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Departments of
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Microbiology,
Comparative Medicine, and
Medicine, University of Alabama, Birmingham, AL 35294
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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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Animal models may be useful to determine the role of retroviral infection in the recruitment of T cells to intestinal tissues and for understanding the underlying mechanisms of the virus-induced pathology. The human peripheral blood lymphocyte-engrafted SCID (hu-PBL-SCID)4 mouse model has been used to study HIV-1 pathogenesis. SCID mice engrafted with HIV-1-infected human PBMC develop some pathogenic features associated with HIV-1 infection in humans, including rapid CD4+ T cell depletion (10, 11, 12, 13, 14). This model has proven effective in examining the in vivo effects of different strains of HIV-1 with varying cellular tropism and cytopathogenicity. In addition, mice have been successfully engrafted with human PBMC from HIV-infected patients (13), thus providing a possible surrogate system not only to examine HIV pathogenesis, but also to determine the effects of retroviral therapy.
The current study was designed to determine whether SCID mice engrafted with human or nonhuman primate PBMC could provide a means to study the effects of HIV-1 or SIV on the homing patterns of T cells to the intestine and other tissues. Immunohistochemical techniques were used to compare tissues from uninfected and infected mice and to determine the extent of T cell localization. Additional methods were used to determine whether virus or proviral DNA could be detected in tissues in which engrafted T cells had localized. We report that infection with HIV-1 or SIV can induce T cell infiltration into intestinal tissues of SCID mice engrafted with human and nonhuman primate PBMC.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Male and female C.B-17 (scid/scid) mice (6–8 wk old) were obtained from the University of Alabama Animal Resources Program and were maintained in cages fitted with microisolators. Cages, bedding, food, and water were autoclaved before use; no antibiotics were administered.
Cells
Human PBMC were isolated from Leukopaks obtained from the American Red Cross (Birmingham, AL) by centrifugation on a Ficoll-Hypaque density gradient (Sigma Chemical Co., St. Louis, MO). All donors were tested for HIV-1 seropositivity and were negative. The cells were washed and resuspended in RPMI 1640 supplemented with L-glutamine, 100 U/ml penicillin, 100 mg/µl streptomycin, and 10% FBS. Viability was determined by trypan blue dye exclusion. The cells were resuspended at 2 to 3 x 107 viable cells/ml in supplemented RPMI 1640. PBMC from normal pig-tailed macaques and chimpanzees were purified from heparanized blood samples and processed as described above.
Isolation of T cell populations
T cell-enriched fractions were prepared from PBMC by rosetting
with 2-aminoethylisothiuronium bromide-treated SRBC overnight at 4°C
(15). The rosetted cells (E+) were separated from the
nonrosetted (E-) cells by density gradient centrifugation.
The E- cells were taken from the gradient interface, and
the T cell-enriched fraction (E+ cells) was prepared by
hypo-osmotic lysis of the SRBC (cell pellet fraction of the density
gradient). T cell subsets were isolated by immunomagnetic bead
separation, according to the protocol of the manufacturer (Dynal, Oslo,
Norway). Briefly, both E- and E+ PBMC (2
x 107 cells/ml) were shaken gently on ice for 30 min with
the appropriate mAb specific for human CD4 or CD8 conjugated to
magnetic beads (Table I
) at a bead:target
cell ratio of 2:1. The CD4+ or CD8+ cells were
magnetically separated from the cells in the supernatant (depleted
population). Both populations of cells were washed, and the magnetic
beads were removed from the positively selected cells with DETACHaBEAD
(Dynal). The cells were extensively washed again in complete medium.
The population purity was determined after each step by FACS analysis
using mAbs against CD4, CD8, and CD19 (Table I) surface Ags, as
described below. The procedure was repeated until a highly enriched
population (>95%) of CD4+ or CD8+ cells was
obtained. CD4-depleted populations from both the E- and
E+ cells were also recovered for further studies.
