REVIEW ARTICLE

Adipose Tissue and Immune Function: A Review

of Evidence Relevant to HIV Infection
John R. Koethe,1 Todd Hulgan,1 and Kevin Niswender2,3
1
3

Division of Infectious Diseases and 2Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University School of Medicine; and
Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville

Keywords. HIV; antiretroviral therapy; adipose tissue; obesity; inammation; immune activation.
Since the introduction of effective antiretroviral therapy
(ART), the prevalence of human immunodeciency virus
(HIV)associated wasting has declined, while the proportion of overweight and obese HIV-infected individuals
has increased [1]. Obese HIV-infected individuals have a
greater prevalence of cardiovascular and metabolic diseases, compared with lean patients [2, 3]. Beyond these
classic comorbidities, the observations that obese
HIV-patients often have greater increases in systemic
inammation and that they possibly have a different
pattern of immune reconstitution have increased interest
in the interaction of adiposity and HIV immunology.
Adipose tissue represents one of the largest organs in
the body and comprises a range of cell types with diverse
energy storage, metabolic regulation, neuroendocrine,
and immunologic functions. HIV infection and ART
cause alterations to adipose tissue distribution and
Received 4 January 2013; accepted 28 March 2013; electronically published 21
July 2013.
Correspondence: John R. Koethe, MD, MS, Division of Infectious Diseases, Vanderbilt University Medical Center, A2200-MCN, 1161 21st Ave S, Nashville, TN
37232-2582 ( john.r.koethe@vanderbilt.edu).
The Journal of Infectious Diseases 2013;208:11941201
The Author 2013. Published by Oxford University Press on behalf of the Infectious
Diseases Society of America. All rights reserved. For Permissions, please e-mail:
journals.permissions@oup.com.
DOI: 10.1093/infdis/jit324

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biology, with broad effects on cytokine and hormone

expression, lipid storage, and the composition of
adipose-resident immune cell populations. The resultant
changes appear to have important consequences for
basal systemic inammation and the adaptive immune
response2 aspects of immunology with direct relevance
to HIV infection. In this review, we synthesize current
literature on the role of adipose tissue in innate and cellular immune function (Table 1), which reveals the multifaceted contribution of adiposity to the bodys response
to HIV infection and highlights key outstanding research
questions in the eld.
PART I: ADIPOSE TISSUE PROMOTES
A PERSISTENT INFLAMMATORY
RESPONSE DURING TREATMENT
OF HIV INFECTION
HIV Infection Alters Adipose Tissue Distribution
and Metabolic Characteristics

Approximately 50% of HIV-infected individuals receiving long-term ART demonstrate altered adipose tissue
distribution, characterized by peripheral lipoatrophy of
the limbs, face, and buttocks; lipohypertrophy of the visceral, cervical, and dorsocervical area (ie, the buffalo
hump); or a combination of these changes [4, 5]. The

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Human immunodeciency virus type 1 (HIV) infection and antiretroviral therapy (ART) have long been
associated with abnormalities in adipose tissue distribution and metabolism. More-recent evidence demonstrates that adipocytes and adipose-resident immune cells have a role in the response to HIV. Clinical and
laboratory studies indicate that viral proteins and antiretroviral medications alter adipocyte biology to enhance
the persistent, systemic inammatory state characteristic of untreated and treated HIV infection. Relationships
between body composition and lymphocyte populations, cellular immune activation, and immune reconstitution in HIV-infected individuals receiving ART suggest that adipose tissue may also affect cellular immune
function. This is further supported by in vitro studies demonstrating the effect of adipocytes and adipokines
on lymphocyte proliferation, differentiation, and activation. Synthesis of the literature on adipose tissue
biology and immune function in uninfected individuals may shed light on major outstanding research
questions in the HIV eld.

Table 1.

