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Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599;
SyStemix, Inc., Palo Alto, CA 94304; and
Aaron Diamond AIDS Research Center, The Rockefeller University, New York, NY 10016
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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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After inoculation of the SCID-hu Thy/Liv mouse with HIV-1, replication of pathogenic HIV-1 isolates reaches high levels at 2 wk postinfection (wpi),5 followed by depletion of CD4+ thymocytes with an inversion of the CD4/CD8 ratio between 3–4 wpi (15, 16, 17, 18). CD4+CD8+ (DP) thymocytes, comprising 80–85% of the total thymocytes, are significantly depleted. In addition, a higher rate of replication and thymocyte depletion is observed with rapidly replicating, syncytium-inducing virus isolated from AIDS patients than with slowly replicating, nonsyncytium-inducing virus isolated from the same patients before AIDS development or from long term nonprogressor patients (19). As observed in the SIV-infected rhesus macaque (20), replication of HIV-1 in the SCID-hu mouse is dependent upon an intact nef open reading frame (21). Analysis of the other HIV-1 accessory genes, such as vpr, vpu, and vif, has demonstrated that, unlike in tissue cultures, mutations in these genes significantly slow down the replication and cytopathic effects of HIV-1 (22, 23). Thus, the SCID-hu Thy/Liv mouse provides a relevant in vivo model to evaluate primary HIV-1 replication and pathogenicity.
Both direct and indirect mechanisms of thymocyte depletion have been implicated in HIV-1-infected thymus organs (16, 18, 24, 25). Target cell depletion may be achieved by a number of HIV-1-encoded factors with cytotoxic or cytostatic activities, as demonstrated in T cells in vitro. For example, vpr has been shown to lead to G2/S phase cell cycle arrest in infected target cells (26, 27). Other HIV-1 proteins, such as Tat, Nef, and gpl20/gp41, have also demonstrated cytotoxic activity in various cell culture systems (28, 29, 30, 31). Apoptosis has been associated with HIV-1-induced T cell death both in vitro and in vivo (32, 33, 34, 35, 36). In the Thy/Liv organ, some thymocytes with condensed nuclei are detected in HIV-1-infected Thy/Liv organs by thin section light microscopy and electron microscopy (16). Biochemically, partial chromosomal loss (detected by propidium iodide staining) (16) and DNA strand breaks (detected by terminal deoxynucleotide transferase labeling) (24) are associated with HIV-1-induced thymocyte depletion. DNA stand breaks are detected both in HIV-1-infected and in uninfected cells. However, data from a recent report suggest that necrosis by cytolytic infection may be a major mechanism of HIV-1-induced thymocyte depletion, and significant levels of apoptosis are only detected at late times postinfection (25). In addition, the intrathymic T progenitor cells can be directly infected and depleted to lead to thymocyte depletion by blocking T cell development (24).
The thymus microenvironment is essential for T cell development. Destruction of thymic epithelial cells has been reported in the human thymus and in the SCID-hu Thy/Liv organ after HIV-1 infection (4, 17). This may block T cell development and result in thymocyte depletion. Indeed, two recent reports suggest that hemopoietic progenitor cells in HIV-1-infected Thy/Liv organs are preferentially depleted by indirect mechanisms (37, 38). It is not clear, however, whether the HIV-1-infected thymic stromal cells are still functional in supporting de novo human T cell development. Only transient T cell development is reported after efficient inhibition of HIV-1 replication (39).
