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,
Departments of
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Pathology and
Biochemistry, Vanderbilt University; and
Veterans’ Affairs Medical Center, Nashville, TN 37212
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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HIV-1 has evolved a variety of strategies to evade detection and destruction by the host immune system (8). One of these strategies involves the down-modulation of cell surface receptors involved in host defense, including CD4 (9), MHC class I (10), and the mannose receptor (7). Among the HIV-derived proteins implicated in regulating these receptors are gp120, Nef, Vpu, and Tat (reviewed in Ref. 9). These proteins use multiple mechanisms for regulating host protein expression, including interference with normal intracellular trafficking, increased host protein degradation, alterations in host protein biosynthesis, and regulation of transcription of host genes. It has recently been reported that Tat transcriptionally represses expression of both the heavy and light chains of the MHC class I complex (10, 11, 12, 13, 14). Since both the mannose receptor and MHC class I are involved in Ag capture and presentation, the current study was designed to investigate the role of Tat in HIV-mediated mannose receptor down-regulation.
The HIV-1 Tat protein is a potent trans-activator of transcription from the viral promoter and is essential for viral replication (reviewed in Refs. 15, 16). The structure of the Tat protein resembles a typical transcriptional activator containing an activation domain and a nucleic acid-binding domain. Functionally, Tat activates HIV-1 transcription through interaction with the transcriptional machinery of the host cell and also promotes elongation of the viral transcript (16). The full-length tat gene product is encoded on two exons which together result in a product of 86–101 aa depending on the viral isolate (17). In late infection Tat mRNA splicing becomes inefficient giving rise to a 72-aa form of Tat encoded only by exon 1. Both exon 1 and exon 2 Tat activate HIV-1 in cell culture system. No functional differences have been demonstrated between these Tat proteins in their ability to activate transcription from the long terminal repeat (LTR)4 in vivo.
Tat regulates the synthesis of multiple host cell genes involved in the
immune response to HIV infection including cytokines
(18, 19, 20), cytokine receptors (21, 22),
macrophage-inflammatory protein 1
(23), and surface
proteins such as HIV coreceptors (24, 25) and MHC class I
proteins (10, 11, 12, 13, 14). Multiple mechanisms including altered
intracellular signaling pathways leading to up- and down-regulation of
cellular transcription factors and altered host gene transcription
appear to be involved in these regulatory events.
Recent work has described in detail the potential mechanisms involved in the regulation of MHC I and ß2-microglobulin by Tat. Repression of both was mapped to the basal promoter and appeared to involve the interference by Tat of the interaction of the host cell transcriptional initiation machinery with the basal promoters. Similarities in the MHC class I and ß2-microglobulin promoters and the mannose receptor promoter led us to speculate that Tat-mediated repression of transcription of these genes might be occurring through similar mechanisms. In the current study, using mannose receptor-reporter constructs, we have shown that mannose receptor transcription is repressed by HIV Tat, and that this repression is targeted to the basal promoter, similar to the inhibition of the MHC class I and ß2-microglobulin promoters. Repression is enhanced by the presence of TAR and is mediated by one- or two-exon Tat. These results demonstrate that Tat-mediated repression of mannose receptor transcription is contributing to HIV-1-induced down-regulation of this receptor, and suggest that this repression may be a general mechanism for regulation of immune receptors including MHC class I, ß2-microglobulin, and the mannose receptor.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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U937 cells were purchased from the American Type Culture Collection (Manassas, VA). These cells were maintained in RPMI 1640 medium with 10% FBS (Life Technologies, Rockville, MD) plus antibiotics.
Plasmids
The mannose receptor promoter used in these studies was derived from the rat gene. Although a partial sequence for the human promoter has been reported (26), no characterization of regulatory elements has been reported. In contrast, detailed characterization of the rat mannose receptor promoter upstream elements has been reported by our laboratory (27), and was thus used for further analysis of Tat-mediated regulation. The mannose receptor-luciferase reporter gene constructs (MR854, MR656, MR228, MR108, and MR48) were prepared as previously described (27) as follows: The 854-bp mannose receptor promoter was cloned into the pGL2 basic vector (Promega, Madison, WI) containing the luciferase cDNA after BglII/SspI digestion (MR854). The proximal 656-bp promoter fragment (MR656) was generated by HindIII digestion of the 854-bp promoter with subsequent ligation into a HindIII-digested pGL2 vector. A construct containing the proximal 228 bp of the mannose receptor promoter (MR228) was generated by digestion of the 854-bp construct with SmaI and PvuII, followed by religation. The -108 (MR108) and -48 (MR48) constructs were generated by PCR using the MR656 as a template, the appropriate sense primers, and a vector-based antisense primer. The products were digested with HindIII and ligated into the pGL2 basic vector at the HindIII/SmaI site. Mutations in the mannose receptor promoter were introduced using a PCR-based approach as described by Ho et al. (28). Complimentary sense and antisense primers containing the desired mutations were obtained from Integrated DNA Technologies (Coralville, IA). The products of the PCR containing the mutations were isolated, digested with the appropriate restriction enzymes, and ligated into MR854 following removal of the specific mutated region.
