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IMMUNOBIOLOGY
From the Institute of Medical Microbiology and
Immunology, University of Copenhagen, Denmark.
The CC chemokine receptor CCR5 is an important coreceptor for human
immunodeficiency virus (HIV), and there is a major thrust to develop
anti-CCR5-based therapies for HIV-1. However, it is not known whether
CCR5 is critical for a normal antiviral T-cell response. This study
investigated the immune response to lymphocytic choriomeningitis virus
in mice lacking CCR5 (CCR5 Chemokines are small inducible proteins that are
involved in the normal trafficking of leukocytes to both lymphoid and
nonlymphoid organs and in the recruitment of leukocytes to sites of
injury and infection.1-3 Moreover, chemokines play an
important role in immune regulation; thus, chemokines have been
reported to mediate activation, costimulation, and differentiation of T
cells and monocytes during innate and adaptive immune
responses.1,4-7 The biologic effects of chemokines are
mediated via their interaction with a large group of 7 transmembrane-spanning, G protein-coupled receptors.8,9
The 2 major families of chemokine receptors are the CXC chemokine
receptors and the CC chemokine receptors (CCR) so named for their
binding of CXC and CC chemokines, respectively.8,10-12 While CXC chemokine receptors traditionally have been associated with
acute inflammatory responses, the CCRs are mostly expressed on cell
types found in connection with chronic inflammation and T cell-mediated
inflammatory reactions: eosinophils, basophils, monocytes, macrophages,
dendritic cells, and T cells.8,13,14
T cells play an important role in antiviral immunity and, in
particular, CD8+ effector T cells are important in
promoting host recovery and virus clearance.15,16 The main
effector function of virus-specific CD8+ T cells is
contact-dependent lysis,17-20 but production of cytokines such as interferon- Influenza-specific CD8+ T cells polarized in vitro into
either cytotoxic T cells type 1 (Tc1) or type 2 (Tc2) cells
have been shown to express a differential chemokine receptor
profile.23 Thus Tc1 cells were shown to express CCR2 and
CCR5 messenger RNA (mRNA), whereas Tc2 cells primarily expressed CCR4.
Importantly, this study revealed that although both subsets were
recruited to the lungs of influenza-infected mice, Tc2 cells did so
with delayed kinetics and did not localize near the infected airway epithelium. As a consequence, virus control was significantly delayed.23 Together, these findings strongly suggest that
CCR2 and CCR5 expression is required for optimal CD8+
effector T-cell function and point toward a role of CCR2 and CCR5 in
the recruitment and positioning of virus-specific T cells. The actual
importance of CCR2 and CCR5 in this process was, however, not addressed
in that study.
Macrophage inflammatory protein-1 To obtain a better understanding of how effector T cells are targeted
to sites of viral infection, we have for several years been using the
murine lymphocytic choriomeningitis virus (LCMV) model.29
LCMV is a noncytopathogenic virus that induces little or no
inflammation unless virus-specific T cells are
present.30,31 The presence of specific effector T cells is
associated with substantial inflammation in infected organs, and
intracerebral infection leads to a fatal T cell-mediated meningitis 6 to 8 days after infection.32 The inflammatory exudate
consists predominantly of CD8+ T cells and
monocytes/macrophages, whereas virtually no CD4+ T cells
are recruited to the inflammatory site.33 By use of this
model, we have recently shown that in vivo activated LCMV-specific CD8+ T cells express CCR2 and CCR5 mRNA.34
Furthermore, following intracerebral infection, up-regulation of
cerebral CCR2 and CCR5 mRNA expression required the presence of T cells
and directly correlated with influx of inflammatory cells into the
central nervous system (CNS).34 Notably, concurrent
analysis of virus-induced cerebral chemokine expression revealed that
although maximal chemokine expression and meningeal inflammation
coincided, chemokine expression was an early event that preceded
inflammation of the CNS.34 Interestingly, MIP-1 Mice
