile Le Saout 1, H. Clifford Lane 2
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1360, United States

A R T I C L E I N F O A B S T R A C T

Article history: HIV immune activation plays an important role in the immunopathogenesis of the disease. The
Available online 26 June 2012 mechanisms driving this immune activation are partially defined and likely are the result of multiple
factors. The introduction of combination antiretroviral therapy (cART) has improved the life expectancy
Keywords: of HIV infected individuals, however there is evidence that in the setting of ‘‘undetectable’’ HIV-RNA
CD4 and CD8 T cell immune activation plasma levels, there is some level of persistent immune activation in these patients. A better
T cell homeostasis understanding of the immune activation pathways should be of value in developing complementary
IL-7
therapies to restore the immune systems of patients with HIV infection. This review discusses the
Type-I IFN
cytokine mediated pathways of immune activation of the CD4 and CD8 T cell pools during HIV infection.
Published by Elsevier Ltd.

1. Pathogenesis of HIV infection immune system: B cells, NK cells, monocytes, macrophages and T
cells (HIV and non-HIV-specific CD4 and CD8 T cells) show
HIV infection targets the immune system leading to a state of evidence of immune activation [10,12–20]. Especially, in the T cell
immunodeficiency in a setting of immune activation. The compartment, immune activation is evidenced by increased T cell
molecular mechanisms causing the pathogenesis of HIV infection proliferation [21–25] and increased expression of cell surface
are still incompletely understood and are probably a composite of activation markers such as HLA-DR and CD38 [26–28]. In some
multiple factors. The acute phase of HIV infection or SIV infected studies this immune activation has been found to be a better
rhesus macaques (RM) is characterized by a substantial drop in correlate of clinical disease progression than CD4 T cell counts or
peripheral CD4 T cell counts and a substantial depletion of memory HIV-RNA levels [13,29], leading to the hypothesis that immune
CD4+ CCR5+ T cells [1–5]. In the chronic phase, a continued decline activation is a critical component in the pathogenesis of the
of CD4 T cells associated with ongoing HIV replication leads to the disease. The studies of SIV infection in natural hosts, Sooty
development of AIDS. The depletion of CD4 T cells by HIV direct mengabeys (SM) and African green monkeys (AGM) have
infection only partially explains the CD4 T cell pool depletion and a contributed to a better understanding of the role of immune
variety of bystander mechanisms have been described as activation in retroviral infections. In these animals, primary acute
contributing factors to CD4+ T cell death [6–9]. infection is associated with a modest and transient decline of
Early observations had shown that the selective depletion of the peripheral blood CD4 T cells in association with a severe depletion
CD4 T cells was accompanied by an aberrant immune activation of of CD4 T cells in mucosal tissues such as gut-associated lymphatic
all the components of the immune system in patients with HIV tissues (GALT) and lung [30,31]. The chronic phase of infection is
infection [10–12]. In the setting of an adaptive immune response characterized by low levels of immune activation despite high
against the virus, virtually all the cellular components of the levels of viremia. In contrast in non-human primates who develop
an AIDS-like illness following SIV infection (such as rhesus
macaques (RM)) the chronic phase of infection is characterized
* Corresponding author at: Laboratory of Immunoregulation, National Institute of by chronic immune activation similar to that observed in human
Allergy and Infectious Diseases, National Institutes of Health, 10 Center Drive, Bldg HIV infection [32].
10 Room 11B07, Bethesda, MD 20892-1360, United States. Tel.: +1 301 496 5309;
There is substantial evidence that immune activation plays an
fax: +1 301 402 4097.
E-mail address: [email protected] (M. Catalfamo). important role in the immunopathogenesis of HIV disease,
1
Laboratory of Immunoregulation, National Institute of Allergy and Infectious however, what triggers this immune activation; or how the
Diseases, National Institutes of Health, 10 Center Drive, Bldg 10 Room 11B07, Bethesda, natural hosts are able to down-regulate this response in the
MD 20892-1360, United States. Tel.: +1 301 443 8313; fax: +1 301 402 4097. chronic phase of the infection are still unresolved questions.
2
Laboratory of Immunoregulation, National Institute of Allergy and Infectious
Diseases, National Institutes of Health, 10 Center Drive, Rm. 4-1479, MSC 1460,
The introduction of combination antiretroviral therapy (cART)
Bethesda, MD 20892-1360, United States. Tel.: +1 301 4966572; fax: +1 301 480 5560. has improved the life expectancy of HIV infected individuals. An

