REVIEW ARTICLE | JUNE 15 2004

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In uence of Coinfecting Pathogens on HIV Expression: Evidence for a Role
of Toll-Like Receptors1
André Bá ca; ... et. al
J Immunol (2004) 172 (12): 7229–7234.
https://doi.org/10.4049/jimmunol.172.12.7229

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BRIEF REVIEWS
Influence of Coinfecting Pathogens on HIV Expression:
Evidence for a Role of Toll-Like Receptors1
André Báfica,2*‡ Charles A. Scanga,* Marco Schito,† Damien Chaussabel,* and Alan Sher2*
Immune activation of HIV gene expression as a conse-
quence of the host response to coinfecting pathogens has
been implicated as an important factor in AIDS progres-
sion. Immune responsiveness to many of the infectious
agents associated with HIV has been demonstrated to de-
pend on a family of innate recognition molecules, known
as Toll-like receptors (TLR). Therefore, TLR-pathogen
interactions could play an indirect role in regulating HIV-
associated disease. In this review, we summarize emerging
evidence for the influence of TLR recognition on HIV gene
activation and AIDS progression. The Journal of Immu-
nology, 2004, 172: 7229 –7234.
he number of people living with HIV/AIDS reached
T 40 million in 2003 (1). Coinfection with non-HIV
pathogens has been postulated to be an important ex-
ogenous factor that influences the severity and rate of disease
progression in HIV⫹ individuals, reducing survival and increas-
ing the risk of HIV transmission (2– 6). The heterologous in-
fectious agents involved include viruses such as human herpes-
virus-6, HSV-1, several protozoan parasites (e.g., Leishmania
donovani, Toxoplasma gondii, Plasmodium falciparum), and bac-
teria (e.g., Mycobacterium ssp. and Neisseria gonorrhea) (6 –10).
In certain regions of the world and, in particular, sub-Saharan
Africa, the high prevalence of chronic and recurrent acute in-
fections with such pathogens and the limited availability of
treatment and control measures are factors that potentially
compound this problem (11).
Enhanced HIV induction as a consequence of microbial-in-
duced immune activation has been implicated as the mecha-
nism responsible for the elevated viral expression observed in
coinfected individuals (3, 12). The term immune activation has
been used to refer to stimulation of the HIV long terminal re-
peat (LTR)3 by means of signals triggered by the immune re-
sponse to non-HIV Ags or infectious agents (13). These signals
can operate in trans through proinflammatory cytokines (e.g.,
TNF, IL-1) induced in a responding immune cell and/or in
*Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy
and Infectious Diseases, and †Chemical Immunology Section, Laboratory of Cell Biology,
National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and
‡
Laboratorio de Imunorregulacao e Microbiologia, Centro de Pesquisas Goncalo Moniz,
Oswaldo Cruz Foundation, Salvador, Bahia, Brazil
Received for publication March 2, 2004. Accepted for publication April 14, 2004.
The costs of publication of this article were defrayed in part by the payment of page charges.
This article must therefore be hereby marked advertisement in accordance with 18 U.S.C.
Section 1734 solely to indicate this fact.
1
This work was supported by the National Institutes of Health Intramural AIDS Targeted
Antiviral Program.
Copyright © 2004 by The American Association of Immunologists, Inc.
OF
JOURNAL IMMUNOLOGY
THE
cis— by transcription factors activated in HIV-infected cells
upon coinfection with a secondary pathogen. Both mechanisms
depend on triggering events initiated when pathogens are rec-
ognized by receptors belonging to the innate immune system.
The major innate recognition system for microbial invaders
in vertebrates is now thought to be the Toll-like receptor (TLR)
Downloaded from http://journals.aai.org/jimmunol/article-pdf/172/12/7229/1177911/7229.pdf by guest on 09 March 2024
family (14, 15). TLR are descended from similar receptors
(Toll) originally discovered in Drosophila (16) and share a Toll/
IL-1R (TIR) domain required for intracellular signaling as well
as an extracellular region containing leucine-rich repeats. At
present, 10 TLR members are known to exist in humans and at
least 11 in mice. In addition to the TLR themselves, IL-1 and
IL-18 receptors share similar intracellular domains and there-
fore are included as members of this family. Importantly, the
different TLR are triggered by conserved molecular structures
(pathogen-associated molecular patterns (PAMP)) expressed by
microbial agents. These PAMP include lipid or lipoprotein
moieties (recognized by TLR1, TLR2, TLR4, and TLR6), pro-
tein motifs (recognized by TLR5), as well as nucleotide se-
quences (TLR3 and TLR9) (14, 15). Although originally
thought to be restricted to individual TLR, it is becoming evi-
dent that recognition of a given pathogen can involve multiple
TLR (17).