Virus
Virus titration Virus titrations were carried out by intracerebral inoculation of 10-fold dilutions of a 10% organ suspension into young adult Swiss mice. Titration endpoints were calculated by the Kärber method and expressed as mean lethal doses (LD50).Survival study Mortality was used to evaluate the clinical severity of acute LCMV-induced meningitis. Mice were checked twice daily until 100% mortality was reached.Assay of LCMV-specific delayed-type hypersensitivity Two different approaches were used to assess LCMV-specific delayed-type hypersensitivity (DTH). (1) Mice were infected locally in the right hind footpad with 103 LD50 LCMV Traub in a volume of 0.03 mL, and the local swelling reaction was followed between day 6 and 13 after infection.39 (2) Mice were infected intravenously with the same dose of virus and challenged in the right hind footpad with 0.03 mL of an immunodominant class I-restricted peptide (LCMV GP33-41, 50 µg/mL) on postinfection day 8 (acute phase) or postinfection day 60 (memory phase).40 The swelling reaction was followed 16, 24, 48, and 72 hours after the peptide challenge. Footpad thickness was measured with a dial caliper (Mitutoyo 7309), and the virus-specific DTH reaction was determined as the difference in thickness of the infected/challenged right and the uninfected left hind footpad.38Cell preparations Mice were killed and their spleens removed. Single-cell suspensions were obtained by pressing the organs through a fine steel mesh. For flow cytometric analysis, erythrocytes were lysed by 0.83% NH4Cl treatment (Gey solution). Cerebrospinal fluid (CSF) was obtained from the fourth ventricle of mice that had been anesthetized with ether and exsanguinated. The total number of CSF cells (cells/µL) was determined by cell counting. The background level of cells in the CSF in uninfected mice is less than 100 cells/µL.31,39Cytotoxicity assay The LCMV-specific Tc activity was assayed in a 51Cr-release assay37 using histocompatible EL-4 cells pulsed for 1 hour with either LCMV GP33-41 or LCMV NP396-404 peptide as targets. Unpulsed EL-4 cells served as control targets. Assay time was 6 hours, and percent specific release was calculated as described previously.37,39In vivo bromodeoxyuridine labeling Mice were given the thymidine analogue bromodeoxyuridine (BrdU; Sigma, St Louis, MO) in their drinking water at a concentration of 0.8 mg/mL for 3 days. BrdU-containing water was protected from light and changed daily.41Monoclonal antibodies The following monoclonal antibodies (mAbs) were purchased from Pharmingen (San Diego, CA) as rat antimouse antibody: fluorescein isothiocyanate (FITC)-conjugated anti-CD49d (common 4-chain of LPAM-1 and VLA-4) (R1-2), Cy-chrome
(Cy)-conjugated anti-CD8a (53-6.7), Cy-conjugated anti-CD4 (RM4-5),
phycoerythrin (PE)-conjugated anti-IFN- (XMG1.2). For BrdU
staining, FITC-conjugated anti-BrdU (B-44; Becton Dickinson, San Jose,
CA) was used.
Flow cytometric analysis To detect intracellular IFN-,42 splenocytes were
cultured at 37°C in 96-well round-bottom plates at a concentration of 2 × 106 cells/well in a volume of 200 µL RPMI medium
supplemented with 10% fetal calf serum (FCS), 50 U/mL murine
recombinant interleukin-2 (IL-2) (R & D Systems, Abingdon, United
Kingdom), and 3 µM monensin (Sigma). The cells were cultured with
LCMV GP33-41 peptide at a concentration of 0.1 µg/mL or without.
After 5 hours of culture, cells were washed once in FACS medium
(phosphate-buffered saline [PBS] containing 1% bovine serum albumin
[BSA], 0.1% NaN3, and 3 µM monensin) and subsequently
incubated with relevant surface antibodies in the dark for 20 minutes
at 4°C. Cells were washed twice in PBS with 3 µM monensin and
resuspended in 100 µL PBS with monensin, and then 100 µL 2%
paraformaldehyde in PBS was added. After 30 minutes of incubation in
the dark at 4°C, cells were washed in FACS medium and resuspended in
PBS with 0.05% saponin. After 10 minutes of incubation in the dark at
20°C, cells were pelleted and resuspended in PBS with 0.05% saponin
and anti-IFN- antibody. After incubation for 20 minutes at 4°C,
cells were washed twice in PBS/saponin and analyzed by flow cytometry.
