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PLENARY PAPER
From the Laboratory of Experimental Internal Medicine,
the Department of Internal Medicine, Division of Infectious Diseases,
Tropical Medicine and AIDS, the Department of Human Retrovirology, the
Department of Intensive Care Medicine, Academic Medical Center,
University of Amsterdam, Amsterdam, the Netherlands.
Concurrent infections in patients with human immunodeficiency virus
(HIV) infection stimulate HIV replication. Chemokine receptors CXCR4
and CCR5 can act as HIV coreceptors. The authors hypothesized that
concurrent infection increases the HIV load through up-regulation of
CXCR4 and CCR5. Using experimental endotoxemia as a model of infection,
changes in HIV coreceptor expression were assessed in 8 subjects
injected with lipopolysaccharide (LPS, 4 ng/kg). The expression of
CXCR4 and CCR5 on CD4+ T cells was increased 2- to 4-fold,
4 to 6 hours after LPS injection. In whole blood in vitro, LPS induced
a time- and dose-dependent increase in the expression of
CXCR4 and CCR5 on CD4+ T cells. Similar changes were
observed after stimulation with cell wall components of
Mycobacterium tuberculosis (lipoarabinnomannan) or
Staphylococcus aureus (lipoteichoic acid), or
with staphylococcal enterotoxin B. LPS increased viral infectivity of
CD4-enriched peripheral blood mononuclear cells (PBMCs) with a T-tropic
HIV strain. In contrast, M-tropic virus infectivity was reduced,
possibly because of elevated levels of the CCR5 ligand cytokines RANTES and MIP-1 During the course of human immunodeficiency virus
(HIV) infection, concurrent infections stimulate viral replication.
Replication of HIV-1 is enhanced in HIV-infected patients with active
tuberculosis, returning to baseline after tuberculostatic
treatment.1,2 Also, a number of other infectious diseases
often encountered during the course of HIV infection has been reported
to accelerate HIV replication.3-6 Lipopolysaccharide
(LPS), the major cell wall component of gram-negative bacteria, and
staphylococcal antigens stimulate HIV expression in
vitro.7,8 Together, these data suggest that concurrent
infection offers an advantage to HIV-1 to infect cells and to replicate.
Chemokines are chemotactic proteins that direct leukocytes to the site
of inflammation. Chemokine receptors CXCR4 and CCR5 can act as HIV
coreceptors, together with CD4, and are essential for viral entry into
cells.9-13 Individuals with a homozygous defect in CCR5
are less susceptible to HIV-1 infection, suggesting a key role for this
receptor in HIV-1 pathogenesis.14,15 Macrophage (M)-tropic
HIV-1 isolates use CCR5 as coreceptor early in the course of HIV
infection, whereas T-cell tropic viruses use CXCR4 for entry into
CD4+ T cells, typically in a later stage of infection. An
expansion of receptor use to include CXCR4 has been associated with a
sharp decline in the number of peripheral CD4+ T
cells,16 indicating that disease progression can correlate with HIV coreceptor type.
Recently, a number of studies have indicated that an increase in CXCR4
and CCR5 expression is associated with an enhanced entry of HIV-1 into
cells of the immune system.17-21 We hypothesized that
during concurrent infection, invading microorganisms or their antigens
up-regulate HIV coreceptors on CD4+ T cells, resulting in
an increase in HIV replication. To test this hypothesis, we studied the
expression of CXCR4 and CCR5 on CD4+ T cells in the
well-defined model of human endotoxemia22 and after in
vitro incubation with a lipid glycoprotein cell wall component of
Mycobacterium tuberculosis (lipoarabinomannam,
LAM), a cell wall component of Staphylococcus
aureus (lipoteichoic acid, LTA) and staphylococcal
enterotoxin B (SEB). The association of HIV coreceptor expression
and HIV infectivity was examined by measuring replication of T- and
M-tropic viruses in LPS-stimulated CD4+-enriched peripheral
blood mononuclear cells (PBMCs). Because cytokines influence HIV-1
replication,23,24 we also determined the role of important
proinflammatory and antiinflammatory cytokines with the use of
neutralizing antibodies and recombinant products.