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The MOLT 4 clone 8 (MOLT) T cell line was maintained in supplemented RPMI 1640. A viral stock was produced by infecting MOLT cells with HIV-1IIIB. Measurements of reverse transcriptase (RT) activity were used to determine HIV-1 infection (16); viral stocks were generated from the culture supernatants and titrated as described previously (16). The stock chosen for use in the hu-PBL-SCID mice was determined to have a 105 median tissue culture infectious dose (TCID50)/ml supernatant on the MOLT cell line.
Several HIV-1 strains were used to infect chimpanzee cells. Additionally, the SIVsmmPBj14 strain of SIV was used to infect macaque cells. Further characterization of this virus was detailed previously (17).
Influenza virus strain A/Udorn//307/72 (H3N2) (a gift from Dr. B. Murphy, National Institutes of Health, Bethesda, MD) was grown and isolated as previously described (18).
Engraftment of SCID mice and infection with lentiviruses
A total of 53 SCID mice were injected i.p. with 2 to 3 x
107 freshly isolated human PBMC (hu-PBL-SCID) or
immunomagnetically sorted cell populations (Table II). In addition, three SCID mice that
did not receive any human cells were used to obtain control samples for
histology and FACS analysis. Four nonengrafted SCID mice were infected
with HIV-1IIIB as additional control samples for histology
and HIV-1 p24 gag detection. Two weeks after injection of
human PBMC, some of the engrafted mice were infected i.p. with
105 TCID50 of HIVIIIB (Table II).
Mice were killed 21 days after engraftment with human cells.
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Influenza control animals
Human PBMC were infected with the influenza virus at 5 to 10
multiplicity of infection for 1 h at 37°C in 1 ml of RPMI 1640
(18). The cells were washed extensively, and viability was determined
as described above. Aliquots of 2.5 x 107 cells
in 0.5 ml of supplemented RPMI 1640 were injected i.p. into SCID mice.
A total of eight mice were engrafted with influenza-infected human PBMC
(Table II
).
Sample collection
Peritoneal cells from hu-PBL-SCID mice were recovered by flushing the cavity with 3 ml of PBS. Sections of the spleen and small intestine were collected for histology; in addition, mesentery, liver, kidney, large intestine, thymus, pleural fat, lungs, salivary gland, testes, ovaries, and fallopian tubes from some animals were collected for histologic examinations. Cells were isolated from the spleen by mechanical dissociation and analyzed by FACS. Intestinal tissues were obtained from SCID mice reconstituted with PBMC from chimpanzees (20 mice) and pig-tailed macaques (33 mice).
Phenotype analysis
Peritoneal and splenic lymphocyte populations were analyzed by
flow cytometry, using a mAb against human MHC class I (Table I) to
distinguish the human cells from the resident mouse cells. In addition,
peritoneal cells were stained with Abs specific for human CD3, CD8, and
CD4 (Table I) to determine the percentage of each T cell subset.