The combined intracellular IFN- Preparation of total RNA Mice were killed at various times after intracerebral infection, and the brain was immediately removed, snap-frozen in liquid nitrogen, and stored in a liquid nitrogen freezer until RNA preparations were to be performed. Total RNA was extracted from homogenized brain by use of the RNeasy midi kit (Qiagen, Hilden, Germany).RNase protection assay experiments Chemokine and chemokine receptor mRNA were detected using the RiboQuant multiprobe RNase protection assay (RPA) system (Pharmingen).34 The following template sets (both from Pharmingen) were used. To detect chemokine mRNA a custom-made template set that included IP-10 in addition to lymphotactin, RANTES, eotaxin, MIP-1 , MIP-1, MIP-2, IFN--inducible protein 10 (IP-10),
monocyte chemotactic protein 1 (MCP-1), and T-cell activation gene 3 (TCA-3) mRNA was used. To detect CC chemokine receptor mRNA,
the mCR5 template set was used. This template set enables the detection
of CCR1, CCR1b, CCR2, CCR3, CCR4, and CCR5 mRNA. Both template sets
included templates for the murine housekeeping genes L-32 (a ribosomal protein) and glyceraldehyde-3-phosphate dehydrogenase (GADPH) to serve
as loading controls. The RPA was performed according to the
manufacturer's instructions. Briefly, -32P]
UTP-labeled antisense RNA transcripts were generated from the template
sets using T7 RNA polymerase. RNA from each sample was allowed to
hybridize to the labeled probe for 16 to 20 hours at 56°C.
Single-stranded RNA was digested with an RNase/T1 mixture, and the
hybrids were analyzed on a denaturing urea-polyacrylamide gel.
Protected fragments were visualized by autoradiography by placing dried
gels on film (Biomax MS-1; Kodak, New Haven, CT) in cassettes with
intensifying screens (Biomax MS; Kodak), which were then exposed at
 80°C. For quantitative results, gels were subjected to
Phosphorimager analysis (Fuji, Tokyo, Japan), and the data were
subsequently analyzed using Image Gauge software (Fuji).
Generation of LCMV-specific T cells Infection with LCMV induces the generation of a large subset of CD8+ T cells and a smaller subset of CD4+ T cells with an activated phenotype.29 Most of these activated T cells represent virus-specific cells as disclosed through staining with specific peptide/major histocompatibility complex (MHC) class I tetramers (CD8+ T cells) or visualized by intracellular IFN- staining (CD8+ and CD4+ T
cells).43,44 To investigate whether lack of CCR5
expression would influence the generation of LCMV-specific T cells, the
frequency of virus-specific CD4+ and CD8+ T
cells present in the spleen of CCR5 / and wild-type mice
was determined on days 8, 10, and 14 after infection (Figure
1A,B). On the indicated days, splenocytes
were briefly restimulated ex vivo with either an immunodominant class I-restricted LCMV peptide (GP33-41)45 or an immunodominant
class II-restricted LCMV peptide (GP61-80).46 As shown in
Figure 1A comparable frequencies of GP33-41-specific
IFN--producing CD8+ T cells were present in the spleen
on days 8 and 14 after LCMV infection in CCR5/ and
wild-type mice, whereas a significantly higher frequency of
GP33-41-specific CD8+ T cells was found in
CCR5/ mice on day 10 after infection. In contrast, the
frequency of GP61-80-specific IFN--producing CD4+ T
cells was significantly higher in CCR5/ mice on all of
the 3 days selected for analysis (Figure 1B). The higher frequencies of
virus-specific T cells observed in CCR5/ mice were not
due to differences in the total number of splenocytes, because the
number of cells per spleen was of similar magnitude in the 2 strains
when compared on day 0 and days 8, 10, and 14 after infection
(Figure 1C).
We next investigated the in vivo proliferation of GP33-41-specific
CD8+ and GP61-80-specific CD4+ cells in
LCMV-infected CCR5
Tc effector function and virus clearance The LCMV-specific CD8+ T cells are required to control the LCMV infection, which they do primarily through perforin-mediated killing of virus-infected cells.17,18,22 To investigate whether absence of CCR5 would influence the Tc effector potential, a functional evaluation of Tc cell activity was performed in CCR5/ and wild-type mice. LCMV-specific Tc responses
were assayed ex vivo on postinfection days 8, 10, and 14 using EL-4
cells pulsed with the immunodominant class I-restricted LCMV peptides
GP33-41 or NP396-404. Because we found that T cells from virus-infected CCR5/ and wild-type mice were about equally cytolytic
using both epitopes, only results for GP33-41 are shown (Figure
3).