During T cell maturation in the thymus, MHC class I (MHCI) is differentially expressed on different subpopulations of thymocytes. Of note, the expression of MHCI on CD4+CD8+ DP thymocytes is lower than that on more mature CD4+ or CD8+ SP thymocytes (40). Thus, lowered expression of MHCI on DP thymocytes is associated with and may be important for normal thymocyte maturation. It has been reported that intrathymic transfer of semiallogeneic thymocytes can induce transient allo-tolerance in host-derived T cells (41). Supporting the idea that proper levels of interaction between MHCI and CD8/TCR on developing thymocytes are important for normal thymocyte maturation, ectopic expression of MHCI on thymocytes leads to thymocyte depletion in a transgenic mouse model (42). Similar results are reported in transgenic mice expressing high levels of CD8 on thymocytes (43). Interference with intrathymic selection signals of immature thymocytes is probably involved. We report here that HIV-1 infection of the thymus organ leads to enhanced expression of MHCI on DP thymocytes by indirect mechanisms in the SCID-hu Thy/Liv mouse and in human fetal thymus organ cultures (HF-TOC).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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mAbs reactive with CD3, CD4, and CD8 were purchased from Becton Dickinson (San Jose, CA). Anti-MHCI mAb W6/32 was obtained from Biodesign (Kennebunk, ME). HC-10 mAb and a cDNA encoding the MHCI gene (44) were provided by Ed Collins (University of North Carolina, Chapel Hill, NC). Human recombinant IL-10, IL-7, and IL-2 were purchased from Endogen (Woburn, MA). HIV-1 isolates used in this study have been described previously: NL4-3 (45); JD and EW (24); A6/87, A7/88, B5/85, B11/88, and D9/90 (46); 89.6 (47); and JR-CSF (15).
Infection of SCID-hu Thv/Liv mice
Animal transplantation procedures for SCID-hu Thy/Liv construction have been previously described (9). Infection of SCID-hu Thy/Liv mice was performed as previously described (24). Briefly, SCID-hu Thy/Liv mice (4–6 mo after transplantation) were infected with supernatant collected from PHA-activated PBMC containing no HIV-1 (mock) or 4 x 103 to 104 TCID50/ml of HIV-1. Fifty microliters (200–2000 TCID50) were injected into each thymus graft. The Thy/Liv organs were harvested at the indicated times, thymocyte suspension was prepared, and thymocyte subpopulations were analyzed by FACS (CD4-PE, CD8-TC, MHCI-FITC).
The study was approved by the institutional review boards, and animal experimentation guidelines were followed.
HF-TOC assays
The HF-TOC procedures are essentially as previously described (48). Briefly, human fetal thymi (19–24 gestational wk) were dissected into approximately 2-mm3 fragments containing about two to four intact thymic lobules and transferred into either mock supernatant or virus-containing supernatant. The vials were gently rocked at room temperature for 2 h, and the fragments were transferred to 0.45-µm pore size Nucleopore filters (Millipore, Bedford, MA) atop gelfoam boats (Upjohn, Kalamazoo, MI) saturated in HF-TOC medium (RPMI, 10% FCS, 50 µg/ml streptomycin, 50 U/ml penicillin G, 1x MEM vitamin solution (Life Technologies, Gaithersburg, MD), and 1x insulin/transferrin/sodium selenite medium supplement (Sigma, St. Louis, MO)) in 6-well tissue culture plates. The fragments were then cultured at 37°C with 5% CO2 for 4–8 days with daily changes of culture medium.
HIV-1 replication and cytokine assays
Measurement of cell-associated p24 production (picograms per
106 thymocytes) was performed using a p24 ELISA kit
(DuPont, Wilmington, DE). Semiquantitative DNA PCR analysis was
performed essentially as previously described (24). Briefly, 10,000
human thymocytes from Thy/Liv grafts or HF-TOC fragments were assayed
by 10-fold dilution of infected cells into uninfected human cells.
Genomic DNA was prepared from the mixed cells (Fig. 4
, lane
1, 10,000 sample cells; Fig. 4, lane 2, 1,000 sample
cells plus 9,000 normal human cells; Fig. 4, lane 3, 100
sample cells plus 9,900 normal human cells). ACH2 cells (1 HIV-1
genome/cell) were used as a standard control. A standard titration
represents samples with 100, 10, 1, 0.1, 0.01, and 0%, respectively,
ACH2 cells. For detecting HIV-1 Rev+ thymocytes, cells were
stained with CD4-PE and CD8-TC, fixed and permeabilized, and followed
by intracellular staining of Rev (anti-Rev-FITC) as previously
described (49). CEM parental cells or CEM stably expressing an HIV-1
rev transgene was used as the control.