The two-exon Tat proviral construct pNL-
and the control vector
pNL-A0 that expresses no proviral sequences were obtained from T. Kevin
Howcroft and Dinah Singer (National Cancer Institute, National
Institutes of Health, Bethesda, MD) (11). The following
reagents were obtained through the AIDS Research and Reference Reagent
Program (Division of AIDS, National Institute of Allergy and Infectious
Diseases, National Institutes of Health): the one-exon 72-aa Tat
expression vector pSV2Tat72 (Alan Frankel, University of California,
San Francisco, CA), HIV-1 Tat protein (John Brady, National Cancer
Institute, National Institutes of Health), and antiserum to HIV-1 Tat
(Bryan Cullen, Duke University, Durham, NC). pGL2 basic and
CMV-Renilla luciferase (CMV-RL) vectors were from
Promega.
Transfections and reporter gene assays
U937 cells were transfected as follows: 6 x 106 U937 cells were suspended in 6 ml of DMEM with antibiotics and l ml was added per well in 6-well plates. Mannose receptor-luciferase promoter constructs (3 µg) were mixed with varying amounts of Tat, pNL-A0, or basic vectors (1 µg) plus CMV-RL (1 µg) in 145 µl of DMEM. Superfect (5 µl; Qiagen, Chatsworth, CA) was added to each DNA solution. The mixture was vortexed and then allowed to stand at room temperature for 15 min. DMEM (300 µl) was added to each solution, and the mixture was added to the cells. RPMI 1640 with 10% FBS and antibiotics (500 µl) was added to each well, and the mixture was incubated for 24 h before assay. At the end of the incubation period, the cells were collected by centrifugation and washed once with PBS. The cells were suspended in 100 µl of Promega lysis buffer and incubated for 10 min at room temperature. Firefly and RL activities were measured using the dual luciferase reporter assay system (Promega) according to the manufacturer’s instructions. The pGL2 basic vector was used as a negative control in transfection assays. In all transfection experiments, the pRL-CMV vector was used to correct for transfection efficiency. Data are expressed as the luciferase activity for each sample normalized to the RL activity.
Effect of exogenous Tat on mannose receptor promoter-luciferase activity
U937 cells were transfected as above with MR228 plus pRL-CMV. At 12 h posttransfection, 1 µg of Tat protein was added, and cells plus Tat were incubated for an additional 24 h. Cells were then assayed using the dual luciferase reporter assay system.
Immunoblot analysis
To confirm that the Tat protein was expressed in our transient transfection experiments, cells transfected as above were lysed in immunoprecipitation buffer (20 mM Tris (pH 7.75) containing 1% Triton X-100, 0.5% deoxycholate, 0.15 M NaCl, 0.02% sodium azide, and 0.34 trypsin inhibitory units of aprotinin/ml). Cell lysate proteins were separated by SDS-PAGE and then transferred to nitrocellulose. The nitrocellulose was blocked with TBS-BSA and then probed with primary Ab to HIV-1 Tat. The blot was washed and then incubated with HRP-conjugated goat anti-rabbit IgG. Tat protein was visualized by incubation of the blot in 0.2 M Tris-HCl (pH 8.5), 2.5 mM luminol, 0.4 mM p-coumaric acid, and 0.0002% H2O2, followed by exposure of X-OMAT film (Kodak, Rochester, NY). Using this method, Tat protein was detected in U937 cells transfected with pSV2Tat72 (data not shown).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The identification of the mannose receptor as an Ag-capture
molecule suggests that this protein is an important participant in
basic immunologic responses (4). As such, decreased
mannose receptor expression could be advantageous for invading
pathogens. Koziel et al. (7) have demonstrated decreased
mannose receptor expression in alveolar macrophages isolated from
HIV-infected patients. To determine whether HIV-mediated
down-regulation of mannose receptor expression occurs at the level of
transcription, an 854-bp mannose receptor promoter-luciferase construct
and a control CMV-driven RL construct were cotransfected into the human
monocyte cell line U937, with or without the Tat expression vector
pSV2Tat72. As shown in Fig. 1
A, mannose
receptor promoter activity was reduced by 60% in the presence of Tat.