Histologic examination
Tissues were fixed in acid alcohol (95% ethanol and 5% glacial
acetic acid), embedded in low melting point paraffin, and processed
according to the method of Sainte-Marie (19). For analysis of the T
cell populations in intestinal tissues of engrafted mice,
immunofluorescence staining was performed using a primate
cross-reactive mAb to CD2-FITC (Table I). To enhance detection of CD2
as well as to check for mouse Ig production ("leakiness"), a goat
anti-mouse Ig conjugated to TRITC (Table I) was added as a
second-step reagent. The tissue sections ranged in length from 12 to 14
mm and were scored for CD2+ cells per section as
follows: +, 1 to 20 cells; ++, 21 to 50 cells; +++, 51 to 100 cells;
and ++++, >101 cells. In some tissues that were positive for CD2,
immunofluorescence staining was performed using an unlabeled mAb (Table I) known to react with CD45KO Ag in paraffin-embedded tissues followed
by the goat anti-mouse Ig-TRITC conjugate. For immunoperoxidase
staining of the hu-PBL-SCID paraffin-embedded sections, unlabeled mAbs
against CD8 and CD57 (Table I) as well as an unlabeled polyclonal
reagent against CD3 (Table I) were used with serial sections of
intestinal tissues. Biotinylated secondary Abs were used in a standard
ABC assay (Elite Vectastain ABC kit for mouse or rabbit, Vector
Laboratories, Burlingame, CA), and color development was achieved with
3-amino-9-ethylcarbazole (Vector). All Abs were shown to recognize the
appropriate lymphocyte populations in normal human tissues from tonsil,
spleen, and intestine (Tissue Procurement Laboratory, University of
Alabama, Birmingham, AL) embedded in paraffin. Additionally, the CD2 Ab
reacted with T cell areas in paraffin-embedded spleen from rhesus
macaques. To ensure that reagents did not detect mouse lymphocytes,
sections of normal spleen and intestine from BALB/c mice were also
tested with the anti-human Abs.
Detection of HIV-1 in peritoneal cells
The recovered peritoneal cells (0.5–2 x 106 cells) from uninfected and HIV-1-infected hu-PBL-SCID mice were resuspended in 1 ml of complete RPMI 1640 supplemented with recombinant human IL-2 (0.5 ng/ml; R&D Systems, Minneapolis, MN). PHA-stimulated human PBMC were washed and resuspended at a concentration of 2 x 107 cells/ml in complete RPMI 1640 supplemented with recombinant human IL-2. Equal volumes of stimulated PBMC and recovered peritoneal cells were cocultured for 1 mo. The culture supernatants were monitored weekly for the presence of HIV-1 p24 capsid Ag using a commercial ELISA kit (Coulter Corp., Hialeah, FL). Cultures were considered positive if two consecutive weekly samples contained >200 pg/ml of p24 Gag Ag.
Detection of HIV-1 proviral DNA in tissues
Genomic DNA was isolated from hu-PBL-SCID intestine and spleen using the QIAmp Tissue Kit (Qiagen, Inc., Chatsworth, CA). Three hundred nanograms of total DNA was added to 25 µl of a standard PCR reaction mixture that also contained 0.4 mM each of the HIV-1 gag gene-specific primer pair SK38 and SK39 (Research Genetics, Huntsville, AL). The amplified DNA was labeled with digoxigenin (DIG) by adding DIG-conjugated dUTP (Boehringer Mannheim, Indianapolis, IN) to the PCR mixture. A 115-bp DNA fragment of the gag gene was amplified (35 cycles) using standard PCR conditions. After separation on a 3% agarose gel and transfer to a nylon membrane, DIG-labeled PCR products were detected with anti-DIG-alkaline phosphatase conjugate and a chemiluminescent substrate, according to the instructions of the manufacturer (Boehringer Mannheim).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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An average of 2.4 x 106 total cells (range,
0.5–6.5 x 106) was recovered from peritoneal lavages
of hu-PBL-SCID mice. To determine whether the SCID mice were engrafted
with human PBMC, cells were analyzed by two-color FACS analysis for
human MHC class I Ags (Fig. 1A). In addition,
recovered peritoneal cells were stained with mAbs to human CD3, CD4,
and CD8 (Fig. 1, B and C, and Table III) to determine the percentage of
recovered T cells. At 2 wk after engraftment, but before HIV-1
inoculation, the normal CD4:CD8 ratio of 2:1 in human PBMC was inverted
(1:2) in peritoneal cells that were recovered. At 7 days after HIV-1
inoculation, the ratio was 1:3 (Table III). Interestingly, the
percentage of CD8+ cells in the recovered cell population
also declined. Since a substantial number of CD8+ cells can
often be recovered from the spleen (Fig. 1C) and
thymus of hu-PBL-SCID mice, movement of these cells into these organs
may account for the decrease observed in the peritoneal cavity.