In vivo study
Flow cytometry
In vitro studies For each experiment, blood was collected from 6 healthy subjects using a sterile collecting system consisting of a butterfly needle connected to a syringe (Becton Dickinson, Mountain View, CA) and incubated at 37°C for 8 hours. Anticoagulation was obtained using heparin (Leo Pharmaceutical Products, Weesp, The Netherlands; final concentration 10 U/mL blood). Whole blood was added to sterile polypropylene tubes and diluted 1:1 with RPMI 1640 (Bio Whittaker, Verviers, Belgium). LPS (from E coli serotype 0111: B4; Sigma, St Louis, MO) was added for the time course (10 ng/mL) and dose-response study. In separate experiments, LAM (mannose-capped, isolated and prepared from M tuberculosis strain H37Rv), kindly provided by J. T. Belisle (Colorado State University, Fort Collins, CO, under National Institutes of Health Contract NO1-A1-75320), LTA or SEB (both from Sigma Chemical, St Louis, MO) were added at a concentration of 1 µg/mL. Whole blood was also stimulated with LPS (10 ng/mL) in the presence of a neutralizing mouse antihuman tumor necrosis factor (TNF) monoclonal antibody (mAb, MAK 195F,25 kindly provided by Knoll, Ludwigshafen, Germany), a neutralizing mouse antihuman interferon- monoclonal antibody
(IFN mAb), a neutralizing mouse antihuman interleukin 10 (IL-10) mAb
(both R&D systems), or an isotype-matched mouse IgG (Central Laboratory of the Netherlands Red Cross Blood Transfusion Service [CLB], Amsterdam, The Netherlands). The concentration of all antibodies was 10 µg/mL. Whole blood was also incubated with recombinant (r) TNF
(Knoll), rIFN, or rIL-10 (both CLB, all 10 ng/mL). In addition,
CD4+-enriched PBMCs were stimulated with PHA for 6 days,
after LPS (10 ng/mL) was either added or omitted for 24 hours. FACS
analysis was performed in whole blood and PBMCs as described above.
Viral TCID50 determination and in vitro HIV-1 infection Viral stocks grown on PBMCs were assayed for their tissue culture infectious dose 50% per milliliter (TCID50) values on CD4+-enriched lymphocytes isolated from fresh buffy coats by standard Ficoll-Hypaque density centrifugation. PBMCs were activated with 5 µg/mL PHA (Sigma Chemical, St Louis, MO) and cultured in RPMI media containing 10% fetal calf serum (FCS) (Bio Whittaker), penicillin (100 U/mL), and streptomycin (100 U/mL) with 100 U/mL IL-2 (Chiron, Amsterdam, The Netherlands). On day 4 of culture, the cells underwent a CD4+ enrichment by incubating with CD8 immunomagnetic beads (Dynal) and separating out the CD8+ lymphocytes. CD4+-enriched lymphocytes were plated at 2 × 105 cells per well in 96-well plates with 5-fold serial dilutions of the virus. The wells were fed on day 7 with fresh media and scored on day 14 for p24 levels and the number of positive wells identified. This figure was used to determine the TCID50 value for each virus. For the HIV-1 in vitro infectivity assay, CD4+-enriched lymphocytes were generated as described above. On day of infection, the CD4+-enriched cells were treated either with or without LPS (100 ng/mL) and cultured for 8 hours at 37°C, after which a T-tropic molecular cloned virus (LAI) and an M-tropic molecular cloned virus (SF162) were used to infect the cells. Infections were performed using 4-fold limiting dilutions of the virus, starting at 240 TCID50 down to 1 TCID50. After a 2-hour incubation period, the cells were spun and washed 3 times and fed with fresh RPMI media containing IL-2. The cultures were carried for 10 days and fed with fresh IL-2 containing media on days 4, 7, and 10. Viral replication was monitored on day 10 by the use of a standard p24 antigen enzyme-linked immunosorbent assay (ELISA) as previously described.26Enzyme-linked immunosorbent assay RANTES, MIP-1 , and MIP-1 were measured with ELISA
(all from R&D Systems) according to the instructions of the
manufacturer. The detection limits of assays were 31.5 (MIP-1,
RANTES) and 15.6 pg/mL (MIP-1).
Statistical analysis All values are given as means ± SEM. In vivo data were analyzed by 1-way analysis of variance. Data of in vitro stimulations of whole blood and end-point viral dilutions required to establish infection of CD4+-enriched lymphocytes in vitro were analyzed using the Wilcoxon test. P < .05 was considered statistically significant.