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Western blot and RNA blot analysis
Western blot analysis was performed with total thymocyte cell extracts prepared from mock- or HIV-1-infected Thy/Liv organs between 10–15 days postinfection (dpi). Thymocytes were meshed out of the thymic stromal cells, and protein extracts from equal number of thymocytes (3 x 106) were run on SDS-PAGE. The anti-MHCI mAb (HC-10) and the chemiluminescent detection system (Amersham, Arlington Heights, IL) were used for Western detection. Total RNA (7.5 µg) isolated from thymocytes prepared as described above were used to analyze MHCI gene expression by standard Northern blot with an MHCI cDNA as probe 44). RNA samples were confirmed by ribosomal RNA bands and by blotting with a human ß-actin cDNA probe.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We analyzed phenotypic changes in thymocytes in HIV-1-infected
Thy/Liv organs. During human thymocyte maturation, MHCI expression was
low in immature CD4+CD8+ DP thymocytes and high
in CD4+ or CD8+ SP thymocytes (Fig. 1). As shown in two representative
Thy/Liv organs at 14 dpi with mock or HIV-1, all DP thymocytes were
induced by HIV-1 infection to express 11-fold (JD infected; Fig. 1A) or 4-fold (NL4-3 infected; Fig. 1B) higher
levels of MHCI. The differences in basal level MCF of MHCI in the two
experiments were due to the setting differences of the FACScan
cytometer in different experiments. Multiple mock samples in the same
experiment always showed similar basal MHCI levels (data not shown).
After HIV-1 infection, surface MHCI expression on
CD4-CD8- (DN) and CD4+ or
CD8+ SP thymocytes was also enhanced by 2- to 6-fold and 2-
to 3-fold, respectively. This suggests that direct infection of
thymocytes is not necessary for MHCI induction.
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C and Table I. The induction of MHCI expression on DP
thymocytes appeared to precede HIV-1-induced thymocyte depletion (18, 24). At later stages postinfection, even higher levels of MHCI on DP
thymocytes were induced (Fig. 1C and Table I). In agreement
with their activity in replication and pathogenicity in the thymus,
HIV-1 isolates from patients before AIDS (A6/87 and B5/85) or from long
term nonprogressors (D9/90) showed significantly lower levels of MHCI
induction than isolates from the same patients after AIDS progression
(A7/88 and B11/88) or other pathogenic isolates, such as NL4-3, JD, and
EW (19, 24). All DP cells were affected, and the level of induction
correlated with the level of HIV-1 replication, as measured by p24
(Table I and data not shown).
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A). Thus, HIV-1 infection of
the SCID-hu Thy/Liv mouse led to induction of MHCI protein expression
in thymocytes.
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B). Therefore, HIV-1
infection of the SCID-hu Thy/Liv mouse induced MHCI mRNA expression in
immature thymocytes, probably via increased transcription. Induction of MHCI on DP thymocytes in HIV-1-infected HF-TOC
To rule out the possibility that murine host factors of SCID-hu
Thy/Liv mice may contribute to the phenotypic changes, we performed
similar experiments in the HF-TOC model (48). As in the SCID-hu Thy/Liv
mouse, HIV-1 infection of HF-TOC also led to induction of MHCI
expression on DP cells (Fig. 3 and Table II), before any significant thymocyte
depletion. Thus, HIV-1 infection of the human thymus induced MHCI
expression on DP thymocytes. In addition, HIV-1 isolates with different
tropism determinants were all able to induce MHCI expression.
CXCR4-tropic isolates (NL4-3 and EW), CCR5-tropic virus (JR-CSF), and
dual tropic isolate (89.6 and JD) were able to efficiently induce MHCI
expression on DP thymocytes. HXB2 failed to replicate efficiently in
SCID-hu Thy/Liv mice or in HF-TOC (23, 48) and showed no induction of
MHCI.
