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HIV - Sitokin
HIV - Sitokin
2005;7
Abstract
Antiretroviral drugs currently in use for treating HIV-1 infection are very effective at maintaining low
viral loads and clinical stability, but have been limited by their inability to eradicate virus in infected
individuals, resulting in the need for indefinite therapy. The inability of antiretroviral drug therapy to
eliminate HIV-1 infection is thought to be due to incomplete restoration of host immunity to the virus.
New strategies to improve control of HIV-1 infection during antiretroviral therapy should target en-
hancement of host immunity. Proinflammatory cytokines are the central mediators of both innate and
adaptive immunity, and modulation of these cytokines has been shown to alter anti-HIV-1 reactivity
in vitro. Modulation of proinflammatory cytokines could therefore be utilized in strategies for immu-
notherapy of HIV-1 infection. The ultimate goal is to find regimens that could more durably suppress
viral replication and potentially eliminate the need for indefinite antiretroviral therapy. This review
presents what is known about the dysregulation of proinflammatory cytokines in HIV-1 infection,
highlighting newly available immune-based therapies that could augment antiretroviral drug thera-
pies. (AIDS Reviews 2005;7:168-80)
Key words
HIV-1. Cytokines. IL-1. IL-6. IL-18. TNF-alpha.
For these reasons, a series of studies are needed in tions normally resulting from the presence of high
order to obtain a realistic picture of how cytokines levels of IL-1β. However, IL-1β-deficient mice are more
impact on disease states. prone to infection by influenza A virus than wild-type
For convenience, it is possible to separate cytokines mice and suffer higher mortality rates, but this defi-
into functional groups, although given the tremendous ciency is not necessarily lethal in such cases1.
redundancy of cytokine actions such generalizations are IL-1β binds to IL-1-receptor type 1 and forms a het-
limited. The proinflammatory cytokines include interleu- erodimer with IL-1 receptor 1 accessory protein which,
kins IL-1β, IL-6, IL-18, and tumor necrosis factor-alpha by increasing binding affinity, results in amplification of
(TNF-α). The Th1/Th2 CD4+ helper T-cell paradigm sug- the response. These actions result in recruitment of the
gests that Th1 immunity, mediated by IL-2, IL-12, and cytosolic adapter protein MyD88 and activation of IL-1
IL-15, generally favors cell-mediated immunity, while receptor activating proteins, which ultimately result in
Th2 immunity, mediated by IL-4, IL-5, and IL-10 gener- translation of enzymes that increase circulating levels
ally favors humoral immunity. Finally, the chemokine of prostaglandin E2, platelet activating factor, nitric
group including IL-8, MIP-1α, MIP-1β, and RANTES has oxide, and adhesion molecules – all important media-
various immunologic functions, but is mainly involved in tors of a proinflammatory state2. Disrupting cleavage,
chemotaxis of immunologically active cells. receptor binding, or MyD88 function can eliminate or
The purpose of this review is to combine the knowl- diminish IL-1β activity.
edge gained from multiple studies to assemble a co-
hesive picture of the cytokine milieu in HIV-1 infection. Alteration in HIV-1 infection
In order to give adequate depth, as well as to highlight
a group of cytokines where potential, new, as yet un- The few studies of the presence of IL-1β in sera of
tried therapies are apparent, this review is limited to HIV-1-infected individuals show both decreased3,4,
proinflammatory cytokines. This information will allow and increased5,6 levels in progressive disease. At the
us to postulate logical avenues of intervention, i.e. new same time, increases in IL-1β protein have been dem-
cytokine-based therapies, for evaluation in clinical tri- onstrated in specialized compartments such as the
als designed to augment the host’s immune response cerebrospinal fluid (CSF) and skin7-9. Cell-stimulation
against HIV-1 infection. studies have generally shown that the capacity of pe-
ripheral blood mononuclear cells (PBMC) and DC in-
Interleukin-1β fected with HIV-1 to produce IL-1β in response to ac-
tivating stimuli such as lipopolysaccharide (LPS) or
Biology CD40L is increased in HIV-1 infection in association
with higher viral load, albeit with significant interindi-
IL-1β is encoded on the long arm of chromosome 2 vidual variability3,6,10-15. High levels of IL-1β appear to
and is produced mainly by monocytes, macrophages, decrease with HAART16 possibly as a result of increased
and dendritic cells (DC) in response to a variety of availability of IL-1β receptor antagonist17. Alteration in
bacterial products, principally via interactions with toll- IL-1β production in response to physiologic stimuli may
like receptors. It is synthesized as an inactive precur- not be specific to HIV-1 infection, in that in vitro studies
sor requiring cleavage by IL-1β converting enzyme show that Epstein-Barr virus (EBV) increases IL-1β se-
(ICE), also known as caspase-1 to the active cytokine. cretion, while hepatitis C virus (HCV) decreases it18,19.