HIV coreceptor expression on circulating CD4+ T cells during human endotoxemia Injection of LPS was associated with transient influenza-like symptoms, including headache, chills, vomiting, myalgia, and fever (peak temperatures: 38.6°C ± 0.3°C). Injection of LPS induced a decrease in the number of lymphocytes (from 1.6 ± 0.1 to 0.3 ± 0.0 × 109/L at 4 hours, P = .048). The fraction of CD4+ T cells decreased from 41.1 ± 3.9% to 28.4 ± 5.7% at 4 hours (P = .05). Intravenous LPS induced an increase in the expression of CXCR4 on circulating CD4+ T cells, peaking after 4 hours (MCF: from 43.8 ± 11.7 at baseline to 187.2 ± 32.1; P = .001), and returning to the initial level of expression after 24 hours (Figure 1). In addition, the fraction of CD4+ T cells expressing CXCR4 also increased significantly, peaking after 6 hours (from 9.3% ± 1.8% at baseline to 42.6% ± 9.7%; P = .002). LPS elicited an up-regulation of CCR5 on circulating CD4+ T cells (MCF: from 40.1 ± 15.2 to 79.4 ± 16.5 at 6 hours; P = .01), returning to baseline after 24 hours. In contrast, the fraction of CCR5-positive CD4+ T cells did not change after injection with LPS. To determine whether the increase in CD4+ T cells positive for CXCR4 or CCR5 was not due to a relative loss of CD4+ T cells negative for CXCR4 or CCR5 from the circulation during endotoxemia, we analyzed the MCF on HIV-coreceptor-positive CD4+ T cells before and after LPS administration. LPS resulted in an increase in the MCF of CXCR4 on CXCR4-positive T cells from 115.2 ± 12.2 at baseline to 325.4 ± 13.1 at 6 hours. The MCF of CCR5 on CCR5 positive CD4+ T cells showed an increase 6 hours after LPS injection (from 91.9 ± 13.8 to 232.2 ± 32.3). MCF of both HIV coreceptors returned to baseline at 24 hours.
HIV coreceptor expression on CD4+ T cells after whole blood stimulation with (myco)bacterial agents Having established that LPS causes an increase in the expression of CXCR4 and CCR5 on circulating CD4+ T cells, we performed a dose response and time course study of this effect in whole blood in vitro (Figure 2). Both HIV coreceptors were up-regulated after 8-hour stimulation with LPS, which lasted for 24 hours (CXCR4) or even 48 hours (CCR5). Because the in vivo effect of LPS was present at 6 hours, we chose to perform additional experiments with the 8-hour incubation period. A dose of 10 ng/mL induced significant up-regulation of both receptors. When higher doses were used, no additional effect was seen (Figure 2). Next, we sought to determine whether other bacterial products also up-regulate HIV coreceptors. For this purpose whole blood was incubated with LAM (a cell wall component of M tuberculosis), LTA (a cell wall component of S aureus) or SEB (a superantigen produced by S aureus). All 3 agents induced an up-regulation of CXCR4 and CCR5 on CD4+ T cells (Figure 3).
HIV coreceptor expression and HIV replication in peripheral blood mononuclear cells To determine whether HIV coreceptor up-regulation on CD4+ T cells correlates with HIV-1 replication, an in vitro system was developed with CD4+-enriched PBMCs. As in whole blood, LPS induced an increase in the fraction of CD4+ cells expressing CXCR4 (from 20.9% at baseline to 49.9% after addition of LPS. Control: 22.3%) and CCR5 (from 9.6% at baseline to 37.8% after addition of LPS. Control: 14.2%; results from one representative experiment of 3 separate experiments). Infectivity of LPS-treated and nontreated CD4+-enriched PBMCs was determined using both the T-tropic (LAI) and M-tropic (SF162) molecular cloned viruses at limiting dilutions of infectivity and determining viral p24 production on day 10 of culture. Because the virus was washed out 2 hours after infection, our assay monitors the infectability of CD4+ cells during this period. With the T-tropic virus, an increase in the infectivity of the CD4+-enriched population was observed in the presence of LPS with a lower TCID50 required to establish infection than in cultures to which no LPS was added (Figure 4). This increase in T-tropic HIV infectivity coincided with the enhancement of CXCR4 cell surface expression. In contrast, the M-tropic virus (SF162) showed an increase in the level of virus required to establish infection on the LPS-treated CD4+-enriched cells in comparison to cells that were not treated with LPS (Figure 4). This decrease in M-tropic infectivity was despite the increase in CCR5 cell surface expression. These results were reproduced in a total of 4 experiments in 3 different donors; for donor C the experiment was performed twice with similar results. Comparison of end-point viral dilutions required to establish infection of CD4-enriched PBMCs in the presence or absence of LPS, revealed an increased infectivity with T-tropic virus in the presence of LPS, with a concurrently decreased infectivity with M-tropic virus (both P = .011 for the difference between with or without LPS). Because it has been previously shown that LPS-treated macrophages can secrete elevated levels of chemokines, we wished to determine whether an enhancement in the secretion of RANTES, MIP-1, and MIP-1 could explain the reduction in M-tropic viral
infectivity. The levels of these chemokines were measured in
supernatant of LPS-stimulated and nonstimulated
CD4+-enriched lymphocytes. LPS induced an increase in the
concentration of MIP-1 (14.6 vs 6.8 ng/mL in non-LPS stimulated
cells) and RANTES (3322 vs 1661 pg/mL ml in non-LPS stimulated cells)
but not of MIP-1.