Ligation of TLR results in the triggering of a cascade of events
that leads to the transcription of many of the genes involved in
immune activation (18). These signals involve the recruitment
of the adaptor molecule myeloid differentiation factor 88
(MyD88) and in certain cases TIR domain-containing adapter
inducing IFN-␤ (TRIF), TRIF-related adapter molecule
(TRAM), and TIR domain-containing adapter protein (TIRAP),
followed by the binding of IL-1R-associated kinase (IRAK)
family members and the activation of TRAF-6, ultimately lead-
ing to the activation of NF-␬B and mitogen-activated protein
(MAP) kinases (Fig. 1). The latter events are important tran-
scriptional regulators for the genes encoding the proinflamma-
tory cytokines TNF and IL-1, which as discussed above can en-
hance HIV LTR activity. In addition, TLR signaling can lead to
direct NF-␬B-dependent LTR triggering and/or the activation
2
Address correspondence and reprint requests to Dr. André Báfica or Dr. Alan Sher, Im-
munobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and
Infectious Diseases, National Institutes of Health, Building 50, Room 6146, 50 South
Drive, Bethesda, MD 20982. E-mail addresses: abafica@niaid.nih.gov and asher@
niaid.nih.gov
3
Abbreviations used in this paper: LTR, long terminal repeat; TLR, Toll-like receptor;
TIR, Toll/IL-1R; PAMP, pathogen-associated molecular pattern; MyD88, myeloid dif-
ferentiation factor 88; TRIF, TIR domain-containing adapter inducing IFN-␤; MAP, mi-
togen-activated protein; Tg, transgenic.
0022-1767/04/$02.00
7230 BRIEF REVIEW: INFLUENCE OF TLR SIGNALING ON HIV EXPRESSION
FIGURE 1. Pathways for the induction of the HIV LTR as a consequence of pathogen-triggered TLR signaling. See Mechanisms implicated in TLR-induced HIV
expression.
of other transcription factors such as AP-1 that have been im-
plicated in HIV induction (19, 20).
In the following review, we will summarize the existing evi-
dence linking microbial-stimulated TLR signaling with HIV
LTR induction and viral expression. This information is of im-
portance for understanding the interaction of coinfecting
pathogens with HIV as well as for designing approaches for
counteracting the effects of immune activation on AIDS pro-
gression.
In vitro evidence for a role of TLR ligands in HIV induction in human
cells
The first evidence for an association of TLR signaling and HIV
induction came from studies in which LPS was shown to stim-
ulate viral LTR activity in chloramphenicol acetyl transferase
reporter-transfected monocyte/macrophage-like cell lines via a
mechanism associated with NF-␬B activation (21). In the same
report, the authors showed that LPS stimulation also induces
HIV replication in chronically infected U1 cells (a monocyte/
macrophage cell line), an effect that had been noted previously
in a study of cytokine production by HIV-infected THP-1 cells
(22). Importantly, no virus induction was observed in a trans-
fected T cell line stimulated in the same fashion with LPS (21).
Although TLR4 had not yet been identified as the receptor for
NF-␬B signaling by LPS, the latter findings were consistent
with TLR4 involvement, because this TLR family member is
not normally expressed by T cells. LPS was also shown in sub-
sequent studies to stimulate HIV replication in infected pri-
mary human monocyte/macrophage cultures (22). Additional
publications documented the ability of lipoarabinomannan
(24), lipophosphoglycan (25), and bacterial DNA (26) to pro-
mote HIV LTR transactivation in stably transfected cell lines,
although the authors were not aware that they were dealing with
TLR ligands.
The above studies involved the effects of immune activation
on integrated LTR or viral expression. Somewhat opposing
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findings were obtained when HIV infection of monocyte/mac-
rophages was initiated immediately before or simultaneously
with microbial stimulation. In these experiments, LPS or my-
cobacterial exposure was found to inhibit HIV replication ei-
ther as a result of chemokine induction and coreceptor blockade
or suppression of other preintegration steps in the viral life cycle
(27–29).
With the discovery of mammalian TLR signaling in 1997
(30), it was logical to conclude that TLR ligation is a key event
in the induction of HIV expression by microbial ligands. For-
mal proof was not obtained until 2001 when it was shown by
Equils et al. (31) that LPS stimulates LTR transactivation in
transfected human dermal microvessel endothelial cells second-
arily transfected with wild-type, but not mutated TLR4. In a
follow-up study, these authors (32) used a similar approach to
establish a role for TLR2 in LTR transactivation by bacterial
TLR2 ligands. More recently, Sundstrom et al. (33) have shown
that HIV-infected human mast cells display increased HIV rep-
lication when stimulated with known TLR2, -4, and -9 ligands.
In a parallel line of investigation, it had been shown that live
microorganisms or crude microbial extracts also promote HIV
expression in monocytic cells in vitro (25, 26). For example,
both live Mycobacterium tuberculosis (24) and L. donovani (25)
were found to stimulate HIV LTR promoter activity in trans-
fected cells as well as virus replication in chronically infected
monocyte/macrophage cell lines. Importantly, in these two
studies, pathogen extracts as well as purified components (e.g.,
mycobacterial lipoarabinomannan and phosphatidylinositol
mannoside, and leishmanial lipophosphoglycan) were also
shown to stimulate the same viral responses, and all of these
stimuli were later shown to be or contain TLR2 agonists (34,
35). Taken together with the later findings of Equils et al. (31,
32), these reports suggested that TLR signaling is the major
pathway for microbial-induced HIV expression, and to date,
three of the known TLR—TLR2, TLR4, and TLR9 — have
The Journal of Immunology 7231

been shown to possess this activity (Table I). Nevertheless, the
involvement of additional microbial recognition receptors and
signaling pathways in the induction of HIV has not been for-
mally ruled out, although as discussed below, there is strong
evidence in a murine transgenic system arguing that TLR sig-
naling is in itself sufficient.