Confounding its measurement is the fact that a number In the case of HIV-1 infection, it has been suggested
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of different stimuli induce IL-1β mRNA transcription that HIV-1 Tat protein and/or gp120 can act as viru-
without resulting in translation of IL-1β precursor. Also, lence factors responsible for increasing physiologic
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the same cells that produce the majority of IL-1β con-
stitutively produce an IL-1 receptor antagonist (IL-1ra).
IL-1β production in response to activating stimuli. This
results in increased numbers of activated cells as tar-
These facts demonstrate multiple levels of control over gets for HIV-1 infection, and therefore increased HIV-1
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IL-1β activity, suggesting the importance of this cyto- replication7,20.
kine for regulation of the inflammatory state. Despite
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this, mice deficient in IL-1β develop normally and are Role in pathogenesis
able to live in non-sterile environments without devel-
pears to be related to both the presence of additional (acting in combination with other cytokines) probably
replication stimuli and the specific viral subspecies21,22. have direct, detrimental effects with respect to symp-
IL-1β appears to contribute to increased in vitro sus- toms in late HIV-1 infection. Despite a plurality of interac-
ceptibility of both naive and memory CD4+ and CD8+ tions between IL-1β, IL-1ra and HIV-1, several points are
T-cells to apoptosis in the setting of HIV-1 infection via clear: first, there is an increased capacity of cells to
the pro-apoptotic Fas/FasL pathway23. Petit, et al. dem- produce IL-1β and IL-1β activity in the setting of chron-
onstrated that Fas/FasL binding, in the appropriate set- ic HIV-1 infection; second, IL-1β increases HIV-1 repli-
ting, can result in T-cell proliferation rather than apopto- cation; and third, inhibitors of IL-1β diminish HIV-1 rep-
sis, and that this effect was abrogated in the presence lication in vitro.
of inhibitors of caspase-1 or IL-1β24. Also, in CHP100
cells, a neuroblastoma cell line found to be useful for Future directions
elucidating the neurotoxic role of gp120, addition of
gp120 not only results in calcium-dependent cellular Given the safety and availability of IL-1 receptor an-
toxicity, but also in increased IL-1β levels and decreased tagonists, it seems logical to consider trials of IL-1β in-
IL-1β inhibitor activity. Furthermore, retinoids, naturally hibitors in animal models and, if promising, continuing
occurring regulators of gene transcription and transla- to look at possible antiviral effects in infected subjects.
tion, are thought to possess inherent anti-HIV-1 proper- Anakinra (Kineret®, Amgen, Thousand Oaks, CA) is
ties, possibly by suppressing Tat and nuclear factor currently the only FDA-approved IL-1β receptor an-
kappa B (NFκB) activity. This activity is both IL-1β and tagonist. Administered parenterally, it has been shown
IL-6 dependent25,26. Finally, in IL-1β-deficient transgenic to be safe and effective when used in the setting of
mice, LPS-induced increases in HIV-1 replication are rheumatoid arthritis30,31. It would be logical to evaluate
blunted, suggesting that IL-1β, in the setting of other this agent in in vitro and/or animal models in order to
physiologic stimuli, augments HIV-1 replication27. determine whether blocking IL-1β could decrease viral
Downstream IL-1β inhibitors, such as cyclooxygen- replication. However, if one prudently assumes that the
ase-2 (COX-2) inhibitors, block apoptosis of neuronal effects of IL-1β are only partially responsible for facili-
cells, suggesting that the presence of HIV-1 proteins tating HIV translation and replication, the effect, at least
results in an increase in IL-1β that is detrimental to at the systemic level, might be minimal. If so, a reason-
neuronal tissue7. Therefore, while the mechanisms are able approach may be to use combination therapy to
as yet incompletely defined, inhibitors of IL-1β (such eliminate both of the proviral mechanisms hypothe-
as IL-1ra analogues, caspase-1 inhibitors, and COX-2 sized by Poli, et al.32. Other strategies could include
inhibitors) seem to curtail detrimental HIV-1-mediated the use of orally active caspase-1 inhibitors, such as
effects in animal and in vitro models28, suggesting that pralnacasan33, that could decrease levels of activated
IL-1β contributes to increased HIV-1 replication and IL-1β (and IL-18), potentially decreasing the toxic sys-
pathogenesis in vivo. temic effects of higher than normal IL-1β (i.e. diarrhea
With respect to the direct toxicity of IL-1β in HIV-1-in- and potentially encephalopathy) while decreasing sys-
fected individuals, high levels of IL-1β, in conjunction with temic proinflammatory effects of IL-1β.