1359-6101/$ – see front matter . Published by Elsevier Ltd.

http://dx.doi.org/10.1016/j.cytogfr.2012.05.007
208 M. Catalfamo et al. / Cytokine & Growth Factor Reviews 23 (2012) 207–214

increasing body of data has clearly demonstrated that despite cytopathic effect of HIV infection on CD4 T cells may explain part of
‘‘undetectable’’ HIV-RNA plasma levels (generally <50 copies/ml) this difference, however, the low number of cells actively infected
following initiation of therapy there remains evidence of persistent at any given point makes this an unsatisfactory explanation of the
immune activation, albeit at a lower level. This persistent immune great dichotomy seen between these two subsets [6–8].
activation takes a variety of forms. Its clinical significance is Increased activation of CD4 and CD8 T cells can be measured
strongly suggested by the increased risks of all-cause mortality by proliferation, in vitro and in vivo, through examination of the
associated with elevated levels of soluble markers of inflammation expression of nuclear antigens such as Ki67, measurement of
and coagulation such as, IL-6, sCD14 and D-dimer [33]. A better DNA content, or labeling with DNA precursors [21,23,34–37].
understanding of the pathways involved in immune activation Studies of in vitro and in vivo labeling in patients with HIV
pathways during HIV infection should be of value in the infection have shown that proliferation of both the CD4 and CD8
development of adjunct therapies that might lead to a more T cell pools is directly related to the level of HIV viremia and
quiescent immune system. significantly decreases after initiation of cART [21–23,25,38].
These earlier studies however, do not explain the selective
2. T cell immune activation depletion of CD4 T cells and expansion of CD8 T cells. One
hypothesis suggested by this observation is that different
It is likely that multiple forces are responsible for the disruption pathways of activation are triggered in CD4 and CD8 T cell
of the immune systems of patients with HIV infection (Fig. 1). An subsets with different end results. Among the possible pathways
unresolved paradox in patients with HIV infection is that while that have been studied are those associated with T cell
both CD4 and CD8 T cells are activated, one sees depletion of the homeostasis and those involved in the response to infection/
CD4 T cell pool and expansion of the CD8 T cell pool. A direct inflammation (pathogen-induced factors).

Fig. 1. Cytokines mediated pathways of immune activation in HIV infection. Distinct pathways in the immune activation of the CD4 and CD8 T cell pools in HIV infection: role
of the homeostatic forces (CD4 T cell counts/lymphopenia and IL-7) and inflammatory forces (HIV-replication and Type-I IFNs).
 M. Catalfamo et al. / Cytokine & Growth Factor Reviews 23 (2012) 207–214 209