Summary of Current Findings and Important Future Research Areas

Summary Points
Part 1: Adipose Tissue and Inflammation
Increased adiposity in HIV-infected individuals is associated with proportionally higher serum inflammation biomarkers implicated in the
development of cardiometabolic diseases [41]
HIV proteins (eg, Vpr and Tat) disrupt adipogenesis and promote adipocytes expression of inflammatory mediators in vitro [51, 52, 54]
Both nucleoside reverse-transcriptase inhibitors and protease inhibitors promote lipodystrophy and adipose tissue inflammation;
intraclass variability exists, and some effects are reversible [5658, 6466]
Adipose tissue from obese subjects has a higher density of inflammatory (M1) macrophages, CD4+ T cells and CD8+ T cells and fewer
T-regulatory cells in both animal and human studies [2835]
Subcutaneous adipose tissue exhibits greater fibrosis and disrupted adipogenesis as compared to visceral adipose tissue in treated HIV
infection but similar expression of inflammatory cytokines [10, 71, 72]

Key Outstanding Research Questions

What are the long-term health outcomes among overweight and obese HIV-infected patients?
Does the relationship between serum inflammation biomarkers and cardiometabolic disease risk differ between obese and nonobese
HIV-infected patients?
What is the proportional contribution of in situ adipose tissue inflammation to circulating biomarker levels in HIV-infected patients?
Does dysregulated lipid storage in peripheral fat promote visceral and dorsocervical fat hypertrophy?
How do immune cell populations in the ectopic accumulations of pericardial, muscle, and hepatic fat observed in treated HIV infection
contribute to metabolic disruptions and disease states?
Why does visceral adipose tissue demonstrate less disrupted adipogenesis than subcutaneous adipose tissue?
Does adipose tissue inflammation attract T cells, or do activated T cells preferentially infiltrate adipose tissue?
What mechanism promotes T-cell infiltration and retention in adipose tissue? Does it differ between subcutaneous and visceral
deposits?
Do adipose-resident immune cell populations in HIV-infected individuals of equivalent adiposity differ by sex, age, or race/ethnicity?
What are genetic determinants of adipose tissue inflammation and immune cell infiltration?
Does adipose tissue promote increased peripheral cellular immune activation in treated HIV infection?
Does circulating leptin affect peripheral T-cell numbers, T-cell activation status, or T-helper cell polarization in vivo?
Abbreviations: ART, antiretroviral therapy; HIV, human immunodeficiency virus; Th1, T-helper cell type 1.

cause of HIV-associated lipodystrophy is hypothesized to be

multifactorial and due to antiretroviral toxicity, direct effects of
HIV infection, and dysregulation of lipid metabolism, among
other factors [6]. Irrespective of etiology, the resultant differences
in adipose tissue metabolic activity are informative for understanding the pathogenesis of this condition. Whole-body positron emission tomography (PET) of 18F-uorodeoxyglucose
(FDG) uptake by regional fat deposits demonstrates higher metabolic activity in subcutaneous extremity and abdominal adipose
tissue deposits of ART treated adults relative to uninfected controls, while uptake in visceral adipose tissue remains normal
despite the frequent enlargement of this compartment on ART
[7, 8]. Furthermore, FDG uptake in subcutaneous extremity fat is
positively correlated with the degree of lipoatrophy, independent
of body mass index (BMI; calculated as the weight in kilograms
divided by the height in meters squared), indicating an accelerated cellular metabolism in lipoatrophic deposits [8]. Subcutaneous fat biopsy specimens from individuals with HIV-associated
lipoatrophy demonstrate reduced mitochondrial DNA (mtDNA)

and structural changes characterized by increased brosis and

apoptosis, heterogeneous mitochondrial mass, and formulation
of lipogranulomas, while the adipocytes demonstrate reduced expression of several transcription factors necessary for cellular differentiation and fatty acid uptake but higher tumor necrosis
factor (TNF-) and interleukin 6 (IL-6) expression [913].
Taken together, these ndings indicate a shift to a proinammatory, probrotic, and dysregulated metabolic state within the
subcutaneous fat tissue of these patients.
The enlargement of the visceral adipose compartment and
the hypertrophy of dorsocervical adipose deposits (ie, the
buffalo hump) in ART-treated individuals has been attributed to an energy excess state resulting from increased circulating lipids in combination with decient energy storage in
atrophied and brotic subcutaneous fat [14, 15]. Studies of dorsocervical fat from HIV-infected individuals have shown less
dysregulated adipogenesis and in situ inammation, compared
with other subcutaneous fat deposits, and a unique pattern of
glucose uptake and gene expression different from the highly
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Part 2: Adipose Tissue and Cellular Immune Function