TNF-α, decrease transepithelial resistance in mucosal
tissues, thereby possibly contributing to HIV-1-associated Interleukin-6
diarrhea29, and in vitro studies demonstrate that IL-1β
directly contributes to neuronal injury, which could Biology
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possibly contribute to HIV-1-associated encepha-
lopathy7. IL-6 is produced by monocytes, macrophages and
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In summary, high IL-1β levels likely facilitate HIV-1
replication by more than one mechanism. Animal and
T-lymphocytes in response to cytokine or antigenic
stimulation. It mediates B-cell terminal differentiation
in vitro models have shown that HIV-1 proteins in- and maturation as well as antibody synthesis by acti-
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crease IL-1β levels as well as those of IL-1β inhibitors. vated B-cells at the mRNA level. Acting synergistically
Exogenously administered IL-1β inhibitors rescue neu- with IL-1β and TNF-α, IL-6 is involved in T-cell activa-
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ronal cells in vitro. IL-1β modulates the Fas/FasL-medi- tion, growth, and differentiation, possibly through its
ated pro-apoptotic potential, possibly resulting in the effect of increasing expression of IL-2 receptors on
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Further, a number of IL-6 responsive nuclear factors,
including C/EBP (CCAAT enhancer binding protein)
known role in osteoclast stimulation. Tenidap decreas-
es HIV-1 replication in chronically HIV-1-infected mono-
and mitogen-activated protein kinase (MAPK) have cyte cell lines, but this may be an IL-6-independent
without the prior written permission
been implicated in increasing HIV-1 replication when effect61. It is logical to hypothesize that anti-IL-6 ther-
activated, and many of these are triggered by pro- apy, in conjunction with other cytokine-blocking mo-
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inflammatory cytokine stimulation 38-43. In primate dalities, could decrease HIV-1 replication in vivo and,
studies, infection with pathogenic SIV, but not nef- as IL-6 seems to act on HIV-1 replication on cells of
ing would be a logical next step in animal models. If these other proinflammatory cytokines, IL-18 levels are in-
results showed promise, safety testing in the HIV-1-in- creased with increasing viremia and decreased by
fected populations would be reasonable. Additional HAART67.
studies evaluating the mechanism whereby IL-6 increas-
es HIV-1 replication in monocytes are needed. Role in pathogenesis
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lated transcription of other cytokine and cytokine re-
ceptor mRNA1,62,63.
able success81,82. Currently, IL-12 is being studied as
an adjuvant in HIV and other therapeutic vaccine strat-
egies83,84. While IL-18 is thought to augment the ability
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Alteration in HIV-1 disease of IL-12 to stimulate Th1-type immunity, it is not es-
sential for Th1 activation. IL-18 appears to be important
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Serum IL-18 levels are increased in HIV-1 disease, for potent innate immunity against a variety of patho-
and there are conflicting data as to whether this effect gens, but this effect is dependent on the production of
in part be due to activation of the NFκB cascade, but GM-CSF, M-CSF, and IFN-γ from monocytes, activate
this effect is only one of many pathways IL-18 may use CTL, and/or induce apoptosis of mature T-cells.
to increase circulating HIV-1. Some or all of these actions may result clinically in
Studies using IL-18 or IL-18 inhibitors for a variety of fever, hypotension, anorexia, and capillary leakage
disease states are currently in their infancy, with the among other events. TNF-α can also act as a potent
majority of studies being performed in murine models. inhibitor of IL-1297.