Mechanisms implicated in TLR-induced HIV expression
The pathways by which microbial TLR ligands trigger HIV ex-
pression have not been fully elucidated, although there are a
number of obvious candidates (Fig. 1). Cytokine-mediated in-
duction of the HIV LTR through NF-␬B activation is thought
to be a major mechanism by which concurrent infectious agents
enhance proviral transcription (11, 36) and may contribute to
TLR-dependent triggering. Thus, serum TNF levels have been
correlated with increased viral loads in patients dually infected
with HIV and M. tuberculosis (11, 36). Furthermore, in vitro
Evidence for TLR involvement in HIV induction in experimental
models
In addition to in vitro studies using HIV⫹ human cells, the role
of immune activation in regulating viral expression has been ex-
amined in a number of experimental animal models involving
either SIV infection of rhesus monkeys (44) or transgenic mice
incorporating proviral DNA clones or LTR reporters constructs
(45– 49). Although not involving live virus infection, the trans-
genic mouse models offer the best opportunity to directly assess
the function of TLR signaling in regulating HIV expression in
vivo. Moreover, these models allow a direct analysis of the ef-
fects of immune activation on the postintegration phase of the
viral life cycle. In general, the studies on HIV transgenic mice
have confirmed the ability of TLR stimuli such as LPS and my-
cobacteria to trigger the HIV LTR and, in the case of the two
systems involving full-length provirus, the induction of viral

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neutralization of TNF has been shown to partially inhibit HIV
replication induced by purified protein derivative from myco-
bacteria in monocytes (36) as well as the enhancement in viral
expression stimulated by live M. tuberculosis in a chronically in-
fected macrophage cell line (24). In contrast, anti-TNF treat-
ment had no effect on HIV replication in U1 cultures stimu-
lated with LPS (21), and in a different study not involving M.
tuberculosis infection, no correlation was observed between
TNF and HIV gene expression in lymph nodes of HIV⫹ indi-
viduals (37). Thus, these findings suggest that, although influ-
encing HIV expression, TNF is not an obligatory signal for
HIV LTR induction.
In addition to indirect cytokine-mediated HIV induction,
the interaction of PAMPs with TLR may result in the MyD88-
dependent activation of HIV transcription through NF-␬B it-
self or MAP kinase-dependent AP-1 (19, 20) (Fig. 1). Other
transcription factors implicated in HIV LTR activation such as
C/EBP, CREB, and Sp1 could also be induced as a consequence
of MAP kinase signaling and promote HIV expression (19, 20,
38 – 42). LTR induction may also involve mechanisms depen-
dent on other adaptor molecules (e.g., TRIF and TRAM) dis-
tinct from those requiring MyD88 or by means of phosphati-
dylinositol 3-kinase-dependent NF-␬B activation (43) (not
shown in Fig. 1). So far, however, none of the above mecha-
nisms have been formally demonstrated to explain TLR-medi-
ated immune activation in HIV-infected human cells. This is-
sue is important because targeting of cytokine-independent
inductive pathways could represent a useful strategy for decreas-
ing HIV loads in coinfected individuals.
Table I. Major evidence for TLR involvement in immune activation of HIV in microbial systems
proteins and even infectious virions (46, 47, 50).
Our group has directly investigated the role of TLR signaling
in HIV induction using a transgenic mouse model (HM 166)
that incorporates full-length copies of the NL4-3 HIV clone
(51). In vitro studies indicated that TLR2, TLR4, and TLR9
agonists are each potent inducers of HIV p24 expression in
transgenic splenocytes, and that, when combined, these micro-
bial stimuli have an additive effect on the viral response (32). To
directly confirm the role of TLR signaling in immune activa-
tion in vitro and in vivo, we created TLR2-deficient HIV-trans-
genic mice (Tg/TLR2⫺/⫺) by crossing HM 166 Tg mice with
TLR2⫺/⫺ animals (51). Splenocytes from these mice, in addi-
tion to failing to produce p24 in response to TLR2 ligands (e.g.,
Pam3Cys, phosphatidylinositol mannoside (PIM)1,2), displayed
severely impaired in vitro p24 production when stimulated with
live as well as heat-killed M. tuberculosis or Mycobacterium
avium. Interestingly, the same mycobacteria-exposed Tg/
TLR2⫺/⫺ spleen cell cultures showed only a partial reduction in
TNF production, and the addition of neutralizing anti-TNF
mAb failed to inhibit the bacterial-induced p24 response. The
latter observations support the existence of a TNF-independent
pathway for immune activation consistent with the findings on
HIV-infected human cells discussed above (21, 36, 37).
A major advantage afforded by HIV animal models is the
ability to analyze the regulation of HIV expression in vivo.
When Tg/TLR2⫺/⫺ mice were infected with live M. avium,
these animals, in contrast to TLR2-sufficient Tg mice, failed to
mount a significant HIV p24 response as detected in either
plasma or ex vivo spleen cell cultures and showed dramatically

TLR Critical Observations Citation

TLR2 TLR2 dependence of HIV-LTR induction by soluble tuberculosis factor from 32

mycobacteria.
Requirement for TLR2 in induction of HIV by M. avium and M. tuberculosis in a HIV- 51
transgenic mouse model.