Higher body mass index was associated with slower CD4+ T-cell decline and progression to AIDS in the pre-ART era [7375]
Obesity is associated with diminished early CD4+ T-cell recovery during ART in preliminary studies [7678]
Congenital lipodystrophy and malnutrition in HIV-uninfected individuals is associated with lower peripheral lymphocyte counts and
decreased T-cell responses [7981, 8486]
Obesity in HIV-uninfected individuals is associated with higher peripheral T-cell counts, T-cell activation, and Th1-type CD4+ T-cell
polarization in preliminary studies [28, 87, 88]
Leptin is constitutively produced in proportion to adipose tissue mass and promotes T-cell proliferation, T-cell activation, and T-helper
cell polarization in vitro [101106]
Pilot studies of recombinant methionyl human leptin have shown beneficial effects in HIV lipodystrophy but no effect on CD4+ T-cell
recovery [107109]

thermogenic, mitochondria-rich brown fat depot characteristically found in this region in uninfected persons [16]. HIV-infected adults with clinically apparent neck fat accumulation
demonstrate higher expression of DIO2 (which encodes type II
iodothyronine deiodinase, a deiodinase that converts T4 to
active T3 and contributes to thermogenesis), characteristic of
brown fat, but uncharacteristically low PET-FDG uptake and
expression of UCP-1 (the gene that encodes uncoupling protein
1 and is expressed in typical brown adipose tissue, which separates oxidative phosphorylation from adenosine triphosphate
synthesis to dissipate energy as heat), suggesting a whitening
of this ordinarily brown depot [17].
In addition to visceral and dorsocervical fat enlargement, the
accumulation of ectopic adipose tissue in a variety of organs in
treated HIV infection may contribute to local inammation and
end-organ disease. HIV-infected men have increased epicardial
fat, associated with a higher risk of CVD events, and increased
hepatic and muscle fat inltration, associated with greater insulin
resistance, compared with uninfected men with similar cardiovascular and metabolic disease risk proles [1820].
Adipose Tissue Constitutively Expresses a Range of
Proinammatory Factors

Obesity is a proinammatory condition in which hypertrophied

adipocytes and adipose-resident immune cells (primarily macrophages and, to lesser extent, lymphocytes and neutrophils) contribute to increase the levels of circulating proinammatory
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cytokines [2123]. Higher adipose tissue mass is primarily due

to adipocyte hypertrophy, rather than to hyperplasia, and interval increases in adipocyte size result in disproportionate increases in IL-6 and TNF- expression [2426]; it is estimated that
adipose tissuederived IL-6 constitutes up to 35% of circulating
levels in obese individuals and serves as a major signaling
pathway for C-reactive protein (CRP) production [27].
Immune cell inltration of adipose tissue accompanies progressive weight gain and contributes to in situ inammation.
Biopsy specimens from obese individuals and animal models
contain higher absolute numbers of resident macrophages and
proportionally greater polarization toward an M1 proinammatory phenotype (characterized by high IL-6, TNF-, and
inducible nitric oxide synthase production), higher numbers of
CD4+ and CD8+ T cells, but fewer T-regulatory cells [2833].
Additionally, there is increased neutrophil inltration, which is
accompanied by greater in situ inammation and reduced
insulin sensitivity in a murine model and by increased vascular
inammation in humans [34, 35]. Adipocyte hypertrophy is associated with increased production of macrophage chemotactic
protein 1 and macrophage inammatory protein 1, which
promote macrophage inltration, and with increased production of interleukin 8, which promotes neutrophil chemotaxis
[3638]. In mice, diet-induced obesity also results in increased
macrophage CCR5 expression, accompanied by greater insulin
resistance and hepatic lipid content, and a shift toward M1 predominance [39]. Future studies are needed to evaluate whether

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Figure 1. Effects of human immunodeciency virus (HIV) infection, antiretroviral therapy, and obesity on adipose tissue biology. Abbreviations: IL-6, interleukin 6; MCP-1, macrophage chemotactic protein 1; MIP-1, macrophage inammatory protein 1; mtDNA, mitochondrial DNA; PPAR-, peroxisome
proliferator-activated receptor ; TNF-, tumor necrosis factor [913, 2126, 2833, 3638, Supplementary data 5155, 64-66, 71, 72].