Role of cytokines in HIV coreceptor up-regulation on CD4+ T cells Both intercurrent infections and experimental endotoxemia result in an enhanced cytokine production. We studied the role of TNF, IFN,
and IL-10 in the LPS-induced effects on HIV coreceptor expression
(Figure 5). Therefore, whole blood was
incubated with LPS in the presence of an irrelevant antibody, or a
neutralizing antibody against either TNF, IFN, or IL-10. The
LPS-induced up-regulation of the fraction of CD4+ T cells
positive for CXCR4 was partially inhibited by anti-TNF and by
anti-IFN (P = .028 versus incubation with LPS
and an irrelevant antibody for both). Anti-IL-10 did not influence the
expression of CXCR4. Similarly, the LPS-induced up-regulation of CCR5
expression was partially inhibited by anti-TNF and by anti-IFN,
although these effects were more modest than for CXCR4
(P = .028 and P = .046, respectively, vs
incubation with LPS and an irrelevant antibody). Anti-IL-10 tended to
reduce the LPS effect. To further examine the role of cytokines in the
absence of LPS stimulation, whole blood was incubated with either rTNF,
rIFN, or rIL-10. In accordance with the inhibiting effect of
anti-TNF and anti-IFN, expression of CXCR4 was up-regulated by rTNF
or rIFN (P = .03 and P = .021,
respectively, vs RPMI), whereas rIL-10 had no effect on CXCR4.
Recombinant TNF or rIFN induced expression of CCR5 on
CD4+ T cells to a lesser extent (P = .03 vs
RPMI for both). In contrast to the absence of an IL-10 effect on CXCR4,
rIL-10 up-regulated CCR5 on CD4+ T cells
(P = .021 compared with RPMI).
Concurrent infections in patients with HIV are associated with an increase in HIV replication3-6 and an enhanced susceptibility of immune cells for HIV infection.27 The chemokine receptors CXCR4 and CCR5 serve as coreceptors for HIV entry in CD4+ T cells. We used the model of intravenous LPS administration to healthy subjects to test the hypothesis that intercurrent febrile diseases may result in enhanced HIV replication through up-regulation of HIV coreceptors on circulating CD4+ T cells. Indeed, we found that during human endotoxemia, both the surface expression of CXCR4 and CCR5 per CD4+ T cell, as well as the fraction of CD4+ T cells expressing CXCR4, increased in peripheral blood. Stimulations of whole blood in vitro with antigens derived from M tuberculosis and S aureus induced similar changes in CXCR4 and CCR5 expression on CD4+ T cells. The heightened expression of CXCR4 correlated with an increase in the infectability of CD4+-enriched PBMCs with a T-tropic HIV-1 molecular cloned virus in vitro. In contrast, CCR5 surface expression did not result in an increased HIV infectability pattern but rather was associated with a decrease in replication of an M-tropic HIV-1 strain. Therefore, pathogens commonly found in HIV-infected patients may increase viral burden in blood by up-regulation of CXCR4. Moreover, intercurrent infections may contribute to the selection of CXCR4-using viruses during the course of disease progression. The human endotoxemia model has some limitations. Intravenous injection of LPS induces a short-lasting febrile illness and an associated transient inflammatory response. In addition, the model uses the circulation as the body compartment to which the stimulus is administered and in which the responses are measured. Hence, in this study the up-regulation of HIV coreceptors was transient, just like the experimentally induced illness, and HIV coreceptor expression was only measured on CD4+ T cells derived from peripheral blood, the body compartment that was challenged with LPS. Presumably, similar changes in HIV coreceptor expression can be observed for longer periods and in other compartments, when clinical diseases are studied. Of special interest is the finding that macrophages may act as a reservoir for HIV during concurrent infections.28 Moreover, M avium, a pathogen commonly found in HIV patients, has been found to increase CCR5 expression and stimulate HIV production within macrophages.20 The effect of LPS on HIV coreceptors in vivo was most evident for CXCR4. This is in agreement with HIV coreceptor expression on macrophages after LPS stimulation.29 CXCR4 expression correlated with infectability of PBMCs with T-tropic strains, thereby supporting the idea