Enhancement of HIV replication in human mast cells by peptidoglycan. 33

TLR4 Activation of HIV-LTR by LPS in TLR4 transfected cells and murine HIV transgenic cells. 31, 32
LPS induced HIV replication in virus-infected human mast cells. 33
Partial protection against AIDS onset in HIV⫹ individuals heterozygous or homozygous for S. Kleeberger, unpublished
a TLR4 allele. observations

TLR9 Activation of HIV by CpG oligonucleotides in human cell lines and infected mast cells as 32, 33
well as murine HIV-transgenic cells.
Increased HIV viral loads in patients given the CpG containing gag antisense GEM91. 57
7232 BRIEF REVIEW: INFLUENCE OF TLR SIGNALING ON HIV EXPRESSION
reduced levels of gag and env transcripts in the same tissue. The
above findings point to TLR2 agonists as the major stimulus of
HIV gene expression in this animal model of mycobacterial
coinfection. Interestingly, TLR2 has been shown to play only a
limited role in in vivo control of mycobacterial infection in mu-
rine infection models (52–55). If a similar situation occurs in
humans, it may be possible to target TLR2-dependent HIV in-
duction without enhancing susceptibility to mycobacterial
pathogens.
In vivo evidence for a role of TLR signaling in regulating HIV
expression in humans
Although the in vitro and experimental animal models data
strongly support a role for TLR in regulating HIV expression,
the evidence for a relationship with human HIV infection and
disease has so far been indirectly investigated. Indeed, the in
vivo situation in humans is complex, because TLR signaling by
triggering chemokine production and interfering with preinte-
gration steps in the viral life cycle could actually result in inhib-
ited HIV replication as evidenced in certain studies (27, 28,
56). Nevertheless, findings from a previous clinical trial with an
antisense construct complementary to gag (GEM91) are con-
sistent with a positive effect of TLR ligation with enhanced viral
load in HIV⫹ patients (57). In this work, GEM91, which had
been shown to potently inhibit HIV replication in vitro studies
(58), was found to actually increase viral burdens when admin-
istered by continuous i.v. infusion for 8 days in a blinded dose
escalation study. On later examination, it was found that
GEM91 contains CpG-like motifs and elimination of these in a
later construct, GEM92, resulted in a loss of the viral enhance-
ment seen with GEM91 (59). The authors of the study specu-
lated that the increased viral loads stimulated by GEM91 may
have been the result of TLR9 stimulation by the CpG-like mo-
tifs present in the construct. These observations also suggest
that DNA vaccine constructs containing CpG motifs run the
possible risk of elevating virus production when administered to
HIV⫹ individuals.
A second approach to assessing the role of TLR signaling in
the regulation of HIV expression would be to quantitate viral
loads and disease progression in coinfected individuals with de-
fined TLR polymorphisms. Such studies correlating association
of human TLR polymorphisms with disease are in their infancy
(60, 61), and we know of no published study examining this
issue in HIV infection. Nevertheless, preliminary data have sug-
gested that individuals heterozygous or homozygous for a TLR4
allele are protected against AIDS onset (S. Kleeberger, unpub-
lished data). This interesting study opens up a possible system
in which to dissect the function of TLR signaling in immune
activation-induced AIDS progression.
TLR signaling as a candidate intervention target in HIV disease
If indeed TLR-dependent immune activation is a contributing
factor to AIDS progression, then targeting of this process may
be of therapeutic benefit. Antagonists as well as Ab and anti-
sense inhibitors have been developed that suppress signaling by
several TLR family members, and such interventions could po-
tentially be used for this purpose (62, 63). An alternative strat-
egy would be to attempt to inhibit the process of TLR signaling
in a selected manner. One well-known procedure of this type is
TLR reprogramming (64, 65). In this technique based on the
phenomenon of LPS tolerance, prior exposure to one TLR
stimulus results in down-modulation of responsiveness to sec-
ondary challenge with the same or related TLR agonist (65–
67). To assess the potential usefulness of this procedure in in-
hibiting TLR-dependent HIV induction, we stimulated HM
166 Tg macrophages or spleen cells with TLR2, TLR4, or
TLR9 ligands, and then assessed HIV p24 production follow-
ing homologous or heterologous challenge with the same li-
gands 48 h later (68). Although prior reprogramming resulted
in a dramatic decrease in TNF, IL-1, and IL-6 production fol-
lowing secondary challenge, p24 production was found to be
unexpectedly increased in the same cell cultures. Because, as
predicted from previous studies (65, 66), NF-␬B activity was
markedly reduced in the reprogrammed cells, these observa-
tions support the existence of non-NF-␬B-dependent pathways
for TLR-dependent immune activation of HIV and suggest
that, at least in the case of this experimental model, reprogram-
ming cannot be used to suppress TLR-mediated HIV induc-
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tion. More recently, experiments using in vitro HIV-infected
primary human macrophages indicate that reprogramming
may lead to inhibition of HIV replication despite increased and
more sustained TNF release (O. Equils, unpublished observa-
tions). Although the explanation for the discrepant results of
tolerization on HIV expression in the murine and human cell
culture experiments is presently unclear, it is of interest that, in
each system, reprogramming had opposing effects on HIV vs
TNF induction following secondary TLR stimulation.
Other strategies that target TLR signaling may offer alterna-
tive therapeutic approaches. For example, TLR-induced HIV
p24 production can be abrogated by pharmacological inhibi-
tion of p38 or phosphatidylinositol 3 kinases in HM 166 trans-
genic spleen cells (M. Schito, unpublished results) or trans-
fected human dermal microvessel endothelial cells (31). These
observations suggest the existence of defined pathways for TLR-
mediated immune activation that could be blocked with spe-
cific biochemical inhibitors as described by others in different
systems (41– 43).