2.1. CD4 T cell immune activation is driven by the homeostatic principal force driving proliferation of naı̈ve CD4 T cells. In contrast,
response to lymphopenia as well as HIV-induced inflammation memory CD4 T cell proliferation was associated with both CD4 T cell
depletion and HIV-RNA levels [50]. These same associations were
Homeostatic responses of the CD4 T cell pool are likely also observed in studies utilizing the in vivo labeling of proliferating
regulated to only allow a limited degree of expansion for each cells with BrdU [51]. These data are consistent with a recent report
individual cell so as to preserve diversity of the repertoire [39,40]. that, in adult humans, the maintenance of the naı̈ve CD4 T cells pool
In lymphopenic conditions such as HIV-induced lymphopenia, is mainly mediated by expansion of peripheral naı̈ve T cells, and also
post-bone marrow transplant and idiopathic CD4 T cell lympho- provides evidence of the important role of peripheral homeostasis in
penia, there is a homeostatic response reflected by robust HIV infection [52,53]. In addition, recent reports in the pathogenic
proliferation of T cells in response to increased levels of model of SIV infection (RM) have suggested independent pathways
homeostatic cytokines such as IL-7 [41–46]. This process, triggered of homeostasis in the naı̈ve and memory T cell compartments in the
in response to alterations in the pool size, is designed to restore context of chronic SIV infection [54].
steady-state levels of CD4 T cells [44,47].
We have recently tested the hypothesis that CD4 T cell 2.2. CD8 T cell immune activation is predominantly driven by HIV-
activation in the setting of HIV infection is the net result of replication and its associated inflammatory environment
homeostatic forces derived from CD4 depletion coupled with the
influence of an inflammatory environment that is generated and The study to define the forces driving proliferation of CD8 T
maintained by HIV-replication (Fig. 1). By measuring ex vivo cells showed that levels of HIV-RNA were the main influence. In
proliferation in a large cohort of HIV infected individuals, we found contrast to CD4 T cells, there was no evidence of homeostatic
that CD4 T cell proliferation was driven by the combination of CD4 forces contributing to the proliferation of CD8 T cells [48]. This
depletion and HIV viral load. The strong associations between CD4 was in agreement with early studies demonstrating that
T cell proliferation and CD4 T cell depletion, suggest that proliferation of the T cells in HIV infected patients was a
homeostatic forces represent an important factor in the CD4 T function of the level of viremia and was significantly reduced
cell immune activation seen in patients with HIV infection after treatment with cART [21,23,25,55]. The studies of in vitro
[41,48,49]. The role of HIV viral load is discussed in the next [50] and in vivo [51] proliferation of the CD8 T cell subsets,
section. showed that the rates of proliferation of naı̈ve CD8 T cells, unlike
To better understand the contribution of homeostatic forces to naı̈ve CD4 T cells, only correlated with HIV-RNA levels, rather
the immune activation of the CD4 T cell pool, we analyzed the than both HIV-RNA levels and homeostatic forces. In addition, an
spontaneous ex vivo proliferation of CD4 T cells from healthy analysis of the relative contributions of CD4 and/or CD8 T cell
controls and HIV infected patients. Our data demonstrated that the counts to the proliferation of the CD8 T cell pool in healthy
CD4 T cell proliferation was highly controlled by the CD4 counts and controls (Fig. 2 and [50]), revealed that CD8 T cell proliferation
this regulatory mechanism was active during HIV infection (Fig. 2). was not influenced by the size of either the CD4 or CD8 T cell
Interestingly, we also found that HIV-induced lymphopenia was the pools. These results highlight intrinsic differences in the
homeostatic regulation of the CD4 and CD8 T cell pool and
suggest that the size of the CD8 T cell pool is not generally under
Contribution of the CD4 T cell counts in the proliferation tight homeostatic control [47,50,53]. In addition, these results
of CD4 and CD8 T cells showed evidence of the great capacity of the CD8 T cell pool to
expand in response to inflammation/viral infection.
(A) 0.8
HIV infected paents
3. Cytokine and immune activation pathways
%BrdU+ T cells

0.6
CD4 T cells
CD8 T cells
In the course of chronic HIV infection, homeostatic forces and
0.4 HIV-induced inflammation differentially affect CD4 and CD8 T cell
CD4 count cells/μl immune activation. These differences are reflected in the ways that
0.2 LOW: <300
HIGH: >800
these T cell pools respond to the inflammatory and homeostatic
environments (Fig. 1).
00
0.0 Viral Load copies/ml
LOW HIGH LOW HIGH LOW: <50
H

CD4 counts CD4 counts HIGH: >10,000 3.1. HIV-induced lymphopenia: the role of IL-7
High viral load Low viral load
It has been shown that levels of IL-7 in serum and tissue during
HIV-induced lymphopenia are strongly correlated with the degree
of CD4 T cell depletion [41]. IL-7 is a member of the common
(B) gamma-chain (gc) family of cytokines that includes IL-2, IL-15 and
0.10
Healthy Controls others. IL-7 is present in most tissues and produced by a variety of
%BrdU+ T cells