that concurrent infections increase CXCR4 expression and subsequent HIV replication. In contrast, CCR5 expression did not correlate with an increase in replication of an M-tropic HIV strain. It has been shown that LPS induces production of CC-chemokines that inhibit HIV replication in T lymphocytes in vitro.30 In accordance, the LPS stimulation of CD4+-enriched cells resulted in the higher production of RANTES and MIP-1. Also, during LPS-induced human endotoxemia, production of CC-chemokines is known to be enhanced.31 Hence, the net effect of LPS or other bacterial products on CCR5 expression and production of CCR5 blocking ligands in vivo remains to be determined. The HIV isolates associated with viral transmission and found early after infection are predominantly those which utilize the CCR5 coreceptor. In patients with an advanced stage of disease, a switch in receptor use from CCR5 to CXCR4 is often observed,16 suggesting that not only the extent of expression but also the type of HIV coreceptor modulates the course of HIV infection. Antigens from microorganisms often causing disease during an HIV infection heighten the susceptibility of macrophages to T-tropic HIV-1 in vitro.29 It has been proposed that a more favorable environment for T-tropic HIV-1 may result in viral transition of M-tropic to T-tropic HIV-1 phenotype, associated with disease progression.29 Indeed, because T-tropic but not M-tropic replication was associated with enhanced HIV coreceptor expression, bacterial antigens may be involved in the emergence of X4 and R5 × 4 variants. It should be noted that we did not directly test our hypothesis that endotoxemia increases the susceptibility of CD4+ T cells to HIV infection. For this, HIV infectability of CD4+ T cells obtained before and 4 to 6 hours after endotoxin injection should have been determined. Such studies are difficult to perform, however, considering the fluctuation in CD4 counts after LPS treatment, and the fact that the cells would need to go through multiple processing steps (unlike with FACS analysis), during which CC chemokine and chemokine receptor patterns may alter, thereby obscuring the true in vivo picture. Nonetheless, these studies could provide further support for our hypothesis. The precise mechanism for the observed up-regulation is unknown.
Presumably, immune activation and subsequent cytokine secretion modulate HIV disease.23 TNF is reported to stimulate HIV
expression in cell cultures,32-34 as well as in specific
T-cell lines,35,36 and during concurrent
infection.24 IFN IL-10 is the most important antiinflammatory cytokine produced in the endotoxemia model.38 It has been reported that IL-10 enhances CCR5, but not CXCR4 expression on monocytes, correlating with an increase in HIV expression.17 Also in a T cell line, IL-10 synergized with TNF in enhancing HIV transcription.39 We examined the effect of anti-IL-10 on LPS-induced HIV coreceptor expression. Similar to the effect on monocytes, IL-10 influenced CCR5, but not CXCR4 on CD4+ T cells, ie, rIL-10 up-regulated CCR5 expression, whereas anti-IL-10 attenuated LPS-induced CCR5 up-regulation. It is speculative why IL-10 only exerts effect on CCR5. Considering the important role of IL-10 in mucosal diseases,40 it was suggested that IL-10 maintains CCR5 expression in mucosal tissues, facilitating primary HIV infection.17 In summary, (myco)bacterial antigens increased the expression of CXCR4 and CCR5 on circulating CD4+ T cells in humans and in whole blood through direct antigenic stimulation of CXCR4 and CCR5 on CD4+ T cells, as well as indirect stimulation of these receptors via cytokines. Expression of CXCR4 correlated with an increase in T-tropic HIV replication. Expression of CCR5 did not correlate with M-tropic replication, possibly because of the production of blocking CC chemokines by bacterial products. Therefore, concurrent infections during the course of an HIV infection may induce a favorable environment for T-tropic viral strains. HIV coreceptors, considered targets for HIV therapy,41 may be important determinants of the course of an HIV infection. Close surveillance and aggressive treatment of intercurrent disease in HIV-infected patients is implicated. For some pathogens, adequate antibiotic prophylaxis may reduce the HIV load.