CCR5 inhibitor treatment (eg, maraviroc) affects macrophage

activation or other aspects of adipose tissue biology in obese
HIV-infected patients.
Greater Adiposity Is Associated With Increased Systemic
Inammation in Treated HIV Infection

HIV Proteins and Some Antiretroviral Agents Disrupt

Adipocyte Biology

There are conicting reports on whether adipocytes express

HIV entry receptors, but if entry does occur it appears that adipocytes may produce early, but not late, viral transcripts unless
further stimulated via exogenous TNF- [49, 50]. Irrespective
of direct infection, many adipose-resident immune cells (eg,
lymphocytes and macrophages) are susceptible to infection,
and adipocytes may be persistently exposed to high local levels
of viral proteins. The viral protein Vpr, in particular, can enter
adipocytes from the extracellular uid in the absence of direct

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Treated HIV infection may be equivalent to obesity in terms of

the level of basal inammation and the presence of other risk
factors for chronic cardiovascular and metabolic diseases.
HIV-infected men who are receiving ART and have a normal
BMI (ie, <25) have statistically equivalent serum CRP levels, as
measured by the high-sensitivity assay (hsCRP; a predictor
of cardiovascular events in several studies), IL-6 levels, and
TNF- levels and similar lipid proles and insulin levels, compared with HIV-uninfected men who are resistant to insulin
and obese (dened as a BMI of >30) [40].
As observed in the general population, serum levels of
hsCRP are also higher among HIV-infected adults with greater
adiposity [4144]. In the Fat Redistribution and Metabolic
Change in HIV Infection (FRAM) cohort, each 2-fold increase
in visceral adipose tissue mass was associated with a 17%
higher hsCRP level, while a similar increase in subcutaneous
adipose tissue mass was associated with a 21% higher level [41].
However, the proportional increase in hsCRP level with each
doubling of visceral or subcutaneous fat mass in HIV-infected
participants was smaller than the change observed in
uninfected controls (34% and 61%, respectively). CRP is a
terminal product of the inammation cascade and may be an
imprecise measure of circulating cytokine levels earlier in the
signaling pathway. For example, there is some evidence that the
serum hsCRP level increases after starting treatment with nonnucleoside reverse-transcriptase inhibitors but decreases during
treatment with protease inhibitors, and hsCRP levels in
HIV-infected patients may also be affected by hepatitis C virus
coinfection, statin use, hepatic steatosis, and other factors
[41, 4548]. Given these and other potential confounders,
translational studies of viral protein and antiretroviral agent
effects on adipocyte function are useful to understand potential
mechanisms underlying the association between adiposity and
circulating inammatory biomarkers in HIV-infected individuals.

viral infection and acts as a potent repressor of peroxisome proliferator-activated receptor (PPAR-). PPAR- is a transcriptional regulator of adipogenesis (ie, the differentiation of
preadipocytes into adipocytes) and the maintenance of normal
lipogenesis, insulin sensitivity, and normal cytokine/adipokine
expression [51, 52]. The interaction of viral proteins and adipocyte biology is complex and an area of continuing research; for
instance, HIV Tat protein has been shown to impair adipogenesis and increase inammatory cytokine expression in preadipocytes in vitro, while HIV Tat-interacting protein 60 has been
shown to act as an adipogenic, positive regulator of PPAR-
transcriptional activity [53, 54]. Interestingly, the effects of HIV
proteins on adipose tissue appear to be independent of plasma
viremia; a recent study found signicantly lower PPAR- and
higher TNF-, interleukin 18, and 2-microglobulin messenger
RNA (mRNA) expression in adipose tissue from long-term nonprogressors (ie, HIV-infected individuals with minimal CD4+ Tlymphocyte loss and low plasma viremia for many years), compared with uninfected controls [55].
Early studies reported that nucleoside reverse-transcriptase inhibitors (NRTIs) promoted lipoatrophy, whereas protease
inhibitors predisposed to visceral lipohypertrophy, but evolving
data reveals intraclass variability in these effects and complex
synergistic relationships [5658]. Loss of limb fat, attributed to
mtDNA polymerase inhibition and impaired respiratory chain
efciency in adipocytes, is more prevalent with older thymidine
analogues (stavudine and zidovudine) than with newer agents
(lamivudine, abacavir, and tenofovir), and there is evidence that
mtDNA haplogroup may inuence susceptibility [11, 57, 5963].
Adipose tissue samples from lipoatrophic individuals treated
with zidovudine or stavudine demonstrate higher macrophage
inltration and proinammatory cytokine production, both of
which increase with treatment duration, compared with samples
from lipoatrophic individuals receiving an abacavir- or tenofovir-based regimen [64]. Some adverse NRTI effects on adipose
tissue appear reversible; patients receiving a stavudine- or zidovudine-containing regimen with reduced mtDNA cellular
content and activity in subcutaneous adipose tissue demonstrated increased mtDNA and mitochondrial gene expression, improved respiratory chain function, and reduced adipocyte
apoptosis after switching to a newer NRTI [65, 66].
Protease inhibitors are implicated in visceral fat accumulation
and a combined phenotype of insulin resistance and dyslipidemia, in addition to higher adipocyte oxidative stress, proinammatory cytokine expression, and apoptosis and reduced
adipokine expression and insulin signaling [58, 6769]. A recent
study investigating the in vitro effect of nelnavir on subcutaneous versus intraabdominal murine preadipocyte cell lines found
increased lipolysis and a greater reduction in insulin signaling
and leptin secretion in subcutaneous cells, compared with visceral
cells, illustrating a possible mechanism for the preferential gain in
central adiposity observed with protease inhibitor treatment [70].