The most relevant measure of the capacity of CD8+ effector
T cells to function in vivo is virus clearance in infected
animals.17,38,48 To evaluate the possible role of CCR5 in
Tc cell-mediated clearance of LCMV, the kinetics of virus clearance
were studied in CCR5
Role of CCR5 in the pathogenesis of LCMV-induced meningitis The above results provide indirect evidence that effector T-cell homing to infected organs such as lungs and liver as well as intrasplenic migration do not require CCR5 expression. However, to study the possible role of CCR5 in T-cell homing to a solid organ, we investigated whether lack of CCR5 expression would influence the recruitment of lymphocytes to the LCMV-infected brain. CCR5/ and wild-type mice were infected intracerebrally
with 103 LD50 LCMV Traub and clinical
susceptibility to meningitis, measured as mortality, was determined
(Figure 5A). As shown in Figure 5A, infected mice of both strains died within 9 days of infection. There
was, however, a tendency toward a slightly accelerated disease pattern
in CCR5/ mice. Therefore, although fatal disease was
induced in the absence of CCR5, the recruitment of effector cells to
the inflammatory site might be quantitatively or qualitatively
different in CCR5/ mice. Consequently, we also
performed quantitatively and qualitatively analyses of the cellular
exudate in the CSF. As shown in Figure 5B, no significant differences
in the number of mononuclear cells contained in the CSF were revealed
on either day 5, 6, or 7 after infection. Similarly, the composition of
the inflammatory exudate with regard to CD8+ T cells and
Mac-1+ monocytes/macrophages was found to be similar in
CCR5/ and wild-type mice (data not shown). Altogether,
the above findings indicate that expression of CCR5 on CD8+
T cells and monocytes/macrophages is not essential for the recruitment of these cells to the inflamed meninges.
However, it might be argued that absence of CCR5 would result in an
altered cerebral chemokine or chemokine receptor profile, which would
allow Tc1 cells and monocytes/macrophages to be recruited to the
infected meninges despite the lack of CCR5 expression. To test this, we
studied cerebral chemokine and CCR gene expression in
CCR5
Virus-induced DTH in the absence of CCR5 Another classical model for studying CD8+ effector T-cell migration to solid tissue is the primary LCMV-induced footpad swelling reaction that represents the response to subdermal virus challenge.39,50 To study the role of CCR5 in this DTH-like reaction, CCR5/ mice and wild-type mice were infected
with 103 LD50 LCMV Traub in the right hind
footpad, and the footpad swelling was measured between postinfection
days 6 and 13. No significant difference in the response pattern of
CCR5/ mice and wild-type mice was observed (Figure
7A), indicating that also a subdermal
inflammatory response can proceed in the absence of CCR5
expression.
To test whether the redundancy of CCR5 was related to the use of live
virus as a local trigger of inflammation, we also measured the ability
of (systemically) infected mice to respond to local challenge (on
postinfection day 8) with an immunodominant viral MHC class
I-restricted peptide (LCMV GP33-41); previous results have established
that this is a valid way of assessing CD8+ T cell-dependent
inflammation.40 However, even under these conditions no
significant difference was observed between CCR5 The role of CCR5 in the memory phase of LCMV infection Although no overt functional impact of CCR5 deficiency was observed in the acute phase of LCMV infection, it could be argued that the redundancy of CCR5 might result from the high number of recently activated effector cells present in mice undergoing acute infection, especially because the number of effector cells was even higher in CCR5/ mice. We therefore wanted to examine the role of
CCR5 in the memory phase of LCMV infection, which we analyzed in
CCR5/ mice and wild-type mice, that had been infected 2 months earlier with 103 LD50 LCMV Traub.