Concluding remarks and questions for future research
It should be clear from this brief review of the literature that
much remains to be done both to confirm the role of TLR sig-
naling in AIDS progression as well as to establish this pathway
as a realistic intervention target for reducing viral burdens in
HIV⫹ individuals coinfected with other pathogens. First and
foremost will be to determine whether HIV expression in hu-
mans is indeed subject to TLR regulation. Although already
supported by published data using transfected cell lines stimu-
lated with microbial extracts (31, 32), this work needs to be
confirmed by means of TLR antagonism or suppression in pri-
mary human cells exposed to intact pathogens. More impor-
tantly, studies cross-correlating TLR polymorphisms with HIV
loads in patients with defined coinfections are needed to estab-
lish a more formal in vivo link between these two parameters
and for providing an epidemiological setting for clinical trials
aimed at intervention based on TLR targeting. On a more basic
front, further information is needed concerning the signaling
pathways by which TLR stimulation regulates HIV expression.
In particular, it will be important to determine whether, as sug-
gested by the animal model studies (51), mechanisms indepen-
dent of either cytokine induction or NF-␬B activation signifi-
cantly contribute to TLR-dependent triggering of the HIV
LTR. If indeed TLR signaling can be established as a potent
The Journal of Immunology
driving force for HIV disease progression, these data will, at the
very least, add further weight to the argument for aggressive
treatment of coinfections in HIV⫹ persons (8). Whether TLR-
directed antagonism will in certain groups of patients provide a
superior strategy for dealing with immune activation of HIV
remains to be determined.
Acknowledgments
We are grateful to Drs. Claire Chougnet, Moshe Arditi, Leonid Margolis, and
Johan Van Weyenbergh for their helpful comments and suggestions, and we
thank Drs. Ozlem Equils and Steven Kleeberger for allowing us to cite their
unpublished data.
References
1. United Nations Program on HIV/AIDS (UNAIDS)/World Health Organization.
2003. AIDS Epidemic Update, December 2003. Publication no. 03.39E. UNAIDS,
Geneva, Switzerland.
2. Quinn, T. C., P. Piot, J. B. McCormick, F. M. Feinsod, H. Taelman, B. Kapita,
W. Stevens, and A. S. Fauci. 1987. Serologic and immunologic studies in patients with
AIDS in North America and Africa: the potential role of infectious agents as cofactors
in human immunodeficiency virus infection. J. Am. Med. Assoc. 257:2617.
3. Bentwich, Z., A. Kalinkovich, and Z. Weisman. 1995. Immune activation is a dom-
inant factor in the pathogenesis of African AIDS. Immunol. Today 16:187.
4. Rizzardini, G., D. Trabattoni, M. Saresella, S. Piconi, M. Lukwiya, S. Declich,
M. Fabiani, P. Ferrante, and M. Clerici. 1998. Immune activation in HIV-infected
African individuals: Italian-Ugandan AIDS Cooperation Program. AIDS 12:2387.
5. Whalen, C., C. R. Horsburgh, D. Hom, C. Lahart, M. Simberkoff, and J. Ellner.
1995. Accelerated course of human immunodeficiency virus infection after tubercu-
losis. Am. J. Respir. Crit. Care Med. 151:1293.
6. Blanchard, A., L. Montagnier, and M.-L. Gougeon. 1997. Influence of microbial in-
fections on the progression of HIV disease. Trends Microbiol. 5:326.
7. Laurence, J. 1992. Viral cofactors in the immune pathogenesis and clinical manifes-
tations of HIV infection. In AIDS and Other Manifestations of HIV Infection, 2nd Ed.
G. P. Wormser, ed. Raven, New York, p. 77.
8. Corbett, E. L., R. W. Steketee, F. O. ter Kuile, A. S. Latif, A. Kamali, and R. J. Hayes.
2002. HIV-1/AIDS and the control of other infectious diseases in Africa. Lancet
359:2177.
9. Cohen, M. S. 1998. Sexually transmitted diseases enhance HIV transmission: no
longer a hypothesis. Lancet 351:5.
10. Orenstein, J. M., C. Fox, and S. M. Wahl. 1997. Macrophages as a source of HIV
during opportunistic infections. Science 276:1857.
11. Lawn, S. D. 2004. AIDS in Africa: impact of co-infections on the pathogenesis of
HIV-1 infection. J. Infect. 48:1.
12. Goletti, D., D. Weissman, R. W. Jackson, N. M. Graham, D. Vlahov, R. S. Klein,
S. S. Munsiff, L. Ortona, R. Cauda, and A. S. Fauci. 1996. Effect of Mycobacterium
tuberculosis on HIV replication: role of immune activation. J. Immunol. 157:1271.
13. Fauci, A. S. 1993. Multifactorial nature of human immunodeficiency virus disease:
implications for therapy. Science 262:1011.
14. Beutler, B., K. Hoebe, X. Du, and R. J. Ulevitch. 2003. How we detect microbes and
respond to them: the Toll-like receptors and their transducers. J. Leukocyte Biol.
74:479.
15. Takeda, K., T. Kaisho, and S. Akira. Toll-like receptors. 2003. Annu. Rev. Immunol.
21:335.