PART II: ADIPOSE TISSUE AFFECTS

LYMPHOCYTE FUNCTION AND MAY ALTER
IMMUNE RECONSTITUTION
A Higher BMI Was Associated With Slower HIV Disease
Progression in the Pre-ART Era

Studies from the pre-ART era found that a higher BMI was
associated with slower disease progression in untreated HIV
infection. In a cohort of HIV-infected drug users, 19% of
the obese participants exhibited a >25% decline in CD4+ T cell
counts after 18 months, compared with 61% of nonobese
participants, despite similar starting CD4+ T-cell counts [73]. In a
longitudinal study of HIV-infected women, a BMI of 30 was associated with a slower progression to a CD4+ T-cell count of
<200 cells/L and a lower risk of an AIDS-dening event or HIVrelated death, while in a similar study each 1-unit decrement in
initial BMI was independently associated with a 24% higher risk
of progression to AIDS [74, 75]. These results suggest that a high
BMI has a protective effect, but it is unclear whether the slower
disease progression and lower mortality observed in the pre-ART
era were due to adiposity or to related factors, such as fewer secondary infections, fewer micronutrient deciencies, reduced gut
permeability, or the absence of HIV-associated wasting.
Recent Evidence Suggests Obesity Is Associated With
Decreased Early Immune Reconstitution

In contrast to data from the pre-ART era that showed a slower

decline in CD4+ T-cell counts in heavier patients, recent studies
have shown that obesity does not increase CD4+ T-cell count recovery during ART and may actually impair it. An analysis from
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the US Military HIV Natural History Study found that obesity

was associated with a signicantly lower adjusted gain in CD4+ Tcell counts after ART, compared with normal-weight patients [76].
A similar analysis of the HIV Outpatient Study cohort, however,
found that patients who were overweight or obese had a statistically equivalent increase in CD4+ T-cell count 39 months after
ART initiation, relative to patients with a normal weight [77].
A more recent cohort study of HIV-infected adults with a
high prevalence of obesity found that 12-month increases in
CD4+ T-lymphocyte counts after treatment initiation were
greatest among those with a pretreatment BMI of 2530, compared with those with BMIs above or below this range [78].
Among patients with a pretreatment CD4+ T-lymphocyte
count of <200 cells/L, those with a BMI of 25 had the highest
odds of reaching a CD4+ T-lymphocyte count of >350 cells/L
at 12 months. These ndings indicate that body composition
affects peripheral CD4+ T-lymphocyte recovery, but the mechanisms underlying this observation and the reproducibility in
other populations are important areas for further study.
Excess Adiposity Is Associated With Changes in Peripheral
Immune Cell Populations and Increased Markers of Cellular
Immune Activation in HIV-Uninfected Persons

A minimum quantity of adipose tissue appears necessary to

maintain normal-range lymphocyte subset counts, but assessing the relationship between adiposity and peripheral T-cell
populations in the setting of HIV infection is confounded by
CD4+ T-cell depletion, variations in immune recovery during
ART, and the effects of cellular immune activation. Thus,
studies of HIV-uninfected individuals may be revealing in this
area, and a synthesis of this literature suggests a positive relationship between adipose tissue and lymphocyte proliferation,
CD4+ T-cell counts, and lymphocyte activation.
In small studies of persons with congenital and acquired
lipodystrophy, lymphocyte subsets, including CD4+ T cells,
were in the low-normal range, but peripheral blood mononuclear cell TNF- expression in response to antigen stimulation
was signicantly reduced, compared with that for normal controls [79, 80]. Similarly, studies of individuals with advanced
clinical malnutrition have found reduced peripheral lymphocyte and eosinophil counts [81], a reversal of the T-helper/
suppressor ratio [82, 83], decreased T-cell primary antibody response and memory response [84], and atrophy of the lymph
tissues, compared with nonmalnourished persons [85, 86].
Last, a longitudinal survey of HIV-uninfected women found
that being overweight, obese, or morbidly obese was independently associated with higher CD4+ and total lymphocyte
counts, compared with being normal weight, while morbid
obesity was associated with a higher CD8+ T-cell count [87].
A recent cross-sectional study of obese, overweight, and
normal-weight HIV-uninfected adults found a 3-fold higher
expression of the surface activation marker CD25 on CD3+