First, we investigated whether lack of CCR5 would result in altered
frequencies of IFN- In agreement with this finding, determinations of the virus content in
spleens and lungs of CCR5 The higher frequency of LCMV GP33-41-specific CD8+ T cells
found on postinfection day 60 in CCR5
CCR5 is a major coreceptor for human immunodeficiency virus
(HIV),54-56 and it is known that patients homozygous for a
32bp deletion allele of the CCR5 gene are quite resistant to
this infection.57,58 In contrast, relatively little is
known about the normal biologic function of this receptor. There are no
reports revealing an increased susceptibility to infection in humans
with the CCR5 deletion mutation. However, this does not necessarily
mean that CCR5 is redundant. Thus, mice deficient in expression of CCR5
are substantially more susceptible to infection with Cryptococcus
neoformans59 and Toxoplasma
gondii,60 exhibit defects in clearance of
Listeria monocytogenes,47 and are impaired in
IFN- With regard to the afferent phase of the antiviral immune response, our
results using CCR5 To study the effect of CCR5 deficiency on the ability of Tc1 effector cells to extravasate at sites of viral infection, we used LCMV-induced T cell-mediated meningitis as our primary experimental model. Additionally, localized subdermal inflammation (footpad swelling), as well as virus clearance in internal organs, was analyzed. All of these reaction types are known to be critically dependent on the recruitment of Tc1 cells,17,32,39,48 and it has previously been found that ligands of CCR5 are prominent among the chemokines produced in virus-infected tissues.28,34,63 Given that CCR5 is the only receptor for MIP-1 Expression of CCR5 was also found to be redundant regarding the ability
of effector cells to eliminate virus in internal organs, including
nonlymphoid tissues. Virus clearance in infected organs is a direct
measure of the capacity of Tc1 cells to function in situ.17,38,48 Therefore, the fact that we did not see any delay in this parameter in CCR5 Also in the case of subdermal inflammation did we find that CCR5 expression was redundant, and similar results were obtained in LCMV-immune mice, demonstrating that the redundancy of CCR5 could not be explained simply by the high numbers of effector cells nor by their activation state (effector Vs memory cells).64 Regarding the memory phase, we found that the frequency of
virus-specific CD8+ T cells in LCMV-immune mice
(postinfection day 60) was somewhat higher in CCR5 Our study does, however, point toward a role for CCR5 as a
down-modulator of the clonal expansion of CD8+ and
CD4+ T cells during the acute phase of LCMV infection,
which for CD8+ T cells at least might be maintained into
the memory phase. Absence of signaling through CCR5 has previously been
reported to result in an enhanced CD4+ T cell-mediated DTH
reaction and in improved production of IFN- In conclusion, this study fails to reveal a significant role for CCR5
in virus-induced Tc1-mediated inflammatory reactions. Whether this
finding may be extrapolated to other types of Tc1-mediated reactions is
not known for certain. However, the observation that CCR5 is also
redundant for a DTH response following local peptide challenge suggests
that redundancy could in fact be a general phenomenon. Although data
from knockout mice should always be interpreted with care, this finding
is encouraging if looked on in the light of the possibility of
developing CCR5-based therapies for treatment of HIV infection. Thus,
if anything, the antiviral T-cell response tends to be augmented in
CCR5
The authors would like to thank Grethe Thørner Andersen and Lone Malte for their skillful technical assistance.
Submitted April 4, 2001; accepted August 31, 2001.
Supported by the Danish Medical Research Council, the Beckett Foundation, and the Novo Nordisk Foundation.
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: Allan Randrup Thomsen, Institute of Medical Microbiology and Immunology, Panum Institute, 3C Blegdamsvej, DK-2200 N, Copenhagen, Denmark; e-mail: a.r.thomsen{at}immi.ku.dk.