We thank Moustapha Chalaby for excellent technical assistance.
Submitted January 12, 2000; accepted June 14, 2000.
Supported by grants from the "Mr. Willem Bakhuys Roozeboom" Foundation to N.P.J. and the Royal Dutch Academy of Arts and Sciences to W.A.P. and T.v.d.P.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Tom van der Poll, Laboratory of Experimental Medicine, Room G2-132, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; e-mail: t.vanderpoll{at}amc.uva.nl.
1. Goletti D, Weissman D, Jackson RW, et al. Effect of Mycobacterium tuberculosis on HIV replication: role of immune activation. J Immunol. 1996;157:1271-1278[Abstract]. 2. Zhang Y, Nakata K, Weiden M, Rom WN. Mycobacterium tuberculosis enhances human immunodeficiency virus-1 replication by transcriptional activation at the long terminal repeat. J Clin Invest. 1995;95:2324-2331. 3. Claydon EJ, Bennett J, Gor D, Forster SM. Transient elevation of serum HIV antigen levels associated with intercurrent infection. AIDS. 1991;5:113-114[Medline] [Order article via Infotrieve]. 4. Denis M, Ghadirian E. Mycobacterium avium infection in HIV-1-infected subjects increases monokine secretion and is associated with enhanced viral load and diminished immune response to viral antigens. Clin Exp Immunol. 1994;97:76-82[Medline] [Order article via Infotrieve]. 5. Israel-Biet D, Cadranel J, Even P. Human immunodeficiency virus production by alveolar lymphocytes is increased during Pneumocystis carinii pneumonia. Am Rev Resp Dis. 1993;148:1308-1312[Medline] [Order article via Infotrieve]. 6. Heng MC, Heng SY, Allen SG. Co-infection and synergy of human immunodeficiency virus-1 and herpes simplex virus-1. Lancet. 1994;343:255-258[Medline] [Order article via Infotrieve]. 7. Akashi A, Ono S, Kuwano K, Arai S. Proteins of 30 and 36 kilodaltons, membrane constituents of the Staphylococcus aureus L form, induce production of tumor necrosis factor alpha and activate the human immunodeficiency virus type 1 long terminal repeat. Infect Immun. 1996;64:3267-3272[Abstract].
8.
Pomerantz RJ, Feinberg MB, Trono D, Baltimore D.
Lipopolysaccharide is a potent monocyte/macrophage-specific stimulator of human immunodeficiency virus type 1 expression.
J Exp Med.
1990;172:253-261 9. Dragic T, Litwin V, Allaway GP, et al. HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature. 1996;381:667-673[Medline] [Order article via Infotrieve]. 10. Choe H, Farzan M, Sun Y, et al. The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. Cell. 1996;85:1135-1148[Medline] [Order article via Infotrieve]. 11. Alkhatib G, Combadiere C, Broder CC, et al. CC CKR5: a RANTES, MIP-1alpha, MIP-1beta receptor as a fusion cofactor for macrophage-tropic HIV-1. Science. 1996;272:1955-1958[Abstract]. 12. Deng H, Liu R, Ellmeier W, et al. Identification of a major co-receptor for primary isolates of HIV-1. Nature. 1996;381:661-666[Medline] [Order article via Infotrieve]. 13. Feng Y, Broder CC, Kennedy PE, Berger EA. HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science. 1996;272:872-877[Abstract]. 14. Liu R, Paxton WA, Choe S, et al. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell. 1996;86:367-377[Medline] [Order article via Infotrieve]. 15. Samson M, Libert F, Doranz BJ, et al. Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature. 1996;382:722-725[Medline] [Order article via Infotrieve].
16.
Connor RI, Sheridan KE, Ceradini D, Choe S, Landau NR.
Change in coreceptor use correlates with disease progression in HIV-1-infected individuals.
J Exp Med.
1997;185:621-628
17.
Sozzani S, Ghezzi S, Iannolo G, et al.
Interleukin 10 increases CCR5 expression and HIV infection in human monocytes.
J Exp Med.
1998;187:439-444
18.
Zella D, Barabitskaja O, Burns JM, et al.