These studies are targeted at controlling a variety of Clinically, pathologic overproduction of TNF-α has
tumors85-88, autoimmune diseases including experi- been implicated in a variety of disease states includ-
mental neuritis and multiple sclerosis, infectious ing: septic shock, overwhelming meningococcemia,
agents89-93, and graft-versus-host disease94-96. cerebral malaria, autoimmune diseases such as rheu-
Given the complexity of IL-18 effects, particularly with matoid arthritis and myasthenia gravis, as well as some
regards to increasing NFκB activity and thereby poten- cancers including hairy cell leukemia and colorectal
tially increasing the replicative capacity of HIV-1, in- cancer. TNF-α is posited to be essential for killing tu-
creasing IL-18 levels in the setting of HIV-1 infection mor cells and has been studied as a therapy for certain
seems likely to worsen disease, as well as leading to types of cancers. Currently, therapeutic use for TNF-α
significant toxicity. Systemically decreasing IL-18 levels is limited by its toxicity, but trials continue with the goal
could potentially decrease HIV-1 replication, but would of finding TNF-α variants which preserve their antitu-
likely have additional effects, such as shifting the CD4+ mor activity while minimizing dose-limiting toxicity2,98.
T-cell population away from the Th1 phenotype, that are
less desirable. A more logical strategy, given the com- Alteration in HIV-1 infection
plexity of IL-18 actions, would be to target downstream
effects of IL-18 that have been implicated in increasing It is generally accepted that TNF-α levels, as well as
HIV-1 replication, such as the NFκB or IFN-γ pathway. those of sTNF-R, are increased in HIV-1, and that these
Also, since IL-18 is activated by caspase-1, the same levels increase with disease progression11,99-101. How-
enzyme responsible for the activation of IL-1β, antago- ever, a recent study reported that in a cross section of
nists of caspase-1 would decrease not only IL-1β activ- HIV-1-infected volunteers, TNF-α levels were initially
ity, but also decrease IL-18 activity. high, but then decreased dramatically late in disease102,
possibly as a result of exhaustion of TNF-α-producing
Tumor necrosis factor-alpha cells. TNF-α levels have been directly correlated with
HIV-1 RNA levels and inversely correlated with CD4+
Biology T-cell counts99,103. There is debate, however, as to
whether TNF-α levels, as well as those of sTNF-R, are
TNF-α is produced by many types of immune cells altered by antiretroviral therapy. For example, signifi-
in response to a number of stimuli, including antibody cantly higher levels of TNF-α and TNF-R have been
cross-linking, LPS, and numerous viral infections, noted in HIV-1-infected as compared to HIV-1-unin-
among others. Because of its generally proinflamma- fected subjects, but the addition of HAART did not
tory effects when present systemically, expression is significantly reduce TNF-α levels among adherent sub-
tightly regulated at all levels. TNF-α activity is mediated jects with good HIV-1 RNA and CD4+ T-cell responses104.
by either of two receptors: TNF receptor 1 (TNF-R1) or Other studies have shown that, in subjects initiating
TNF receptor 2 (TNF-R2), which are ubiquitously pres- HAART, decreases in TNF-α producing CD4+ and CD8+
No part of this publication may be
ent, both on nucleated cell surfaces and in soluble form. T-cells precede decreases in total CD4+ and CD8+ cell
The soluble forms of TNF-R1 and TNF-R2 (sTNF-R) gen- counts as well as changes in viral load. This suggests
reproduced or photocopying
erally act to attenuate the activity of TNF-α, but may
simultaneously act as a reservoir for available TNF-α.
an important pathogenic role for TNF-α in viral replica-
tion as well as potentially a means of monitoring re-
TNF-α binds membrane-bound TNF-R resulting in sponse to treatment or predicting failure of HIV-1
without the prior written permission
trimerization of membrane-bound TNF-R, and initiates therapy105,106.
cell-type dependent, intracellular signaling cascades,
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many of which are NFκB dependent, resulting in a Role in pathogenesis
huge array of biological effects. TNF-α, depending
tion between increased levels of TNF-α and increased This can be overcome by addition of physiologic levels
plasma HIV-1 viral load has been repeatedly demon- of TNF-α and IL-1β, dramatically increasing viral tran-
strated, both in vivo and in vitro99,107-111. Studies per- scription by increasing LTR-mediated viral replication.
formed in transgenic mice deficient in TNF-α and IL-1β In addition to the role of TNF-α in increasing replication
have shown these cytokines to be essential for HIV-1 in chronically infected patients with HIV-1, there is likely
replication in vivo112. Recently, Capini, et al. showed a macrophage dependent, nef-mediated, anti-apoptotic
that some HIV-1-infected slow progressors possess effect whereby productively infected CD4+ T-lympho-
naturally occurring anti-TNF-α antibodies113. Clinical cytes, which physiologically should be targeted for
studies using TNF-α administration for Kaposi’s sar- apoptosis in order to eliminate infection, are maintained
coma in HIV-1-infected subjects, or MS-8209 (an am- in the circulation, possibly contributing to the pool of
photericin B derivative known to increase TNF-α levels) latently infected T-cells120,128.