The specificity of this decrease was demonstrated by the fact that the
activity of the CMV promoter was only minimally affected by Tat
expression. To determine whether Tat-mediated repression of the mannose
receptor promoter occurred in a dose-dependent manner, transfections
were performed with increasing quantities of the pSV2Tat72 expression
vector. Fig. 1B shows that the degree to which mannose
receptor promoter activity is inhibited is dependent on the amount of
pSV2Tat72 added; promoter inhibition was >70% at the highest
concentration of the Tat expression vector.
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The region of the mannose receptor promoter through which Tat
mediates repression was determined using a variety of mannose receptor
promoter truncations (27). Tat-mediated transcriptional
repression was observed at similar levels for the MR854, MR656, MR228,
MR108, and MR48 mannose receptor promoter constructs (Fig. 2A). Similar results have been
found for the MHC class I promoter where repression was mediated
through the proximal 68 bp (11) and the
ß2-microglobulin promoter where repression was
mediated through the proximal 94 bp (13).
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B. First, there is a functional
TATA box at -33 bp (27). Similar to the findings by
Carroll et al. (13) for the
ß2-microglobulin promoter, mutation of the TATA
box in the mannose receptor promoter did not block Tat-mediated
inhibition of promoter activity (Fig. 3).
Second, MR48 contains a consensus PU.1 binding site at -18 bp that has
been shown to be required for full mannose receptor promoter activity
in a rat macrophage cell line (B. S. Egan and V. L. Shepherd,
unpublished results). Willbold et al. (29) have
demonstrated that the equine infectious anemia virus (EIAV) Tat protein
binds to the EIAV-LTR at a PU.1 binding site (GTTCCTGTTTT).
To determine whether the inhibitory effect of HIV-1 Tat occurs through
the PU.1-binding element, the site at -18 bp of the mannose receptor
promoter (GAGGAA) was mutated to GACCAA. In two separate experiments,
this mutation reduced the effect of Tat on mannose receptor promoter
activity from 63% repression (wild type) to 44% repression (PU.1
mutation) as shown in Fig. 3, suggesting that Tat may interfere with
PU.1 binding to this site.
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The Tat protein is encoded on two exons and the full-length Tat
protein is synthesized from a spliced viral transcript giving rise to
an 86–101 aa protein depending on the isolate (16).
During late HIV infection, splicing of the Tat transcript becomes
inefficient, resulting in the expression of a 72-aa Tat protein. Both
Tat proteins are capable of activating transcription through the HIV
LTR. Conflicting reports have appeared concerning the effectiveness of
one-exon vs two-exon Tat in down-regulation of MHC I transcription
(11, 14). To determine whether HIV-mediated
down-regulation of mannose receptor expression requires one- or
two-exon Tat, cotransfections were performed using the 854-bp mannose
receptor promoter-luciferase construct and expression vectors encoding
one-exon Tat (pSV2tat72), two-exon Tat (pNL-), or a vector
lacking the tat coding region (pNL-A0). Fig. 4 shows that both forms of Tat are
capable of repressing mannose receptor promoter activity. A direct
quantitative comparison of the two forms is not possible since Tat
transcription is driven from the SV40 promoter in pSV2tat72 and driven
from the HIV LTR in pNL-.
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It has been well documented that Tat can be secreted in a
biologically active form by acutely infected cells or by
Tat-transfected cell lines and can then be taken up by neighboring
uninfected cells (30). This results in the transactivation
of the HIV-1 LTR as well as regulation of cellular gene promoters. For
example, Verhoef et al. (31) have shown that coculture of
cells containing an HIV LTR-CAT construct with Tat-expressing cells
results in LTR activation. This effect is attributed to Tat being
released from one cell and entering the nucleus of another cell to
directly activate LTR-mediated transcription. Using this general
mechanism, HIV can then modulate the expression of cellular genes in
uninfected cells. To test the effect of extracellular Tat protein on
the activity of the mannose receptor promoter, recombinant Tat protein
was added to U937 cells 12 h posttransfection with MR854, and
cultures were allowed to incubate for an additional 24 h. As shown
in Fig. 5, addition of exogenous Tat
resulted in decreased promoter activity. These data suggest that direct
infection of cells is not required to down-regulate mannose receptor
expression, providing HIV with a mechanism to compromise immune
function in uninfected cells.