Interferon- 19. Dolei A, Biolchini A, Serra C, Curreli S, Gomes E, Dianzani F. Increased replication of T-cell-tropic HIV strains and CXC-chemokine receptor-4 induction in T cells treated with macrophage inflammatory protein (MIP)-1alpha, MIP-1beta and RANTES beta-chemokines. AIDS. 1998;12:183-190[Medline] [Order article via Infotrieve].
20.
Wahl SM, Greenwell-Wild T, Peng G, et al.
Mycobacterium avium complex augments macrophage HIV-1 production and increases CCR5 expression.
Proc Natl Acad Sci U S A.
1998;95:12574-12579
21.
Wu L, Paxton WA, Kassam N, et al.
CCR5 levels and expression pattern correlate with infectability by macrophage-tropic HIV-1, in vitro.
J Exp Med.
1997;185:1681-1691 22. Van der Poll T, Lowry SF. Biological responses to endotoxin in humans. In: Tellado JM,Forse RA,Solomkin JS, eds. Modulation of the Inflammatory Response in Severe Sepsis. Basel, Switzerland: Karger AG; 1995:18-32. 23. Fauci AS. Host factors and the pathogenesis of HIV-induced disease. Nature. 1996;384:529-534[Medline] [Order article via Infotrieve]. 24. Peterson PK, Gekker G, Chao CC, et al. Human cytomegalovirus-stimulated peripheral blood mononuclear cells induce HIV-1 replication via a tumor necrosis factor-alpha-mediated mechanism. J Clin Invest. 1992;89:574-580. 25. Moller A, Emling F, Blohm D, Schlick E, Schollmeier K. Monoclonal antibodies to human tumor necrosis factor alpha: in vitro and in vivo application. Cytokine. 1990;2:162-169[Medline] [Order article via Infotrieve].
26.
McKeating JA, McKnight A, Moore JP.
Differential loss of envelope glycoprotein gp120 from virions of human immunodeficiency virus type 1 isolates: effects on infectivity and neutralization.
J Virol.
1991;65:852-860
27.
Toossi Z, Sierra-Madero JG, Blinkhorn RA, Mettler MA, Rich EA.
Enhanced susceptibility of blood monocytes from patients with pulmonary tuberculosis to productive infection with human immunodeficiency virus type 1.
J Exp Med.
1993;177:1511-1516
28.
Orenstein JM, Fox C, Wahl SM.
Macrophages as a source of HIV during opportunistic infections.
Science.
1997;276:1857-1861 29. Moriuchi M, Moriuchi H, Turner W, Fauci AS. Exposure to bacterial products renders macrophages highly susceptible to T-tropic HIV-1. J Clin Invest. 1998;102:1540-1550[Medline] [Order article via Infotrieve].
30.
Verani A, Scarlatti G, Comar M, et al.
C-C chemokines released by lipopolysaccharide (LPS)-stimulated human macrophages suppress HIV-1 infection in both macrophages and T cells.
J Exp Med.
1997;185:805-816 31. O'Grady NP, Tropea M, Preas HL 2nd, et al. Detection of macrophage inflammatory protein (MIP)-1alpha and MIP-1beta during experimental endotoxemia and human sepsis. J Infect Dis. 1999;179:136-141[Medline] [Order article via Infotrieve]. 32. Poli G, Fauci AS. Human Cytokines; Their Role in Disease and Therapy. Vol 265. Cambridge, MA: Blackwell Science; 1995. 33. Mellors JW, Griffith BP, Ortiz MA, Landry ML, Ryan JL. Tumor necrosis factor-alpha/cachectin enhances human immunodeficiency virus type 1 replication in primary macrophages. J Infect Dis. 1991;163:78-82[Medline] [Order article via Infotrieve]. 34. Michihiko S, Yamamoto N, Shinozaki F, Shimada K, Soma G, Kobayashi N. Augmentation of in-vitro HIV replication in peripheral blood mononuclear cells of AIDS and ARC patients by tumour necrosis factor. Lancet. 1989;1:1206-1207[Medline] [Order article via Infotrieve].
35.
Folks TM, Clouse KA, Justement J, et al.
Tumor necrosis factor alpha induces expression of human immunodeficiency virus in a chronically infected T-cell clone.
Proc Natl Acad Sci U S A.
1989;86:2365-2368
36.
Kinter AL, Ostrowski M, Goletti D, et al.