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Because detection of viral Ags by ELISA is more sensitive than that by classical RT assays, ELISA kits were used to detect HIV p24 Gag Ag in supernatants from cocultured peritoneal cells. Virus replication was demonstrated by detection of p24 Gag in 68% of the cocultures of peritoneal cells from mice engrafted with human PBMC and infected with cell-free HIV-1. On the average, over 300 pg/ml of viral p24 was detected in the cultures by the fourth week of coculture. In mice that received human cells but no virus, no detectable levels of p24 (<0.055 OD) were found in peritoneal cocultures.
HIV-1 infection induces T cells to migrate into intestinal tissues of hu-PBL-SCID mice
In both uninfected and HIV-1-infected hu-PBL-SCID mice, T cells
were found in the spleen and peritoneal lavage (Fig. 1, B
and C). To reduce the biohazard associated with
HIV-1-infected tissues, all samples were fixed and paraffin embedded;
however, this process destroys some cell surface epitopes, including
CD4. Thus, Abs against CD2 were used to detect human T cells in the
tissue sections. In the uninfected engrafted SCID mice, T cells were
mainly seen in the spleen and were occasionally detected in the thymus
and mesentery, but not in intestinal tissues. Of interest,
CD2+ T cells were found not only in the spleens of the
HIV-1-infected hu-PBL-SCID mice, but also in the intestines (Fig. 2B and Table IV). T cells were located in the lamina
propria (LP), intraepithelial lymphocyte (IEL) compartment, and an
occasional Peyer’s patch in the small intestine (Fig. 2B
and Table V). The number of
CD2+ cells per section ranged from 10 to >100 (Table IV).
T cells in the small intestine displayed an uneven distribution among
the villi. Along the length of the small intestine, some areas
contained large numbers of T cells within several villi, followed by
areas where only a few T cells were detected. T cells were also
detected in the large intestines. To analyze the phenotype of the
CD2+ cells further, serial sections were reacted with
anti-human CD8 and CD57 (to exclude the NK cell population); no
positive cells were detected (Fig. 3,
C and D, and Table VI). Polyclonal Abs against the
cytoplasmic tail of human CD3 were also used to detect T cells (Fig. 3E). In the majority of experiments, CD3+
cells correlated with areas containing CD2+ cells; however,
this polyclonal reagent demonstrated some cross-reactivity to murine T
cell epitopes. In two of the control mice that did not receive human
cells, low numbers of CD3+ cells were detected
(3–10/section); however, these mice were not "leaky," as shown by
both negative serum Ab levels and immunofluorescence staining of murine
tissues for mouse Ig. In serial sections of intestinal tissues that
were shown to contain CD2+ cells, a mAb against CD45RO was
used to characterize these cells further. Although this Ab did identify
CD45RO+ cells in SCID intestinal tissues, which correlated
with the location of CD2+ cells, the surface fluorescence
intensity was weak (data not shown). However, similar weak surface
CD45RO+ fluorescence was observed using the same mAb on
normal human tissues, such as small intestine and spleen.
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To determine whether another RNA virus which primarily infects via
mucosal routes would also induce T cell migration into intestinal
tissues, we engrafted SCID mice with influenza-infected human PBMC. As
with other hu-PBL-SCID mice, T cells were detected in the spleen and
peritoneal cavity. Measurable levels of human Ig were detected in the
sera of these animals (data not shown). In five paraffin sections of
intestine from three SCID mice engrafted with influenza-infected human
PBMC, no CD2+ T cells were observed (Table IV).