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  A. R. Thomsen Lymphocytic Choriomeningitis Virus-Induced Central Nervous System Disease: a Model for Studying the Role of Chemokines in Regulating the Acute Antiviral CD8+ T-Cell Response in an Immune-Privileged Organ J. Virol., January 1, 2009; 83(1): 20 - 28. [Full Text] [PDF]
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P. J. Holst, C. Orskov, K. Qvortrup, J. P. Christensen, and A. R. Thomsen CCR5 and CXCR3 Are Dispensable for Liver Infiltration, but CCR5 Protects against Virus-Induced T-Cell-Mediated Hepatic Steatosis J. Virol., September 15, 2007; 81(18): 10101 - 10112. [Abstract] [Full Text] [PDF]
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C. L. Thio, J. Astemborski, A. Bashirova, T. Mosbruger, S. Greer, M. D. Witt, J. J. Goedert, M. Hilgartner, A. Majeske, S. J. O'Brien, et al. Genetic Protection against Hepatitis B Virus Conferred by CCR5{Delta}32: Evidence that CCR5 Contributes to Viral Persistence J. Virol., January 15, 2007; 81(2): 441 - 445. [Abstract] [Full Text] [PDF]
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 M. M. Lederman, A. Penn-Nicholson, M. Cho, and D. Mosier Biology of CCR5 and its role in HIV infection and treatment. JAMA, August 16, 2006; 296(7): 815 - 826. [Abstract] [Full Text] [PDF]
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 J. E. Christensen, C. de Lemos, T. Moos, J. P. Christensen, and A. R. Thomsen CXCL10 Is the Key Ligand for CXCR3 on CD8+ Effector T Cells Involved in Immune Surveillance of the Lymphocytic Choriomeningitis Virus-Infected Central Nervous System J. Immunol., April 1, 2006; 176(7): 4235 - 4243. [Abstract] [Full Text] [PDF]
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N. Ank, K. Petersen, L. Malmgaard, S. C. Mogensen, and S. R. Paludan Age-Dependent Role for CCR5 in Antiviral Host Defense against Herpes Simplex Virus Type 2 J. Virol., August 1, 2005; 79(15): 9831 - 9841. [Abstract] [Full Text] [PDF]
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C. de Lemos, J. E. Christensen, A. Nansen, T. Moos, B. Lu, C. Gerard, J. P. Christensen, and A. R. Thomsen Opposing Effects of CXCR3 and CCR5 Deficiency on CD8+ T Cell-Mediated Inflammation in the Central Nervous System of Virus-Infected Mice J. Immunol., August 1, 2005; 175(3): 1767 - 1775. [Abstract] [Full Text] [PDF]
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V. Monceaux, L. Viollet, F. Petit, R. H. T. Fang, M.-C. Cumont, J. Zaunders, B. Hurtrel, and J. Estaquier CD8+ T Cell Dynamics during Primary Simian Immunodeficiency Virus Infection in Macaques: Relationship of Effector Cell Differentiation with the Extent of Viral Replication J. Immunol., June 1, 2005; 174(11): 6898 - 6908. [Abstract] [Full Text] [PDF]
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 J. E. Christensen, A. Nansen, T. Moos, B. Lu, C. Gerard, J. P. Christensen, and A. R. Thomsen Efficient T-Cell Surveillance of the CNS Requires Expression of the CXC Chemokine Receptor 3 J. Neurosci., May 19, 2004; 24(20): 4849 - 4858. [Abstract] [Full Text] [PDF]
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A. N. Madsen, A. Nansen, J. P. Christensen, and A. R. Thomsen Role of Macrophage Inflammatory Protein-1{alpha} in T-Cell-Mediated Immunity to Viral Infection J. Virol., November 15, 2003; 77(22): 12378 - 12384. [Abstract] [Full Text] [PDF]
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E. Song, S.-K. Lee, D. M. Dykxhoorn, C. Novina, D. Zhang, K. Crawford, J. Cerny, P. A. Sharp, J. Lieberman, N Manjunath, et al. Sustained Small Interfering RNA-Mediated Human Immunodeficiency Virus Type 1 Inhibition in Primary Macrophages J. Virol., July 1, 2003; 77(13): 7174 - 7181. [Abstract] [Full Text] [PDF]
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M. Lindow, A. Nansen, C. Bartholdy, A. Stryhn, N. J. V. Hansen, T. P. Boesen, T. N. C. Wells, T. W. Schwartz, and A. R. Thomsen The Virus-Encoded Chemokine vMIP-II Inhibits Virus-Induced Tc1-Driven Inflammation J. Virol., July 1, 2003; 77(13): 7393 - 7400. [Abstract] [Full Text] [PDF]
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Abstract
Introduction