0.08 CD4 T cells cells, including: fibroblastic reticular cells (FRC) in the T cell zone of
CD8 T cells
0 06
0.06
lymphoid organs; thymic, liver and intestinal epithelial cells;
fibroblasts; keratinocytes; and dendritic cells [56–58]. Studies
CD4 count cells/μl
0.04
LOW: <500
have shown that IL-7 plays a crucial role in naı̈ve and memory T cell
HIGH: >800 homeostasis by regulating survival, proliferation and repertoire
0.02
diversity [39,43]. IL-7 signals through the IL-7 receptor (IL-7R), a
0.00 heterodimer consisting of the common-gamma chain receptor (gc
LOW HIGH or CD132) and the IL-7 receptor alpha chain (IL-7Ra or CD127).
CD4 counts Engagement of IL-7R by IL-7 activates Janus kinase-signal
Fig. 2. Contribution of the homeostatic forces (CD4 T cell counts) and HIV-RNA
transducers and activators of transcription (JAK-STAT) (mainly
levels in the proliferation of CD4 and CD8 T cell pools. HIV infected patients (A) and JAK1, JAK3 and STAT5), phosphatidylinositol 3-kinase (PI3K) and
healthy controls (B). Src family kinases signaling pathways [59,60].
210 M. Catalfamo et al. / Cytokine & Growth Factor Reviews 23 (2012) 207–214