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Using FACS-based detection of HIV-1 Rev proteins (49) in
HIV-1-infected HF-TOC samples, we showed that <5% of the DP
thymocytes were productively infected, whereas all or most DP
thymocytes were induced to express 5- to 9-fold higher levels of MHCI
(Fig. 3). Therefore, indirect mechanisms were involved in the induction
of MHCI expression on DP thymocyte cells.
As previously reported in HIV-1-infected SCID-hu Thy/Liv mice (15, 17, 21, 22, 23, 24), analysis of HIV-1 proviral DNA loads at various times
postinfection (2–6 wpi) estimated that <10% of total thymocytes were
directly infected (Fig. 4A).
High levels of MHCI induction on the majority of DP thymocytes were
observed in the HIV-1-infected Thy/Liv organs (4- to 25-fold). Thus,
most DP thymocytes with high MHCI expression were not directly
infected, especially at early times postinfection.
When DP thymocytes from HIV-1-infected Thy/Liv organs at 2 wpi were
purified, and proviral DNA was measured, <10% (1–10%, assuming one
proviral genome per cell) were directly infected (Fig. 4B).
No significant thymocyte depletion was detected at this time point, and
MHCI levels on all DP thymocytes were induced by 7-fold in this Thy/Liv
organ infected with NL4-3.
When productively infected thymocytes were measured by intracellular
staining of HIV-1 Rev, a very low level (1–5%) of total thymocytes
was detected (Fig. 4C) at 2 wpi. As shown in a representative Thy/Liv
organ at 2 wpi, DP thymocytes (81%) were induced to express 7-fold
higher MHCI. Therefore, the majority of the DP cells, although induced
to express high levels of MHCI, were not directly infected by HIV-1.
Induction of IL-10 production in HIV-1-infected thymus organs and IL-10-induced MHCI expression on DP thymocytes
To identify possible cytokines induced by HIV-1 infection, we
analyzed the production of a number of cytokines in HIV-1-infected
Thy/Liv organs or HF-TOC (50). IL-10 production was induced in
HIV-1-infected Thy/Liv organs or HF-TOC by a number of HIV-1 isolates
(Fig. 5A and data not shown).
IL-10 has been reported to be induced in HIV-1-infected patients (51)
and in lymphoid organs of feline immunodeficiency virus-infected cats
(52). In addition, IL-10 has been reported to, depending on cell type,
inhibit or induce MHC class II expression (53). Both NL4-3- and
JD-infected Thy/Liv organs showed significant induction (2- to 5-fold)
of IL-10 expression at 2 wpi, before significant thymocyte depletion
(Fig. 5A). Similar induction was observed in the HF-TOC
model. As induction of IL-10 is not directly correlated with levels of
MHIC induction (Fig. 5A), we further tested the effect of
exogenous IL-10 on MHCI expression in the HF-TOC model. When provided
exogenously in HF-TOC assays, IL-10 induced expression of MHCI on DP
thymocytes in a dose-dependent fashion (Fig. 5B). Therefore,
HIV-1 infection of the thymus organ led to up-regulation of IL-10
production. Increased levels of IL-10 in the thymus can partly
contribute to the induction of MHCI expression. Other cytokines are
also likely to contribute to the induction of MHCI expression in
HIV-infected thymus organs.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In PBMC or T cell lines, it has been reported that the MHCI level is down-regulated by HIV-1 infection. HIV-1 Tat, Nef, and Vpu have all been reported to reduce surface expression of MHCI in HIV-1-infected cells (54, 55, 56). In our thymus models, the majority of the thymocytes affected were not directly infected by HIV-1, suggesting that indirect (viral or host) mediators were induced by HIV-1 infection. Therefore, the mechanisms of HIV-1-induced MHCI expression in immature thymocytes are different from those of MHCI suppression in PBL or T cell lines directly infected by HIV-1.