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To gain insight into the mechanism by which Tat mediates
repression of mannose receptor promoter activity, an experiment was
designed to examine the possibility that Tat functions as a
trans factor in the nucleus. Previous studies have shown
that TAR, a sequence found in the nascent HIV-1 transcript, enhances
the transactivation properties of Tat (16). It has also
been shown that TAR augments repression of the
ß2-microglobulin promoter (13). We
therefore reasoned that if Tat is gaining entry to the nucleus and
acting as a repressor of the transcriptional machinery, TAR might
enhance this effect. Cells were transfected with MR854 plus pSV2Tat72
in the presence and absence of the pNL-A0 vector which expresses the
TAR sequence but no viral protein sequences. Fig. 6 shows that Tat expression alone reduces
mannose receptor promoter activity by 60%, and the addition of pNL-A0
further reduces this activity to 20% of control levels. These data
suggest that the Tat effects on mannose receptor expression require the
Tat protein domain that binds to the TAR element. This same Tat domain
is involved in both HIV-1 transactivation and repression of
ß2-microglobulin promoter activity, since TAR
enhances both of these effects. This result also suggests that
Tat-mediated down-regulation of mannose receptor promoter activity
occurs in the nucleus, since TAR-Tat interactions are localized to the
nucleus.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Regulation of the mannose receptor could be advantageous to the
invading virus for several reasons. First, interaction of a variety of
pathogens with the mannose receptor has been implicated in the
initiation of signaling pathways leading to production of mediators
that contribute to pathogen killing. For example, Yamamoto et al.
(32) reported that interaction of C. albicans
with surface mannose receptors resulted in production of IL-1, IL-6,
and GM-CSF, and studies by Garner et al. (33) demonstrated
that binding of C. albicans mannan induced TNF-
production. More recently, Shibata et al. (34) reported
that the macrophage mannose receptor mediated chitin-induced production
of IL-12. Virus may then decrease mannose receptor expression to avoid
triggering of signaling pathways and mediator production potentially
lethal to HIV-1. Further support for this hypothesis comes from a
recent study by Milone and Fitzgerald-Bocarsly (35) in
which they reported that the mannose receptor on dendritic cells
mediated the production of IFN- by HIV-1-infected cells. Second,
gp120 contains high mannose groups which are known to act as
high-affinity ligands for the mannose receptor (36). The
study by Milone and Fitzgerald-Bocarsly (35) also
suggested that gp120 released from infected cells was acting as a
mannose receptor ligand for the induction of IFN-. If a
gp120-mannose receptor interaction is used by HIV-1 to gain entry into
cells, then down-regulation of this receptor would prevent entry of
additional virus, a mechanism suggested to be important in HIV-mediated
down-regulation of CD4 on T cells to prevent nonproductive infection
(37). Third, the mannose receptor is involved in delivery
of Ags to intracellular compartments containing MHC class II molecules
(4). Removal of this receptor from the cell surface would
dramatically compromise the ability of the host cell to participate in
the presentation of foreign Ags, including those from HIV.
Tat regulation of both the MHC class I gene and the ß2-microglobulin gene has been studied in some detail (10, 11, 12, 13, 14). Howcroft et al. (10, 11) first reported that Tat down-regulated transcription of the MHC class I gene. The same group has recently described a similar repression of transcription of the ß2-microglobulin light chain, an associated component of MHC class I (13). Repression of both of these genes as with the mannose receptor occurs through the basal promoter region. The MHC class I basal promoter lacks a consensus TATA box, and activity appears to be dependent on the presence of two overlapping CCACCC (S box) motifs which bind an Sp1-like factor. Two other Sp-1-dependent promoters, the MDR1 promoter and the minimal SV40 early promoter, were also found to be repressed by Tat. Although the exact mechanism involved in Tat-mediated repression of Sp1-containing promoters is not known, it has been suggested that Tat binds to an Sp1-related factor, resulting in interference with the assembly of the transcription complexes (11). Jeang et al. (38) reported that Tat can bind to Sp1, and a more recent report suggests that Tat modulates Sp1 activity through enhanced phosphorylation (39). Sp1 is known to bind the TFIID complex and can also interact with the TATA-binding protein directly (40). Pugh and Tjian (41) have reported that Sp1 plays a critical role in transcriptional activation in TATA-less promoters. Therefore, the physical interaction of Tat and Sp1 or an Sp1-like factor might block the interaction of Sp1 with the appropriate transcription initiation factors and/or the S box element in the promoter itself.