Consistent with the observation that homeostatic forces can by IL-2 exhibit increased expression of CD25 and FOXP3 and thus
drive proliferation of the CD4 T cell pool during HIV infection, we are similar to regulatory T cells [76]. Phase III trials of this cytokine,
found increased mRNA expression of genes associated with gc however, demonstrated that these increases were of no clinical
cytokine signaling (such as IL2RG, SOCS1 and STAT5) in naı̈ve and benefit [77]. The reason for this paradox is still unclear but likely
memory CD4 T cells from patients with HIV-associated CD4 reflects the fact that any benefits derived from CD4 T cell expansion
lymphopenia. In contrast, the CD8 T cell subsets showed decreased were countered by the well-known ‘‘cytokine-storm’’ side effects
expression of these transcripts [50]. In addition, naı̈ve CD4 and CD8 of IL-2. More recently IL-7 has entered the clinical arena and has
T cells were able to respond to in vitro stimulation with IL-7 as been shown capable of inducing increases in numbers of not only
measured by STAT-5 phosphorylation. However, memory CD8 T CD4 T cells, but CD8 T cells as well [78,79]. Whether or not these
cells showed an impaired response to IL-7 consistent with the increases will prove to be of clinical benefit is under study. As in the
reported decrease of CD127 on this subset [61,62]. Memory CD4 T case of IL-2 the ‘‘blips’’ of viremia observed during IL-7
cells were able to phosphorylate STAT-5 in response to in vitro administration appear to be transient and similar to the viruses
stimulation. These observations are again consistent with the present prior to therapy [80]. IL-15 has been extensively studied in
hypothesis that CD4 and CD8 T cell subsets respond differently to non-human primate SIV models of HIV infection. Studies of IL-15 in
homeostatic forces [50]. acute SIV infection have demonstrated increases in the levels of SIV
It has been suggested that HIV-induced lymphopenia and the [81] while studies in chronic SIV infection have shown little, to no
associated increased levels of IL-7 play a role in the up-regulation effect [82,83]. Of note is the fact that the route and duration of IL-
of the expression of the death receptor Fas on naı̈ve T cells and an 15 administration may lead to drastically different effects on the
increased sensitivity to Fas-mediated apoptosis in T cells that immune system. In this regard, continuous I.V. infusion of low-
express CD127 [63–66]. dose IL-15 has been associated with a 100-fold increase in the
An important component of CD4 T cell homeostasis is the levels of effector memory CD8 T cells [84].
circulation of cells through lymphoid organs where they have the
opportunity to encounter their cognate antigen and/or to receive 3.2. The role of Type-I IFN and the HIV-induced inflammatory
survival signals from homeostatic cytokines [67]. Lymphoid organs environment
of patients with chronic HIV infection and non-human primate
modes of pathogenic SIV infection demonstrate increased fibrosis Type-I IFNs are a group of cytokines that exhibit anti-viral and
suggesting that these relationships may be altered in the setting of immunoregulatory properties in the setting of a viral infection
HIV infection [68–70]. Such alterations in lymphoid tissue [85]. In HIV infection, Type-I IFNs have also been associated with
mediated homeostasis including exposure to IL-7 and other immunopathogenesis. In vitro, plasmacytoid dendritic cells from
survival signals may play a role in the depletion of CD4 and CD8 healthy controls can be induced by infectious or non-infectious
naı̈ve [71] and memory [72] T cells. Of note is the fact that this HIV to secrete Type-I IFNs [86] that can lead to an increased
process can be at least partially reversed by cART [73]. expression of death receptors (DR5/TRAIL) on primary CD4 T cells
[86,87]. Type-I IFN-dependent increases of the enzyme 2,3-
3.1.1. gc-cytokines and therapy dyoxigenase (IDO) in plasmacytoid dendritic cells have been
Given these data it is not surprising that gc using cytokines have detected in the lymphoid tissues of patients with HIV infection
been studied as possible therapeutic agents in patients with HIV [88,89]. IDO catalyzes the degradation of an essential amino acid
infection in general, and patients with persistent lymphopenia in (tryptophan) which is important for the metabolism of T cells [90].
particular. Extensive studies with IL-2 have demonstrated that this Taken together, these observations have led to the hypothesis that
cytokine is capable of increasing levels of naı̈ve and central chronic exposure to Type-I IFN can play a role in the pathogenesis
memory CD4 T cells with minimal effects on the CD8 T cell pool of HIV infection. The role of the chronic exposure to Type-I IFNs and
(Fig. 3) [74,75]. While capable of inducing ‘‘bursts’’ of HIV viremia immunopathogenesis of HIV infection have also been noted in
in patients not on effective cART, IL-2 administration was not studies of non-pathogenic SIV infection (SM and AGM). The acute
associated with increases in plasma levels of HIV. The cells induced infection in these animals is very similar to that observed in
pathogenic models of SIV infection (RM) in which a robust Type-I
IFN response dominates this first phase of the infection. In the
Changes in CD4 T cell counts in the setting of a chronic phase, while SM and AGM are able to down-regulate the
randomized, controlled trial of IL-2 inflammatory response and interferon production, SIV infected RM
1600 are not and show a sustained Type-I IFN response and progression
1400 IL 2 + Anti-Retroviral
IL-2 Anti Retroviral CD4 to AIDS [32]. This downregulation of Type-I IFN response is seen in
4+ T cells/µl

Anti-Retroviral p <0.001 the non-pathogenic models despite high viral replication and is
1200
associated with decreases in immune activation and increases in
1000
transcriptional profiles of regulatory cytokines [91–93]. In humans
800 with chronic HIV infection a strong transcriptional profile of genes
CD4

600 associated with Type-I IFN signaling has been described [94–97].
400 To understand any differences in the effects of HIV infection and
interferon exposure in the immune activation of CD4 and CD8 T
200 IL-2 Every 8 Weeks
cells we analyzed the transcriptional profile of genes associated
0
0 2 4 6 8 10 12 14 with Type-I IFN signaling in naı̈ve and memory CD4 and CD8 T cell
Month of Study subsets. Both CD4 and CD8 T cells from viremic HIV infected
individuals showed increased mRNA transcripts associated with
IL-2 n = 30 30 30 30 30 29 30 29 29 29 29 29 29 29 29 Type-I IFN signaling. Interestingly, naı̈ve and memory CD4 T cells
ARVs demonstrated enhanced STAT1 phosphorylation in response to
29 29 29 29 29 29 29 28 28 26 27 28 29 29 29
alone Type-I IFN in vitro. This was not observed in the CD8 T cell subset
Fig. 3. Effect of IL-2 administration in CD4 T cell counts. The error bars represent 2
[50]. These results highlight differences in the ability of CD4 and
SE and approximate the 95 percent confidence intervals. Values at month 0 (base line) CD8 T cells from patients with HIV infection to respond to Type-I
are the means of three values measured before the beginning of the study. IFN. This enhanced responsiveness of CD4 T cells to Type-I IFN may
 M. Catalfamo et al. / Cytokine & Growth Factor Reviews 23 (2012) 207–214 211