16. Lemaitre, B., E. Nicolas, L. Michaut, J. M. Reichhart, and J. A. Hoffmann. 1996. The
dorsoventral regulatory gene cassette Spatzle/Toll/Cactus controls the potent antifun-
gal response in Drosophila adults. Cell 86:973.
17. Underhill, D. M. 2003. Toll-like receptors: networking for success. Eur. J. Immunol.
33:1767.
18. Kopp, E., and R. Medzhitov. 2003. Recognition of microbial infection by Toll-like
receptors. Curr. Opin. Immunol. 15:396.
19. Pereira, L. A., K. Bentley, A. Peeters, M. J. Churchill, and N. J Deacon. 2000. A
compilation of cellular transcription factor interactions with the HIV-1 LTR pro-
moter. Nucleic Acids Res. 28:3.
20. Rohr, O., C. Marban, D. Aunis, and E. Schaeffer. 2003. Regulation of HIV-1 gene
transcription: from lymphocytes to microglial cells. J. Leukocyte Biol. 74:736.
21. Pomerantz, R. J., M. B. Feinberg, D. Trono, and D. Baltimore. 1990. Lipopolysac-
charide is a potent monocyte/macrophage-specific stimulator of human immunode-
ficiency virus type 1 expression. J. Exp. Med. 172:253.
22. Molina, J. M., D. T. Scadden, R. Byrn, C. A. Dinarello, and J. E. Groopman. 1989.
Production of tumor necrosis factor ␣ and interleukin 1 ␤ by monocytic cells infected
with human immunodeficiency virus. J. Clin. Invest. 84:733.
23. von Briesen, H., C. von Mallinckrodt, R. Esser, S. Muller, K. Becker,
H. Rubsamen-Waigmann, and R. Andreesen. 1991. Effect of cytokines and lipopoly-
saccharides on HIV infection of human macrophages. Res. Virol. 142:197.
24. Zhang, Y., K. Nakata, M. Weiden, and W. N. Rom. 1995. Mycobacterium tuberculosis
enhances human immunodeficiency virus-1 replication by transcriptional activation
at the long terminal repeat. J. Clin. Invest. 95:2324.
25. Bernier, R., S. J. Turco, M. Olivier, and M. Tremblay. 1995. Activation of human
immunodeficiency virus type 1 in monocytoid cells by the protozoan parasite Leish-
mania donovani. J. Virol. 69:7282.
26. Stacey, K. J., M. J. Sweet, and D. A. Hume. 1996. Macrophages ingest and are acti-
vated by bacterial DNA. J. Immunol. 157:2116.
7233
27. Verani, A., G. Scarlatti, M. Comar, E. Tresoldi, S. Polo, M. Giacca, P. Lusso,
A. G. Siccardi, and D. Vercelli. 1997. C-C chemokines released by lipopolysaccharide
(LPS)-stimulated human macrophages suppress HIV-1 infection in both macro-
phages and T cells. J. Exp. Med. 185:805.
28. Zybarth, G., N. Reiling, H. Schmidtmayerova, B. Sherry, and M. Bukrinsky. 1999.
Activation-induced resistance of human macrophages to HIV-1 infection in vitro.
J. Immunol. 162:400.
29. Goletti, D., S. Carrara, D. Vincenti, E. Giacomini, L. Fattorini, A. R. Garbuglia,
M. R. Capobianchi, T. Alonzi, G. M. Fimia, M. Federico, et al. 2004. Inhibition of
HIV-1 replication in monocyte-derived macrophages by Mycobacterium tuberculosis.
J. Infect. Dis. 189:624.
30. Medzhitov, R., P. Preston-Hurlburt, and C. A. Janeway, Jr. 1997. A human homo-
logue of the Drosophila Toll protein signals activation of adaptive immunity. Nature
388:394.
31. Equils, O., E. Faure, L. Thomas, Y. Bulut, S. Trushin, and M. Arditi. 2001. Bacterial
lipopolysaccharide activates HIV long terminal repeat through Toll-like receptor 4.
J. Immunol. 166:2342.
32. Equils, O., M. L. Schito, H. Karahashi, Z. Madak, A. Yarali, K. S. Michelsen, A. Sher,
and M. Arditi. 2003. TLR-2 and TLR-9 signaling results in HIV-LTR transactivation
and HIV replication in HIV-1 transgenic mouse spleen cells: implications of simul-
taneous activation of TLRs on HIV replication. J. Immunol. 170:5159.
33. Sundstrom, J. B., D. M. Little, F. Villinger, J. E. Ellis, and A. A. Ansari. 2004. Sig-
naling through Toll-like receptors triggers HIV-1 replication in latently infected mast
Downloaded from http://journals.aai.org/jimmunol/article-pdf/172/12/7229/1177911/7229.pdf by guest on 09 March 2024
cells. J. Immunol. 172:4391.
34. Jones, B. W., T. K. Means, K. A. Heldwein, M. A. Keen, P. J. Hill, J. T. Belisle, and
M. J. Fenton. 2001. Different Toll-like receptor agonists induce distinct macrophage
responses. J. Leukocyte Biol. 69:1036.
35. de Veer, M. J., J. M. Curtis, T. M. Baldwin, J. A. DiDonato, A. Sexton,
M. J. McConville, E. Handman, and L. Schofield. 2003. MyD88 is essential for clear-
ance of Leishmania major: possible role for lipophosphoglycan and Toll-like receptor
2 signaling. Eur. J. Immunol. 33:2822.