Comparison of the mannose receptor promoter and the MHC class I
promoter reveals several important differences that might suggest that
Tat is repressing activity of these promoters through different
elements (Fig. 7). First, the mannose
receptor promoter contains an Sp1 binding site, and this site has been
implicated in myeloid-specific expression in the murine system
(42). However, this site is not present in the basal,
Tat-inhibitable promoter. Second, the mannose receptor promoter
contains a functional TATA box (TTTAAAA), whereas the MHC class I
promoter contains the sequence TCTAAA which does not conform to any of
the sequences previously reported to function as a TATA box
(43). Careful examination of the mannose receptor promoter
and the ß2-microglobulin promoter reveals many
shared features (Fig. 7) which suggest that Tat may be mediating
repression of these promoters through a similar mechanism. Both the
mannose receptor and the ß2-microglobulin
promoters contain a triad composed of a CAATT box or inverted CAATT
box, a TATA box, and an Inr-like element. Carroll et al.
(13) reported that mutation of any of these elements in
the ß2-microglobulin promoter did not reduce
Tat-mediated repression, and they suggested that regulation might
involve the interaction of the host transcriptional initiation complex
with all three elements. Although the mannose receptor promoter
contains a CAATT box at -65 bp, this element is not in the MR48
construct which is modulated by Tat. Similar to studies of the
ß2-microglobulin promoter, mutation of the
mannose receptor TATA box sequence did not alter the Tat-mediated
repression of promoter activity. Although we have not examined the
effect of mutating the Inr sequence in the mannose receptor promoter,
our data are consistent with the findings using the
ß2-microglobulin promoter supporting a model
where Tat alters the initiation of transcription through interaction
with the basal initiation machinery.
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B, c-Fos, and NFAT1 (39, 44, 45, 46, 47),
the mannose receptor -48-bp promoter does not contain consensus
sequences for any of these factors.
Tat has also been shown to increase synthesis of specific cytokines
including TNF-, IL-1, and IL-6 that may act in an autocrine fashion
to regulate macrophage proteins (18, 19, 20, 21). In addition,
immunosuppressive effects of Tat have been linked to the up-regulation
of expression of TGF-ß (48). Recent evidence from our
laboratory and others has shown that the mannose receptor is
transcriptionally down-regulated by macrophage-activating cytokines
such as IFN-
(49) and transcriptionally up-regulated by
IL-45 and GM-CSF
(V. L. Shepherd, manuscript in preparation). Increased synthesis
of inflammatory cytokines by Tat could possibly contribute to increased
synthesis of host transcription factors. However, there are no
sequences in the mannose receptor basal promoter that are known to
interact with cytokine-induced factors. In addition, our finding that
the presence of TAR enhances the effect of Tat would suggest that
repression of mannose receptor transcription is localized in the
nucleus.
The finding in the current study that exogenous Tat can also repress mannose receptor promoter activity suggests that Tat can be secreted by an infected cell and enter neighboring macrophages. At least two mechanisms have been reported for entry of Tat into host cells. First, Frankel and Pabo (50) reported as early as 1988 that Tat could freely cross membranes and gain entry into host cells in vitro. The basic domain of the Tat protein contains a putative nuclear localization signal which mediates its rapid translocation to the nucleus (51). Second, various surface molecules including integrins (52) and ß chemokine receptors (53) have been implicated in Tat binding to host cells. However, the role of these surface proteins in delivery of Tat to the nucleus is not yet known.
In the current paper, we have described Tat-mediated transcriptional
repression from the mannose receptor promoter. This is the third
molecule described which is involved in innate host defense that is
down-regulated by Tat. Repression of all three of these proteins (the
mannose receptor, MHC class I, and
ß2-microglobulin) appears to share a common
mechanism involved in repression: interference by Tat with the
interaction of the initiation machinery and the host gene promoter.