have confirmed that HIV-1 replication is increased in In vitro and in vivo, mycobacteria can induce TNF-α
the presence of increased TNF-α levels114,115. Con- expression, resulting in increased HIV-1 replication in
versely, it has been repeatedly shown that TNF-α, via the setting of coinfection with HIV-1 and contributing
TNF-R2, is capable of decreasing HIV-1 replication in to acceleration of both disease processes129-132. Al-
monocyte-derived macrophages, purified microglial tered TNF-α levels in HIV-1-infected patients possibly
cell cultures and mixed brain cell cultures, possibly via contribute to HIV-1-associated diarrheal disease29,133.
decreasing expression or activity of beta chemokine TNF-α levels in the CSF are higher in HIV-1-infected
receptors116-120. patients with encephalopathy, suggesting a role for
The mechanisms by which TNF-α increases HIV-1 TNF-α in the pathogenesis of HIV-1-associated en-
replication are incompletely understood, and there like- cephalopathy134-136.
ly is variation in this ability between strains of HIV-1121. An important mechanism for the stimulation of APC
One mechanism whereby TNF-α increases HIV-1 repli- effector function is to effectively present appropriate
cation is by stimulating the proinflammatory signaling antigens and stimulate T-cells. Vpu, one of the intrinsic
cascade via TNF-R1 activating NFκB, resulting in in- HIV-1 proteins, appears to block TNF-α-induced anti-
duction of HIV-1 replication in previously latent cells122. gen processing, effectively inhibiting its physiologic
A circuit has been described in in vitro culture systems antiviral activity against HIV-1 infection. Vpu appears
in which HIV-1, NFκB, and TNF-α each exert positive to inhibit NFκB-dependent antigen degradation, thus
feedback upon the other, thereby amplifying virus rep- limiting the physiologic activity of TNF-α to stimulate
lication and inducing changes in cellular gene expres- antigen processing and presentation137. Finally, in vitro
sion in a manner which is independent of HIV-1 replica- experiments examining HIV-1 pathogenesis using a
tion123. TNF-α produced by macrophages in the recombinant plasmid encoded Vpr show that this pro-
presence of HIV-1 is thought to be instrumental in in- motes HIV-1 replication by a TNF-α-dependent mech-
ducing T-cell anergy124. anism138. In summary, TNF-α is capable, via TNF-R1, of
The TNF-α upregulation of CXCR4 expression may rep- increasing HIV-1 replication in vivo and in vitro. TNF-α,
resent another mechanism whereby it increases HIV-1 while in some cases inhibiting HIV-1 replication in
replication110. Although this upregulation increases sus- monocyte systems via downregulation of CCR5 recep-
ceptibility to X4 tropic virus, there is concurrent down- tors, is concurrently capable of upregulating CXCR4
regulation of CCR5 in some cell populations, mediated receptors, thus increasing susceptibility to X4 virus
partially by TNF-α, possibly in conjunction with IL-13, strains. Finally, it is largely held that TNF-α in particular,
No part of this publication may be
which results in decreasing HIV-1 replication117,125. Ad- and proinflammatory cytokines in general, increase in
ditionally, it has been shown that in humans TNF-α is activity as HIV-1-disease progresses, probably until
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involved in the development of lymphoid follicles, HIV-1
trapping and, consequently, early host immune re-
immunologic defects are so pronounced that cells are
no longer capable of cytokine production.