have detrimental consequences on CD4 T cell homeostasis and a classic antiviral in this setting. Also of note is the fact that
survival. Given this and the data on the impact of homeostatic responses of patients with hepatitis C to IFN-alpha are better in
cytokines in the setting of HIV infection, we can postulate a patients with lower levels of IFN-associated gene activation pre-
scenario whereby exposure to homeostatic cytokines creates a therapy [99]. In addition, IFN-alpha may have a therapeutic effect
state within the CD4 (but not the CD8) T cell pool where chronic in some patients with HIV infection, but only in those patients not
exposure to Type-I IFN leads to depletion of the pool. In contrast exhibiting high levels of IFN-alpha in vivo at the time therapy is
the CD8 pool has little response to homeostatic forces and initiated.
undergoes expansion in the setting of an antigen-driven and
inflammatory stimuli.
4. Inflammation and biomarkers: IL-6, sCD14 and D-dimer

3.2.1. IFN-alpha and therapy

The introduction of cART has improved the life expectancy of
One seeming paradox in the clinical management of patients
HIV infected individuals. While antiretroviral therapies are
with HIV infection is the fact that this cytokine has anti-neoplastic
capable of suppressing plasma levels of HIV to <50 copies/ml
and anti-viral activities when given therapeutically (Fig. 4). IFN-
for extended periods of time, levels of viral replication return to
alpha is licensed for the treatment of AIDS-related Kaposi’s
baseline within weeks of stopping therapy and thus patients with
sarcoma. Of note is the fact that the clinical efficacy of IFN-alpha
HIV infection today face the likelihood of life-long therapy. An
in this setting is directly correlated with the CD4 T cell count of the
increasing body of data are clearly demonstrating that despite
patient, strongly suggesting that this anti-tumor effect is due to
plasma levels of HIV that are ‘‘undetectable’’ there is evidence of
modulation of the immune system rather than due to a direct anti-
persistent virus and persistent immune activation in patients
proliferative effect of IFN. Similarly, when given to patients with
receiving antiretroviral therapy [100,101]. This persistent intra-
early stages of HIV infection, IFN-alpha has an anti-viral effect that
cellular reservoir of HIV is felt to be present at several anatomical
is stronger than the anti-retroviral effect of the first licensed
locations such as the peripheral lymphoid tissue, gastrointestinal
antiretroviral drug, zidovudine (AZT) [98]. Again supporting the
tract and central nervous system [8,102–105]. The persistent
hypothesis that IFN-alpha has potentially positive immunomodu-
immune activation seen in patients with HIV infection despite
latory effects in patients with early stages of HIV infection are the
HIV-RNA levels <50 copies/ml is likely associated with this
observations that the anti-retroviral effects of IFN-alpha are most
reservoir and is clinically significant. Compared to control
pronounced in patients with the highest CD4 counts and that the
populations, patients with HIV infection have been shown to
loss of activity seen over time is not associated with the emergence
have increased levels of the inflammatory markers IL-6 and sCD14
of resistant strains of HIV. In other words, IFN-alpha is not acting as
and the fibrinogen breakdown product D-dimer. Patients with
higher levels of these biomarkers are at an increased risk of all-
cause mortality and significant hepatic, metabolic, renal and
cardiovascular morbidity is observed in these patients despite HIV
RNA levels <50 copies/ml [33,106]. Levels of these biomarkers are
directly correlated with levels of HIV RNA following discontinua-
tion of cART reflecting the important relationships between viral
load, inflammation, coagulation and end-organ damage in the
setting of HIV infection.
In summary, the immune systems of patients with HIV
infection are characterized by an immunodeficiency occurring
in the setting of immune activation. The CD4 T cell pool declines
while the CD8 T cell pool expands. Homeostatic cytokines such as
IL-7 and pro-inflammatory cytokines such as IFN-alpha are
elaborated and may play a significant role in some of the
pathologic aspects of HIV infection. An interaction between IL-7
and IFN-alpha signaling may be responsible for the death of CD4 T
cells. Both of these cytokines have been studied as potential
therapeutic agents in the setting of HIV-1 infection. While IL-7 has
been shown capable of expanding the CD4 and CD8 pools of T cells
the clinical impact of these expansions is, as yet, unknown. IFN-
alpha is a FDA-approved treatment for Kaposi’s sarcoma and has
been shown to have anti-HIV properties but the precise
mechanisms whereby these effects take place have not been
determined. Further understanding the role of these and other
cytokines in the setting of HIV-1 infection will not only expand our
knowledge of the pathogenesis and treatment of HIV but also
enhance our understanding of the role of the cytokines in health
and disease.