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Given the invasive nature of intraabdominal fat biopsies, there

are fewer data on visceral adipocytes than on subcutaneous adipocytes from human subjects. In a study of paired subcutaneous
and visceral adipose tissue samples from lean HIV-uninfected
individuals, in vitro exposure to nelnavir, lopinavir, or ritonavir,
but not atazanavir, resulted in increased lipolysis and release of
free fatty acids, decreased glyceroneogenesis (ie, the recycling of
free fatty acids into adipocytes), and increased IL-6 and TNF-
secretion in subcutaneous but not visceral tissue [71]. A small
study of HIV-infected individuals with lipodystrophy found
similar mtDNA content and mRNA expression of TNF- and
markers of macrophage inltration in both subcutaneous and
visceral adipose biopsy specimens but lower mRNA expression
of markers of adipogenesis (PPAR-, adiponectin, GLUT4, and
lipoprotein lipase) in subcutaneous tissue specimens, compared
with visceral tissue specimens [72]. These results suggest less derangement of cellular metabolism and storage capacity in visceral
adipocytes. Thus, multiple lines of evidence across ART classes
reveal differential and unique effects in visceral versus subcutaneous adipose tissue, potentially explaining the range of lipophenotypes during HIV infection.

Obesity Is Characterized by Increased Adipose Tissue T-Cell

inltration

Progressive adipose tissue accumulation is accompanied by

increased CD8+ T-cell inltration and a shift toward a higher
ratio of CD8+ T cells to CD4+ T cells. CD8+ T-cell inltration
appears to be a key event preceding the depletion of visceral
adipose tissue T-regulatory cells and the increased CD4+ T-cell
activation observed in murine models of diet-induced obesity
[32, 33]. Increased adipose-resident CD8+ T-cell activation also
potentiates adipocyte expression of IL-6 and TNF- in mice,
whereas CD8+ T-cell depletion reverses this effect [33]. Last,
T-cell inltration appears to be an early and necessary step
preceding proinammatory macrophage recruitment into
adipose tissue; in murine models, antibody-induced CD8+
T-cell depletion resulted in reduced M1 macrophage inltration but no change in M2 macrophages [33].
While these ndings are intriguing, the relative ease of
obtaining surgical biopsy specimens from mice and the higher
density of T cells per unit of adipose tissue in rodents contributes
to a preponderance of animal data, which may or may not be relevant to human health. Additional studies are needed to determine whether the density and phenotype of adipose-resident
T cells differs between HIV-infected and HIV-uninfected individuals and to further characterize the relationship between
peripheral CD4+ and CD8+ T-cell activation and adipose tissue
biology in the setting of HIV infection.
Adipose Tissue Hormones Alter Lymphocyte Function and May
Alter the Immune Response to HIV

Adipokines are hormones produced by adipocytes, which demonstrate a range of metabolic, neuroendocrine, and immunomodulatory properties (Table 2). Adiponectin has important

Table 2.

Summary of Adipokine Effects on Immune Cells

Leptin [9799, 101106, 110112]

Produced in proportion to fat mass
Structural similarity to IL-6
Increases TNF-, IL-6, and IL-12 production from monocytes
and macrophages
Stimulates neutrophil proliferation and reactive oxygen species
production
Increases naive CD4+ T-cell proliferation and Th1 polarization
Increases antigen-stimulated CD4+ and CD8+ T-cell activation
marker expression
Promotes increased antigen-stimulated Th1-type cytokine
release (principally INF-)
Suppresses Th2 production of IL-4
Stimulates hepatocytes to express C-reactive protein
Adiponectin [9093]
Markedly decreased in visceral obesity and HIV infection
Serum levels inversely correlate with insulin resistance
Inhibits macrophage differentiation and decreases IL-6 and
TNF- production
Increases IL-10 production
Decreases endothelial adhesion molecules
Reduces T-cell proliferation
Abbreviations: IL-4, interleukin 4; IL-6, interleukin 6; IL-10, interleukin 10; IL12, interleukin 12; HIV, human immunodeficiency virus; IFN-, interferon ;
Th1, T-helper cell type 1; Th2, T-helper cell type 2; TNF-, tumor necrosis
factor .