36. Toossi, Z. 2003. Virological and immunological impact of tuberculosis on human
immunodeficiency virus type 1 disease. J. Infect. Dis. 188:1146.
37. Li, Q., K. Gebhard, T. Schacker, K. Henry, and A. T. Haase. 1997. The relationship
between tumor necrosis factor and human immunodeficiency virus gene expression in
lymphoid tissue. J. Virol. 71:7080.
38. Yeo, S. J., D. Gravis, J. G. Yoon, and A. K. Yi. 2003. Myeloid differentiation factor
88-dependent transcriptional regulation of cyclooxygenase-2 expression by CpG
DNA: role of NF-␬B and p38. J. Biol. Chem. 278:22563.
39. Ma, W., W. Lim, K. Gee, S. Aucoin, D. Nandan, M. Kozlowski, F. Diaz-Mitoma, and
A. Kumar. 2001. The p38 mitogen-activated kinase pathway regulates the human in-
terleukin-10 promoter via the activation of Sp1 transcription factor in lipopolysaccha-
ride-stimulated human macrophages. J. Biol. Chem. 276:13664.
40. Uematsu, S., M. Matsumoto, K. Takeda, and S. Akira. 2002. Lipopolysaccharide-
dependentprostaglandinE2 productionisregulatedbytheglutathione-dependentpros-
taglandin E2 synthase gene induced by the Toll-like receptor 4/MyD88/NF-IL6 path-
way. J. Immunol. 168:5811.
41. Cohen, P. S., H. Schmidtmayerova, J. Dennis, L. Dubrovsky, B. Sherry, H. Wang,
M. Bukrinsky, and K. J. Tracey. 1997. The critical role of p38 MAP kinase in T cell
HIV-1 replication. Mol. Med. 3:339.
42. Shapiro, L., K. A. Heidenreich, M. K. Meintzer, and C. A. Dinarello. 1998. Role of
p38 mitogen-activated protein kinase in HIV type 1 production in vitro. Proc. Natl.
Acad. Sci. USA 95:7422.
43. Francois, F., and M. E. Klotman. 2003. Phosphatidylinositol 3-kinase regulates hu-
man immunodeficiency virus type 1 replication following viral entry in primary
CD4⫹ T lymphocytes and macrophages. J. Virol. 77:2539.
44. Croix, D. A., S. Capuano III, L. Simpson, B. A. Fallert, C. L. Fuller, E. C. Klein,
T. A. Reinhart, M. Murphey-Corb, and J. L. Flynn. 2000. Effect of mycobacterial
infection on virus loads and disease progression in simian immunodeficiency virus-
infected rhesus monkeys. AIDS Res. Hum. Retroviruses 16:1895.
45. Gazzinelli, R. T., A. Sher, A. Cheever, S. Gerstberger, M. A. Martin, and P. Dickie.
1996. Infection of human immunodeficiency virus 1 transgenic mice with Toxoplasma
gondii stimulates proviral transcription in macrophages in vivo. J. Exp. Med.
183:1645.
46. Browning Paul, J., E. J. Wang, M. Pettoello-Mantovani, C. Raker, S. Yurasov,
M. M. Goldstein, J. W. Horner, J. Chan, and H. Goldstein. 2000. Mice transgenic for
monocyte-tropic HIV type 1 produce infectious virus and display plasma viremia: a
new in vivo system for studying the post-integration phase of HIV replication. AIDS
Res. Hum. Retroviruses 16:481.
47. Wang, E. J., J. Sun, M. Pettoello-Mantovani, C. M. Anderson, K. Osiecki, M.
L. Zhao, L. Lopez, S. C. Lee, J. W. Berman, and H. Goldstein. 2003. Microglia from
mice transgenic for a provirus encoding a monocyte-tropic HIV type 1 isolate produce
infectious virus and display in vitro and in vivo upregulation of lipopolysaccharide-
induced chemokine gene expression. AIDS Res. Hum. Retroviruses 19:755.
48. Tanaka, J., H. Ozaki, J. Yasuda, R. Horai, Y. Tagawa, M. Asano, S. Saijo, M. Imai,
K. Sekikawa, M. Kopf, and Y. Iwakura. 2000. Lipopolysaccharide-induced HIV-1
expression in transgenic mice is mediated by tumor necrosis factor-␣ and interleu-
kin-1, but not by interferon-␥ nor interleukin-6. AIDS 14:1299.
49. Yull, F. E., W. Han, E. D. Jansen, M. B. Everhart, R. T. Sadikot, J. W. Christman, and
T. S. Blackwell. 2003. Bioluminescent detection of endotoxin effects on HIV-1 LTR-
driven transcription in vivo. J. Histochem. Cytochem. 51:741.
50. Doherty, T. M., C. Chougnet, M. Schito, B. K. Patterson, C. Fox, G. M. Shearer,
G. Englund, and A. Sher. 1999. Infection of HIV-1 transgenic mice with Mycobacte-
rium avium induces the expression of infectious virus selectively from a Mac-1-positive
host cell population. J. Immunol. 163:1506.
7234 BRIEF REVIEW: INFLUENCE OF TLR SIGNALING ON HIV EXPRESSION
51. Bafica, A., C. A. Scanga, M. Schito, S. Hieny, and A. Sher. 2003. Cutting edge: in vivo
induction of integrated HIV-1 expression by mycobacteria is critically dependent on
Toll-like receptor 2. J. Immunol. 171:1123.