HIV replication in CD4+ T cells of HIV-infected individuals is regulated by a balance between the viral suppressive effects of endogenous beta-chemokines and the viral inductive effects of other endogenous cytokines.
Proc Natl Acad Sci U S A.
1996;93:14076-14081 37. Kinter AL, Poli G, Fox L, Hardy E, Fauci AS. HIV replication in IL-2-stimulated peripheral blood mononuclear cells is driven in an autocrine/paracrine manner by endogenous cytokines. J Immunol. 1995;154:2448-2459[Abstract]. 38. van der Poll T, de Waal Malefyt R, Coyle SM, Lowry SF. Antiinflammatory cytokine responses during clinical sepsis and experimental endotoxemia: sequential measurements of plasma soluble interleukin (IL)-1 receptor type II, IL-10, and IL-13. J Infect Dis. 1997;175:118-122[Medline] [Order article via Infotrieve]. 39. Rabbi MF, Finnegan A, Al-Harthi L, Song S, Roebuck KA. Interleukin-10 enhances tumor necrosis factor-alpha activation of HIV-1 transcription in latently infected T cells. J Acquir Immune Defic Syndr Hum Retrovirol. 1998;19:321-331[Medline] [Order article via Infotrieve]. 40. Schreiber S, Heinig T, Thiele HG, Raedler A. Immunoregulatory role of interleukin 10 in patients with inflammatory bowel disease. Gastroenterology. 1995;108:1434-1444[Medline] [Order article via Infotrieve].
41.
Moore JP.
Coreceptors: implications for HIV pathogenesis and therapy.
Science.
1997;276:51-52
© 2000 by The American Society of Hematology.
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  M. A. Brockman, D. S. Kwon, D. P. Tighe, D. F. Pavlik, P. C. Rosato, J. Sela, F. Porichis, S. Le Gall, M. T. Waring, K. Moss, et al. IL-10 is up-regulated in multiple cell types during viremic HIV infection and reversibly inhibits virus-specific T cells Blood, July 9, 2009; 114(2): 346 - 356. [Abstract] [Full Text] [PDF]
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 |
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 M. Montano, M. Rarick, P. Sebastiani, P. Brinkmann, J. Skefos, and R. Ericksen HIV-1 burden influences host response to co-infection with Neisseria gonorrhoeae in vitro Int. Immunol., January 1, 2006; 18(1): 125 - 137. [Abstract] [Full Text] [PDF]
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 A. K. De, C. L. Miller-Graziano, S. E. Calvano, K. Laudanski, S. F. Lowry, L. L. Moldawer, D. G. Remick Jr, N. Rajicic, D. Schoenfeld, and R. G. Tompkins Selective Activation of Peripheral Blood T Cell Subsets by Endotoxin Infusion in Healthy Human Subjects Corresponds to Differential Chemokine Activation J. Immunol., November 1, 2005; 175(9): 6155 - 6162. [Abstract] [Full Text] [PDF]
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S. Knapp, S. Gibot, A. de Vos, H. H. Versteeg, M. Colonna, and T. van der Poll Cutting Edge: Expression Patterns of Surface and Soluble Triggering Receptor Expressed on Myeloid Cells-1 in Human Endotoxemia J. Immunol., December 15, 2004; 173(12): 7131 - 7134. [Abstract] [Full Text] [PDF]
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 R. Jotwani, M. Muthukuru, and C.W. Cutler Increase in HIV Receptors/Co-receptors/{alpha}-defensins in Inflamed Human Gingiva Journal of Dental Research, May 1, 2004; 83(5): 371 - 377. [Abstract] [Full Text] [PDF]
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 E. Vicenzi, P. Panina-Bodignon, G. Vallanti, P. Di Lucia, and G. Poli Restricted replication of primary HIV-1 isolates using both CCR5 and CXCR4 in Th2 but not in Th1 CD4+ T cells J. Leukoc. Biol., November 1, 2002; 72(5): 913 - 920. [Abstract] [Full Text] [PDF]
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A. Glatzel, D. Wesch, F. Schiemann, E. Brandt, O. Janssen, and D. Kabelitz Patterns of Chemokine Receptor Expression on Peripheral Blood {gamma}{delta} T Lymphocytes: Strong Expression of CCR5 Is a Selective Feature of V{delta}2/V{gamma}9 {gamma}{delta} T Cells J. Immunol., May 15, 2002; 168(10): 4920 - 4929. [Abstract] [Full Text] [PDF]
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Abstract
Introduction