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214 M. Catalfamo et al. / Cytokine & Growth Factor Reviews 23 (2012) 207–214

Dr. Marta Catalfamo received a Biochemistry degree at particularly the cross-talk between the cytokines asso-
the National University of Tucuman. Argentina. She ciated with the homeostatic (IL-7) and the inflammatory
obtained her PhD degree in Immunology from the Au- (Type-I IFN) environments induced by HIV infection.
tonomous University of Barcelona, Spain. She did her
postdoctoral studies in human CD4 and CD8 T cell
function, and she defined a new regulated secretory
pathways for the chemokine RANTES. After completing H. Clifford Lane received his M.D. degree from the
her post-doctoral training at the National Cancer Insti- University of Michigan in 1976. He then completed
tute, NIH, she joined as staff scientist at the Laboratory an internship and residency at the University of Michi-
of Immunoregulation at NIAID, NIH. Her research focus- gan Hospital, Ann Arbor, Michigan. In 1979, he came to
es in understanding the cytokine-driven mechanisms of the National Institutes of Health (NIH) as a clinical
immune activation during HIV infection. Her work has associate in the Laboratory of Immunoregulation (LIR)
delineated clear differences in the activation of CD4 and of the National Institute of Allergy and Infectious Dis-
CD8 T cell pools in patients with HIV infection. Her studies are directed to address eases (NIAID). He is currently chief of the Clinical and
how the homeostatic response to CD4 T cell depletion and the inflammatory Molecular Retrovirology Section of the LIR and the
response to HIV infection affect the immune activation of CD4 and CD8 T cell clinical director, director of the Division of Clinical
subsets. Particularly, the interactions of the signaling pathways between IL-7 and Research and Deputy Director for Clinical Research
Type I IFNs associated with these two environments. and Special Projects of NIAID.

Dr. Cecile Le Saout obtained her Master’s degree in He became one of the first investigators to study immunopathogenic mechanisms
Biology and Health in 2005 and her PhD degree in of HIV disease, ultimately making a series of observations that helped establish the
Immunology in 2009, from the University of Montpellier field of HIV immunopathogenesis. In the clinical arena, he has studied innovative
II, France. She joined the Laboratory of Immunoregula- approaches to therapy and has used experimental therapeutic interventions as a
tion at the National Institute of Allergy and Infectious means of furthering our understanding of HIV pathogenesis. Among other things, he
Diseases, NIH for post-doctoral training in 2010. Her has investigated the strategies of syngeneic bone marrow transplantation, adoptive
research is focused on elucidating the molecular mech- transfer of lymphocytes, and role of the cytokines alpha interferon and IL-2 in the
anisms of T cell immune activation during HIV infection, treatment of patients with HIV infection.