T cells from nonhuman primates home to intestinal tissues after infection with HIV-1 or SIV
Intestinal tissues collected from SCID mice engrafted with
HIV-1-infected chimpanzee or SIV-infected pig-tailed macaque PBMC were
also evaluated using the anti-human CD2 Ab. CD2+
cells were found in the intestinal tissues from SCID mice engrafted
with SIV-infected macaque lymphocytes (Fig. 2, C and
D, and Table IV) and were consistently detected in the mice
given cell-associated virus. The number of CD2+ cells
detected in the pig-tailed macaque PBMC-engrafted SCID mice ranged from
25 to >300/section of intestinal tissue, which was generally higher
than those seen in the hu-PBL-SCID mice (Table IV). In mice that
received uninfected macaque lymphocytes, no CD2+ cells were
detected 21 days postengraftment. CD2+ cells were also
observed in intestinal tissues from SCID mice that were engrafted with
chimpanzee lymphocytes and subsequently infected with HIV-1. The number
of CD2+ T cells in these latter mice ranged from 3 to 45
cells/section, which was considerably lower than that in hu-PBL-SCID
mice (Table IV). Also, the distribution of CD2+ T cells in
the intestines of these mice was similar to that observed in the
hu-PBL-SCID mice, with localization to the IEL compartment, LP, and an
occasional Peyer’s patch (Fig. 2, C and D, and
Table V).
CD2+ cells in the intestine are derived from CD4+ cells
Because CD4 epitopes are not well preserved in paraffin sections,
immunomagnetically sorted populations from the same human donor were
used to determine the phenotype of the CD2+ T cells
observed in the SCID mice. Purity was determined by FACS analysis
before reconstituting SCID mice with either CD4+- or
CD8+-purified populations (Table II). To ensure that E
rosetting did not influence the engraftment, PBMC were E rosetted, and
the E- and E+ cells were pooled to form a
reconstituted total PBMC population. To determine whether the
intestinal CD2+ cells were from a cell population other
than CD4+ cells, CD4+-depleted populations from
both the E+ and E- cells were pooled and
engrafted into SCID mice. CD2+ cells were only detected in
the intestines of HIV-1-infected mice engrafted with total
reconstituted PBMC or CD4+-purified populations (Fig. 3F and Table VII). These
experiments indicate that the CD2+ cells in the intestine
were probably derived from the CD4+ T cell population.
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Although some effort was made to identify p24 protein in the
intestines of hu-PBL-SCID mice that contained CD2+
cells, fluorescence microscopy and RT-PCR yielded no positive results
for p24 protein or mRNA (data not shown). However, spleen and
intestinal tissues from the HIV-1-infected, human PBMC-engrafted SCID
mice contained proviral copies of HIV-1, as determined by PCR
amplification of a portion of the gag gene (Fig. 4, A and C).
Similar sections from mice that were engrafted with uninfected human
cells or from unengrafted SCID mice inoculated with HIV-1 were negative
for HIV-1 proviral DNA (Fig. 4B). DNA isolated from
uninfected and infected U937 cells, a promonocytic cell line was used
as negative and positive controls, respectively (Fig. 4B). The detection of HIV-1 proviral DNA from various
sections of the small intestine appeared to correspond with the
distribution of CD2+ cells along the length of the small
intestine.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Because it has been reported that HIV-1 infection of hu-PBL-SCID mice leads to a loss of CD4+ lymphocytes (10, 13, 14, 23), we determined CD4:CD8 ratios in cells recovered after peritoneal lavage and observed that a change occurred before HIV-1 infection. Another report of diminished CD4:CD8 ratios in the absence of HIV infection proposed that this decrease may result from the proliferation of CD8+ cells in response to murine Ags (23). After infection with HIV-1, the ratio was further decreased, perhaps as a result of migration of CD4+ T cells to the intestine.
For several reasons, we examined CD2 expression to identify primate T cell populations in tissues from engrafted SCID mice. First, we showed that the mAb to CD2 reacted with primate, but not murine, T cells. Second, the CD2 Ab recognized Ag in paraffin-embedded tissues. Finally, CD2 has been implicated as an accessory molecule in cell adhesion and cellular interactions and is highly expressed on the majority of normal human and murine intestinal T cells (24). CD2 can also be expressed on a subset of NK cells. However, consecutive sections tested for CD57, an NK cell Ag that is not destroyed by paraffin-embedding procedures, yielded negative results in intestinal tissues from engrafted SCID mice. This Ab was shown to detect NK cells in control paraffin-embedded human tissues, including intestine.