insulin-sensitizing effects, and circulating levels decline with increasing adiposity and during HIV infection [90]. Adiponectin
also has a potent antiinammatory effect in vitro by inhibiting
macrophage differentiation and production of TNF-, reducing
adipose tissue endothelial adhesion molecule expression,
stimulating the production of interleukin 10 and interleukin 1
receptor antagonist, and reducing T-cell proliferation [9193],
all of which would be predicted to be salutary effects for reducing inammation and immune activation.
Leptin, an adipokine encoded by the ob gene and produced
roughly in proportion to fat cell mass, was initially characterized as a regulator of appetite via receptors in the hypothalamus
but also appears to have a range of local and potentially systemic immune effects [9496]. Leptin independently induces
expression of proinammatory cytokines by macrophages and
monocytes [97, 98] and acts directly on hepatocytes to promote
CRP expression [99]. Mature CD4+ T cells express the long
isoform of the leptin receptor [100, 101], and in vitro leptin
stimulates T-cell proliferative responses, polarizes naive CD4+
T-cell proliferation toward the Th1 phenotype, and promotes a
marked increase in Th1-type cytokine production, principally
interferon [101105]. Leptin also enhances in vitro expression of activation markers (CD69, CD25, and CD71) on both
CD4+ and CD8+ T cells after antigen stimulation in a dosedependent manner [104, 106].
A single-arm study administering physiologic quantities of recombinant methionyl human leptin (r-metHuLeptin) to HIVuninfected adults with congenital or acquired lipodystrophy
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T cells from obese subjects, compared with nonobese subjects,

and the ratio of T-helper 1 (Th1; proinammatory) to T-helper
2 (Th2; inammation-repressing) CD4+ T-lymphocytes was
also signicantly higher in this group [88]. Additionally, BMI
was closely associated with the total number of Th1-type CD4+
T cells. Similarly, an analysis of the European CODAM cohort
of HIV-uninfected individuals found that greater waist circumference was associated with higher circulating markers of cellular immune activation (neopterin and soluble CD25) [28]. Last,
the recent nding that the ratio of mtDNA to nuclear DNA
in subcutaneous adipocytes from HIV-infected individuals
positively correlates with CD38 and HLA-DR expression on
peripheral CD8+ and CD4+ T cells suggests a linkage between
cellular immune activation and adipose tissue biology [89].
Taken together, these data suggest that insufcient fat stores
may be associated with lower immune cell populations and
reduced response to antigen, whereas excess adiposity and the
preservation of adipocyte mtDNA content may be associated
with increased cellular immune activation.

CONCLUSIONS
The complex alterations in adipose tissue biology and energy
storage observed in HIV-infected individuals have been an active
research area since early in the epidemic, but adipose tissue may
also have important roles in modulating the immune response to
HIV infection. As the proportion of overweight and obese HIVinfected individuals continues to rise, understanding the role of
adipose tissue in the pathogenesis of immune activation will be
critical to optimizing long-term health outcomes.
Supplementary Data
Supplementary materials are available at The Journal of Infectious Diseases
online (http://jid.oxfordjournals.org/). Supplementary materials consist of
data provided by the author that are published to benet the reader. The
posted materials are not copyedited. The contents of all supplementary data
are the sole responsibility of the authors. Questions or messages regarding
errors should be addressed to the author.

Notes
Acknowledgment. We thank Dr Steven Grinspoon for his assistance in
reviewing a draft manuscript.
Financial support. This work was supported by the National Institute
of Allergy and Infectious Diseases (grant K23 100700 to J. K.) and the
Tennessee Valley Healthcare System (to K. N.).
Potential conicts of interest. T. H. has served as principal investigator
on research grants from Merck to Vanderbilt University. All other authors
report no potential conicts.
All authors have submitted the ICMJE Form for Disclosure of Potential
Conicts of Interest. Conicts that the editors consider relevant to the
content of the manuscript have been disclosed.

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found an increase in total CD4+ and CD8+ T cells, but trials in

HIV patients to date have not shown a clear benet for immune
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