52. Feng, C. G., C. A. Scanga, C. M. Collazo-Custodio, A. W. Cheever, S. Hieny,
P. Caspar, and A. Sher. 2003. Mice lacking myeloid differentiation factor 88 display
profound defects in host resistance and immune responses to Mycobacterium avium
infection not exhibited by Toll-like receptor 2 (TLR2)- and TLR4-deficient animals.
J. Immunol. 171:4758.
53. Reiling, N., C. Holscher, A. Fehrenbach, S. Kroger, C. J. Kirschning, S. Goyert, and
S. Ehlers. 2002. Cutting edge: Toll-like receptor (TLR)2- and TLR4-mediated patho-
gen recognition in resistance to airborne infection with Mycobacterium tuberculosis.
J. Immunol. 169:3480.
54. Drennan, M. B., D. Nicolle, V. J. Quesniaux, M. Jacobs, N. Allie, J. Mpagi,
C. Fremond, H. Wagner, C. Kirschning, and B. Ryffel. 2004. Toll-like receptor 2-de-
ficient mice succumb to Mycobacterium tuberculosis infection. Am. J. Pathol. 164:49.
55. Scanga, C. A., A. Bafica, C. G. Feng, A. W. Cheever, S. Hieny, and A. Sher. 2004.
MyD88-deficient mice display a profound loss in resistance to Mycobacterium tuber-
culosis associated with partially impaired Th1 cytokine and nitric oxide synthase 2
expression. Infect. Immun. 72:2400.
56. Margolis, L. B., S. Glushakova, J. C. Grivel, and P. M. Murphy. 1998. Blockade of
CC chemokine receptor 5 (CCR5)-tropic human immunodeficiency virus-1 replica-
tion in human lymphoid tissue by CC chemokines. J. Clin. Invest. 101:1876.
57. Agrawal, S., and R. R. Martin. 2003. Was induction of HIV-1 through TLR9? J. Im-
munol. 171:1621.
58. Lisziewicz, J., D. Sun, F. F. Weichold, A. R. Thierry, P. Lusso, J. Tang, R. C. Gallo,
and S. Agrawal. 1994. Antisense oligodeoxynucleotide phosphorothioate complemen-
tary to Gag mRNA blocks replication of human immunodeficiency virus type 1 in
human peripheral blood cells. Proc. Natl. Acad. Sci. USA 91:7942.
59. Agrawal, S. 1999. Importance of nucleotide sequence and chemical modifications of
antisense oligonucleotides. Biochim. Biophys. Acta 1489:53.
60. Bochud, P. Y., T. R. Hawn, and A. Aderem. 2003. Cutting edge: a Toll-like receptor
2 polymorphism that is associated with lepromatous leprosy is unable to mediate my-
cobacterial signaling. J. Immunol. 170:3451.
61. Hawn, T. R., A. Verbon, K. D. Lettinga, L. P. Zhao, S. S. Li, R. J. Laws, S. J. Skerrett,
B. Beutler, L. Schroeder, A. Nachman, et al. 2003. A common dominant TLR5 stop
codon polymorphism abolishes flagellin signaling and is associated with susceptibility
to Legionnaires’ disease. J. Exp. Med. 198:1563.
62. Sabroe, I., R. C. Read, M. K. Whyte, D. H. Dockrell, S. N. Vogel, and S. K. Dower.
2003. Toll-like receptors in health and disease: complex questions remain. J. Immunol.
171:1630.
63. Quesniaux, V. F., and R. Bernhard. 2004. Toll-like receptors: emerging targets of
immunomodulation. Expert Opin. Ther. Patents 14:85.
64. Dobrovolskaia, M. A., and S. N. Vogel. 2002. Toll receptors, CD14, and macrophage
activation and deactivation by LPS. Microbes Infect. 4:903.
65. Dobrovolskaia, M. A., A. E. Medvedev, K. E. Thomas, N. Cuesta, V. Toshchakov,
T. Ren, M. J. Cody, S. M. Michalek, N. R. Rice, and S. N. Vogel. 2003. Induction of
in vitro reprogramming by Toll-like receptor (TLR)2 and TLR4 agonists in murine
macrophages: effects of TLR “homotolerance” versus “heterotolerance” on NF-␬B
signaling pathway components. J. Immunol. 170:508.
66. Yeo, S. J., J. G. Yoon, S. C. Hong, and A. K. Yi. 2003. CpG DNA induces self and
cross-hyporesponsiveness of RAW264.7 cells in response to CpG DNA and lipopoly-
saccharide: alterations in IL-1 receptor-associated kinase expression. J. Immunol. 170:
1052.
Downloaded from http://journals.aai.org/jimmunol/article-pdf/172/12/7229/1177911/7229.pdf by guest on 09 March 2024
67. Jacinto, R., T. Hartung, C. McCall, and L. Liwu. 2002. Lipopolysaccharide- and li-
poteichoic acid-induced tolerance and cross-tolerance: dystonic alterations in IL-1 re-
ceptor-associated kinase. J. Immunol. 168:6136.
68. Bafica, A., C. A. Scanga, O. Equils, and A. Sher. 2004. The induction of Toll-like
receptor tolerance enhances rather than suppresses HIV-1 gene expression in trans-
genic mice. J. Leukocyte Biol. 75:460.