In all three primate PBMC-engrafted models, CD2+ cells were detected in the LP and IEL compartment of SCID intestines after HIV-1 or SIV infection. The results of engraftments with purified cell populations suggested that it was CD4+ cells that homed to the intestine after HIV-1 infection. In both the histology and the cell-sorting studies, no CD8+ cells were found in the intestinal tissues, nor were any NK cells detected. While it may not be surprising that HIV-1 induced only CD4+ T cells to migrate, the numbers of CD4+ cells found in the IEL compartment were unexpected, since the majority of murine and human IEL are CD8+; however, CD4+ cells can be detected in human and macaque IEL compartments (25, 26). Although we were unable to use immunofluorescence to determine whether the CD2+ cells in the paraffin-embedded tissues were CD4+, it is important to note that the human IEL compartment can also have cells with a CD4-CD8- (double negative, 20–40%) or a CD4+CD8+ (double positive, 1–8%) phenotype (27). Similar phenotypes have also been observed within the murine IEL compartment (28). Negative CD8 staining suggests that these CD2+ cells are not double positive. Although our studies with enriched T cell populations demonstrated that the CD2+ cells in the SCID intestine can be derived from CD4+ cells, the possibility remains that these cells may have lost surface expression of CD4.
Since only SCID mice engrafted with primate PBMC and infected with HIV-1 or SIV harbored T cells in intestinal tissues, we suggest that these lentiviruses may alter the homing patterns of primate T cells in engrafted SCID mice and perhaps in infected humans. The nature of viral replication and infectivity may influence the number of cells homing to the intestinal tissues. The use of different primate species infected with viral strains that have diverse clinical consequences may provide insight into the mechanisms that are the basis of this migration. For example, SIVsmmPBj14 is the most virulent SIV strain, inducing acute disease and death within 1 to 2 wk in pig-tailed macaques (9). HIV-infected patients live several years before progressing to AIDS (29). On the other hand, chimpanzees infected with HIV-1 can develop some symptoms characteristic of human HIV-1 infections but, in general, do not progress to AIDS (30, 31). Lack of progression to disease may be linked to less efficient replication of HIV-1 by chimpanzee PBMC compared with that by human lymphocytes. This may explain why migration of CD2+ cells into the intestine of engrafted SCID mice from all three primates occurs, yet the numbers of CD2+ cells located in the intestines differ greatly. Detection of HIV-1 proviral DNA in intestinal tissues indicated that some of the migrating cells were infected. It is also possible that the number of lymphocytes in the intestinal tissues is correlated directly with the total number of infected cells in individual mice and/or the number of engrafted cells present at the time the mice were killed. It should also be noted that the macaque PBMC were infected in vitro before inoculation into SCID mice, whereas cell-free HIV-1 was injected 2 to 3 wk after engraftment with human or chimpanzee PBMC.
We have demonstrated that HIV-1 can apparently alter the primate T cell migration patterns in the chimeric SCID model. Taken together with the recent findings that chemokine receptors, such as CXCR4 (32, 33, 34, 35) and CCR5 (36, 37), serve as coreceptors for HIV-1 and that chemokines can cause migration of cells in vivo (38), we are currently investigating the effects of HIV-1 on the expression of mucosal homing receptors. The results from the present and planned studies may explain the increased cellular infiltration in mucosal tissues of asymptomatic HIV-infected patients as well as the early lymphocytic infiltration into intestinal tissues of SIV-infected macaques.