sponses126. Physiologic levels of TNF-α, acting in syn-
without the prior written
Previous permission
ergy with IL-1β, have been shown to be important me- clinical trials
diators for permitting mother-to-child transmission. In
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studies by Vidricaire, et al., trophoblasts, a major com-A number of agents chosen for their ability to modi-
ponent of the placental/infant barrier, are generally fy TNF-α levels have been evaluated for a variety of
sociated Kaposi’s sarcoma. This trial resulted in in- rently approved for the treatment of a variety of autoim-
creased HIV-1 p24 levels, providing further evidence mune diseases. Infliximab, a chimeric, humanized,
that raising TNF-α levels increases HIV-1 replication115. anti-TNF MAb, is currently approved for the treatment
Thalidomide and pentoxifylline, both weak TNF-α in- of methotrexate refractory rheumatoid arthritis and
hibitors, have been studied in small clinical trials for Crohn’s disease. It has demonstrated efficacy for oth-
HIV-1 alone and for HIV-1-related opportunistic infec- er autoimmune diseases and is undergoing evaluation
tions with variable success at decreasing TNF-α levels for a diverse group of conditions including sarcoidosis
or decreasing viral load99,139-147. Based on the limited and graft-versus-host disease157. Two additional anti-
success of these trials, rolipram, a related phosphodi- TNF-α agents (etanercept and adalimumab) are also
esterase 4 (PDE4) inhibitor known to decrease TNF-α FDA approved for rheumatoid arthritis. These drugs,
levels, has been tested in several in vitro systems. In although generally safe and well tolerated, are associ-
these studies it was successful in decreasing HIV-1 ated with increased risk of opportunistic infections in-
p24 levels, although whether this effect was based on cluding reactivation tuberculosis158. New generations
inhibition of TNF-α, PDE4, or more likely a combination of orally active anti-TNF-α therapies that more specifi-
of both, remains to be elucidated148-151. Topotecan, a cally target steps of the TNF-α secretion and activation
topoisomerase I inhibitor FDA approved for the treat- cycle are in development159. These may have potential
ment of ovarian cancer, has been shown in vitro to as therapy for HIV-1 infection and might act synergisti-
decrease HIV-1 replication in a topoisomerase-defi- cally with currently available therapies, but at present
cient cell line, thus indicating antiviral activity indepen- are accompanied by high risk for HIV-1 infected indi-
dent of its known antineoplastic mechanism, and pos- viduals. Optimally, an agent that was specific for the
sibly related to its demonstrated TNF-α blocking TNF-R1 without impacting TNF-α action at TNF-R2
ability152. Another TNF-α inhibitor, S9a, inhibited HIV-1 would deserve serious consideration as an anti-HIV-1
replication in vitro in acute and chronically infected therapy.
T-cell lines via downregulation of the TNF-α promoter
and consequent NFκB inhibition153. Summary
In vitro studies performed by Skolnik, et al.154 have
shown that thiazolidinediones such as rosiglitazone (PPAR), In the past decade there has been important prog-
currently being studied as treatment for HIV-1-associated ress in the development of clinically relevant cytokine-
lipodystrophy, inhibit both HIV-1 replication and TNF-α based therapies. New cytokine-based therapies with
production. These data suggest that the decrease in increased specificity have demonstrated effectiveness
HIV-1 replication is TNF-α dependent. It seems likely for both autoimmune and neoplastic diseases. The
that at least some of the decrease in HIV-1 replication goal of specifically targeting defined defects induced
seen in in vitro infected PBMC, U1 cells, and alveolar by a pathogenic process is valid, but despite recent
macrophages is due to decreased TNF-α. Most recent- progress, currently impractical. Additional research is
ly, a phase I clinical trial designed to test the safety and needed to better understand exactly what cytokines
tolerability of CPI-1189 (a synthetic benzamide with pur- are disrupted and how addition or subtraction of these
ported anti-TNF-α effects) in 42 HIV-1-infected subjects cytokines would alter the immunologic environment in
with cognitive-motor impairment demonstrated safety, each disease state. Ultimately, however, while animal
but no clinical efficacy or alteration in CNS TNF-α lev- models can show us gross effects of altering the cyto-
els155. One clinical trial evaluated the TNF-α MAb (cA2), kine milieu, it is only in human trials that we can truly
No part of this publication may be
administered in two parenteral doses of 10 mg/kg given observe how alteration of specific cytokine functions
at a 14-day interval in six HIV-1-infected subjects. In this will affect the clinical status of a patient.
reproduced or photocopying
trial, cA2 was safe, well tolerated, and achieved a de-
crease of blood TNF-α level, but the study was of insuf-
Fortunately, a number of potentially useful cytokine
modifying agents are currently FDA approved and
ficient size to demonstrate CD4 or HIV-1 RNA changes have been shown to be safe in different patient popu-
without the prior written permission
with 42 days of follow-up156. lations (Table 1). The TNF-α antagonists adalimumab,
infliximab, and etanercept are currently FDA approved
Future directions of the publisherfor rheumatoid arthritis and are being regularly used to
treat Crohn’s disease. These agents are too broadly
IL-1β Fevers, anorexia, Probably increased, Anakinra FDA approved for RA, 30,31,160,161
176
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