In addition to production of viral proteins, HIV-1 infection in the
Thy/Liv organ leads to increased production of cytokines such as IL-4,
IL-6, IL-10, and TGF-ß (50). IFN-
, which stimulates MHCI gene
expression, was not significantly induced by HIV-1 in the Thy/Liv organ
at 2 wpi (50) (data not shown). Among the induced cytokines, IL-4
showed no significant activity on MHCI induction in HF-TOC (data not
shown). IL-10, which was shown to inhibit MHC class II expression in
macrophages (53), appeared to induce MHCI expression on thymocytes in
HF-TOC (Fig. 5B). However, the level of IL-10 induction is
not directly correlated to that of MHCI induction (Fig. 5A
and data not shown). Other viral or host factors or a combination of
factors may also be involved in the MHCI induction. IL-10-neutralizing
Ab may be employed in the HF-TOC model to confirm that IL-10 is
involved in HIV-1-induced MHCI expression on thymocytes, although
efficient Ab penetration of the HF-TOC fragments has not been
demonstrated.
An important question related to HIV-1-induced thymocyte depletion is
whether direct infection is required. The replication level of HIV-1 in
the Thy/Liv organ is relatively low, especially at early time points.
Less than 10% (maximal estimation) of thymocytes are infected at 2 wpi
as measured by PCR detection of proviral DNA (15, 17, 18, 21, 22, 23, 24, 57).
This is consistent with the lack of significant mutations during HIV-1
infection in the SCID-hu Thy/Liv mouse (57). Our data show that HIV-1
infection leads to the induction of MHCI expression on all DP
thymocytes, yet only a small fraction of them are directly infected by
HIV-1 (Figs. 1, 3, 4, and 5). Therefore, indirect mechanisms are
clearly involved, at least at early (10–15 dpi) times postinfection. A
recent report suggests that higher viral loads may be detected at later
times postinfection in some biopsies of HIV-1-infected Thy/Liv organs
(25, 39). In the SCID-hu Thy/Liv organs we analyzed, HIV-1 infection
appeared to be comparably lower by PCR even at later time points.
Experimental differences, such as viral infection and/or PCR assays,
may contribute to the discrepancy. The biopsy analysis of
HIV-1-infected Thy/Liv organs, in contrast to whole organs, may also
have biased sampling due to uneven distribution of HIV-1-infected cells
in the Thy/Liv organ.
MHCI expression is usually low on DP thymocytes during thymopoiesis
(Fig 1A), suggesting that low levels of MHCI on DP cells are
associated with and may be required for proper thymocyte selection
and maturation. It has been reported that thymocytes expressing
allo-MHC can induce allo-specific tolerance in host T cells (41).
Indeed, in transgenic mice overexpressing MHCI (42) or CD8 (43) on
thymocytes, severe thymocyte depletion was observed. This may be due to
increased affinity/avidity among TCR, CD8, and MHCI on DP thymocytes to
interfere with proper intrathymic selection (58).
The exact mechanisms and the significance of HIV-1-induced MHCI expression on immature thymocytes are not clear. As in the transgenic mouse models, induction of MHCI expression on DP thymocytes by HIV-1 may contribute to HIV-1-induced thymocyte depletion. MHCI on DP thymocytes may interact with CD8/TCR to interfere with the proper selection signals required for thymocyte maturation and survival. In addition, MHCI itself or in combination with other receptors may transduce signals affecting cell survival (59, 60). Further studies of HIV-1 pathogenesis in the SCID-hu Thy/Liv mouse and in the HF-TOC model will not only help understand the mechanisms of HIV-1-induced thymus destruction, but will also shed light on the mechanisms of thymocyte selection and maturation.
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Acknowledgments |
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Footnotes |
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2 Current address: Xcyte Therapies, Seattle, WA 98134.
3 Current address: Gladstone Institute of Virology and Immunology, University of California, San Francisco, CA 94141-9100.
4 Address correspondence and reprint requests to Dr. Lishan Su, Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599-7295. E-mail address:
5 Abbreviations used in this paper: wpi, weeks postinfection; DP, double positive; HF-TOC, human fetal thymus organ culture; MHCI, MHC class I; SP, single positive; dpi, days postinfection.
Received for publication January 21, 1999. Accepted for publication March 31, 1999.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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