Since intraepithelial T cells appear to play a critical role in surveillance and repair of damaged intestinal epithelium (39), it is reasonable to speculate that these cells may participate in a carefully regulated process that maintains the integrity of the epithelium in the healthy intestine. Our data suggest that in vivo HIV-1/SIV infection may induce infiltration of T cells into the intestine, specifically the IEL compartment. Such infiltration may produce significant changes in the regulatory role played by the resident IELs, perhaps altering normal gut physiology. If such changes compromise the integrity of the mucosal barrier, the intestine might become more susceptible to those secondary infections common in HIV-infected individuals.
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Acknowledgments |
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Footnotes |
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2 H.D. and J.E.C. contributed equally to the body of work in this manuscript.
3 Address correspondence and reprint requests to Dr. James E. Cummins, Jr., Department of Microbiology, University of Alabama, 730 BBRB, 845 19th St. South, Birmingham, AL 35294-2170.
4 Abbreviations used in this paper: hu-PBL-SCID, human peripheral blood lymphocyte severe combined immunodeficient; RT, reverse transcriptase; TCID, tissue culture infectious dose; TRITC, tetramethylrhodamine isothiocyanate; DIG, digoxigenin; LP, lamina propria; IEL, intraepithelial lymphocytes.
Received for publication April 28, 1997. Accepted for publication November 7, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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/ß T cell receptor-positive intraepithelial lymphocytes and Peyer’s patch lymphocytes. Eur. J. Immunol. 23:1333.[Medline]
T cells. Science 266:1253.This article has been cited by other articles:
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  J. Wang, S. Marschner, and T. H. Finkel CXCR4 engagement is required for HIV-1-induced L-selectin shedding Blood, February 15, 2004; 103(4): 1218 - 1221. [Abstract] [Full Text] [PDF]
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 H. Hale-Donze, T. Greenwell-Wild, D. Mizel, T. M. Doherty, D. Chatterjee, J. M. Orenstein, and S. M. Wahl Mycobacterium avium Complex Promotes Recruitment of Monocyte Hosts for HIV-1 and Bacteria J. Immunol., October 1, 2002; 169(7): 3854 - 3862. [Abstract] [Full Text] [PDF]
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 J. J-Y. Chen, J. C. Huang, M. Shirtliff, E. Briscoe, S. Ali, F. Cesani, D. Paar, and M. W. Cloyd CD4 lymphocytes in the blood of HIV+ individuals migrate rapidly to lymph nodes and bone marrow: support for homing theory of CD4 cell depletion J. Leukoc. Biol., August 1, 2002; 72(2): 271 - 278. [Abstract] [Full Text] [PDF]
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 F Schafer, S Kewenig, N Stolte, C Stahl-Hennig, A Stallmach, F-J Kaup, M Zeitz, and T Schneider Lack of simian immunodeficiency virus (SIV) specific IgA response in the intestine of SIV infected rhesus macaques Gut, May 1, 2002; 50(5): 608 - 614. [Abstract] [Full Text] [PDF]
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 M. A. Poles, J. Elliott, P. Taing, P. A. Anton, and I. S. Y. Chen A Preponderance of CCR5+ CXCR4+ Mononuclear Cells Enhances Gastrointestinal Mucosal Susceptibility to Human Immunodeficiency Virus Type 1 Infection J. Virol., September 15, 2001; 75(18): 8390 - 8399. [Abstract] [Full Text] [PDF]
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 S. Marschner, B. A. Freiberg, A. Kupfer, T. Hunig, and T. H. Finkel Ligation of the CD4 receptor induces activation-independent down-regulation of L-selectin PNAS, August 17, 1999; 96(17): 9763 - 9768. [Abstract] [Full Text] [PDF]
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H. H. Donze, J. E. Cummins Jr., R. S. Schwiebert, P. N. Fultz, S. Jackson, and J. Mestecky Human and Nonhuman Primate Lymphocytes Engrafted into SCID Mice Reside in Unique Mesenteric Lymphoid Structures J. Immunol., August 1, 1998; 161(3): 1306 - 1312. [Abstract] [Full Text] [PDF]
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