Supporting this model are the findings from several groups that Tat can
bind to components of the basal transcription machinery
(9). Why does Tat repress transcription from specific host
promoters using host cell transcriptional initiation factors, while
activating HIV transcription using the same basal machinery? The answer
to this question may be that other trans factors in the
nucleus control whether Tat acts as a repressor or activator. In the
HIV LTR, in addition to the TAR domain, there is a modulatory region
and a core region (8). The core region contains a basal
promoter including three copies of Sp1 elements and a TATA box. The
modulatory region contains numerous cis-acting sequences for
the binding of host nuclear transcription factors including NF-B,
NFAT, and AP-1. Although HIV replication can occur in an
NF-B-independent fashion, the presence of Tat and NF-B
dramatically enhance viral replication. In addition, Tat has been
reported to dramatically up-regulate NFAT-driven transcription
(54). The finding that Tat increases SV40 promoter
activity in the presence of upstream enhancer elements and represses
promoter activity when these elements are removed further supports the
role of additional cis-elements in the promoter in
Tat-mediated repression (11). Studies are currently
underway to further define the mechanisms involved in Tat-mediated
down-regulation of mannose receptor transcription.
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Footnotes |
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2 R.L.C. and B.S.E. contributed equally to the work reported in this publication.
3 Address correspondence and reprint requests to Dr. Virginia L. Shepherd, Veterans Affairs Medical Center, Research Service, 1310 24th Avenue South, Nashville, TN 37212.
4 Abbreviations used in this paper: LTR, long terminal repeat; RL, Renilla luciferase; EIAV, equine infectious anemia virus; TAR, transactivation response.
5 B. S. Egan, R. Abdolrasulnia, and V. L. Shepherd. IL-4 mediates transcriptional up-regulation of the mannose receptor in dendritic cells through a Stat 6-independent mechanism. Submitted for publication.
Received for publication November 8, 1999. Accepted for publication September 25, 2000.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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  P. Kalantari, O. F. Harandi, P. A. Hankey, and A. J. Henderson HIV-1 Tat Mediates Degradation of RON Receptor Tyrosine Kinase, a Regulator of Inflammation J. Immunol., July 15, 2008; 181(2): 1548 - 1555. [Abstract] [Full Text] [PDF]
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 M. G. Quaranta, B. Mattioli, L. Giordani, and M. Viora The immunoregulatory effects of HIV-1 Nef on dendritic cells and the pathogenesis of AIDS FASEB J, November 1, 2006; 20(13): 2198 - 2208. [Abstract] [Full Text] [PDF]
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 R. L. Caldwell, R. Gadipatti, K. B. Lane, and V. L. Shepherd HIV-1 TAT represses transcription of the bone morphogenic protein receptor-2 in U937 monocytic cells J. Leukoc. Biol., January 1, 2006; 79(1): 192 - 201. [Abstract] [Full Text] [PDF]
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 M. A. Calzado, R. Sancho, and E. Munoz Human Immunodeficiency Virus Type 1 Tat Increases the Expression of Cleavage and Polyadenylation Specificity Factor 73-Kilodalton Subunit Modulating Cellular and Viral Expression J. Virol., July 1, 2004; 78(13): 6846 - 6854. [Abstract] [Full Text] [PDF]
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Y. Liu, H. Liu, B. O. Kim, V. H. Gattone, J. Li, A. Nath, J. Blum, and J. J. He CD4-Independent Infection of Astrocytes by Human Immunodeficiency Virus Type 1: Requirement for the Human Mannose Receptor J. Virol., April 15, 2004; 78(8): 4120 - 4133. [Abstract] [Full Text] [PDF]
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B. O. Kim, Y. Liu, B. Y. Zhou, and J. J. He Induction of C Chemokine XCL1 (Lymphotactin/Single C Motif-1{alpha}/Activation-Induced, T Cell-Derived and Chemokine-Related Cytokine) Expression by HIV-1 Tat Protein J. Immunol., February 1, 2004; 172(3): 1888 - 1895. [Abstract] [Full Text] [PDF]
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 S. D. Swain, S. J. Lee, M. C. Nussenzweig, and A. G. Harmsen Absence of the Macrophage Mannose Receptor in Mice Does Not Increase Susceptibility to Pneumocystis carinii Infection In Vivo Infect. Immun., November 1, 2003; 71(11): 6213 - 6221. [Abstract] [Full Text] [PDF]
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S. M. Wahl, T. Greenwell-Wild, G. Peng, G. Ma, J. M. Orenstein, and N. Vazquez Viral and host cofactors facilitate HIV-1 replication in macrophages J. Leukoc. Biol., November 1, 2003; 74(5): 726 - 735. [Abstract] [Full Text] [PDF]
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A. Poggi, R. Carosio, A. Rubartelli, and M. R. Zocchi {beta}3-Mediated engulfment of apoptotic tumor cells by dendritic cells is dependent on CAMKII: inhibition by HIV-1 Tat J. Leukoc. Biol., March 1, 2002; 71(3): 531 - 537. [Abstract] [Full Text] [PDF]
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