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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 91 No. 8 (April 15), 1998:
pp. 2672-2678
Human Immunodeficiency Virus-1 Infection Interrupts Thymopoiesis
and Multilineage Hematopoiesis In Vivo
By
Morgan Jenkins,
Mary Beth Hanley,
Mary Beth Moreno,
Eric Wieder, and
Joseph M. McCune
From the Gladstone Institute of Virology and Immunology, San
Francisco, CA; and the Departments of Microbiology and Immunology and
Medicine, University of California, San Francisco, San Francisco,
CA.
 |
ABSTRACT |
It is still uncertain whether multilineage hematopoietic progenitor
cells are affected by human immunodeficiency virus-1 (HIV-1) infection
in vivo. The SCID-hu Thy/Liv model is permissive of long-term
multilineage human hematopoiesis, including T lymphopoiesis. This model
was used to investigate the effects of HIV-1 infection on early
hematopoietic progenitor function. We found that both lineage-restricted and multilineage hematopoietic progenitors were
depleted from grafts infected with either a molecular clone or a
primary isolate of HIV-1. Depletion of hematopoietic progenitors (including CD34+ cells, colony-forming units in
methylcellulose, and long-term culture-initiating cells) occurred
several days before the onset of thymocyte depletion, indicating that
the subsequent rapid decline in thymocyte numbers was due at least in
part to loss of thymocyte progenitors. HIV-1 proviral genomes were not
detected at high frequency in hematopoietic cells earlier than the
intrathymic T-progenitor cell stage, despite the depletion of
such cells in infected grafts. Proviral genomes were also not detected
in colonies derived from progenitor cells from infected grafts. These
data demonstrate that HIV-1 infection interrupts both
lineage-restricted and multilineage hematopoiesis in vivo and suggest
that depletion of early hematopoietic progenitor cells occurs in the
absence of direct viral infection.
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INTRODUCTION |
ALL MODELS OF T-CELL depletion in human
immunodeficiency virus-1 (HIV-1) disease must invoke the failure of
hematopoietic organs to produce sufficient T cells to match the rate of
their destruction. Several lines of evidence implicate impaired
thymopoiesis as a causative factor in HIV-1-associated T-cell
depletion.1 HIV-1 infection of thymus in vivo has been
demonstrated.2 Intrathymic T progenitor cells have been
shown to be infectable by HIV-1 in vitro3,4 and in the
SCID-hu Thy/Liv model.5 The thymic pathology induced by
HIV-1 in the SCID-hu Thy/Liv model may be strain-dependent5-7 and includes both thymocyte depletion
and destruction of thymic epithelium.8 Prethymic progenitor
cells in bone marrow may also be infected and depleted by HIV-1,
although the frequency of HIV-1 infection of primitive progenitors
appears to be low.9-15 In particular, it is uncertain
whether HIV-1 effects on central hematopoietic organs such as bone
marrow or fetal liver are directly mediated by HIV-1 infection or are
the indirect result of altered levels of cytokines and trophic
factors.16,17 Animal model systems for HIV-1 infection may
assist in defining the pathology of HIV-1 for the design and testing of
therapies to reverse or prevent HIV-1-associated cytopenias. In
addition, the determination of the earliest stages in thymocyte
development affected by HIV-1 infection will be important for the
design of therapies to reconstitute immune function.
Among experimental models of HIV-1 infection, the SCID-hu Thy/Liv mouse
uniquely allows the study of human hematopoietic function at both the
thymic and prethymic stages.18 The conjoint organ formed by
transplantation of human fetal thymus and liver not only supports
long-term lymphopoiesis, but also maintains a self-replenishing pool of
primitive hematopoietic progenitor cells that show potential for
development into myeloid and erythroid lineages.
We have used this model to study the effects of HIV-1 infection on
early stages of hematopoiesis. Using both a molecular clone and primary
strains of HIV-1, we found that depletion of intrathymic T-progenitor
cells was a common feature of HIV-1 infection. Using both phenotypic
and functional analyses of earlier hematopoietic progenitor cells, we
found that HIV-1 infection resulted in depletion of both
lineage-restricted and multilineage progenitor cells. Depletion of
hematopoietic progenitor cells preceded the loss of
CD4+CD8+ and CD4+CD8
thymocytes, suggesting that HIV-1 infection interrupted thymocyte development at an early progenitor stage. However, proviral genomes were found to be most concentrated at the stage of the intrathymic T-progenitor cell and were seen in only low copy number in earlier progenitor cells and their progeny in methylcellulose cultures. These
in vivo observations support a role for diminished hematopoietic progenitor cell function in the pathogenesis of HIV-1 infection.
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MATERIALS AND METHODS |
Animals and virus infection.
SCID-hu Thy/Liv mice were constructed as described18-20 and
maintained under specific pathogen-free barrier conditions. All animals
used in each experiment carried liver and thymus tissue from a single
fetal donor. Protocols for the use of fetal tissue were approved by the
UCSF Committee on Human Research, and protocols for the care and use of
SCID-hu mice were approved by the Committee on Animal Research. Thy/Liv
grafts were infected by intragraft injection of 2,000 TCID50 of each isolate or an equivalent volume of medium
for mock infection controls, as described.20
Virus stocks.
HIV-1 virus stocks were generated by low passage propagation of primary
strains (JD and PD) or molecular clones (NL4-3) in cultures of
phytohemagglutinin-activated peripheral blood mononuclear cells
(PBMCs).20 NL4-3 is an infectious molecular clone of
HIV-121 that has been maintained as a plasmid stock and not
extensively passaged in tissue culture. JD and PD are uncloned, early
passage, syncytium-inducing primary strains of HIV-1. Virus stocks were titrated on PBMC blasts and subjected to endpoint analysis as described.20
Thymocyte immunophenotyping and sorting.
Monoclonal antibodies were obtained from Becton Dickinson
Immunocytometry Systems (fluorescein isothiocyanate [FITC]-conjugated anti-CD4, phycoerythrin [PE]-conjugated anti-CD8, biotin-conjugated anti-CD3 and anti-CD8, PE-conjugated anti-CD34, and conjugated isotype
controls; Mountain View, CA) and from Caltag (TRI-COLOR-conjugated anti-CD3 and anti-CD8, TRI-COLOR-conjugated streptavidin, and conjugated isotype controls; Burlingame, CA). Cell sorting
was performed on a Becton Dickinson FACS Vantage fluorescence-activated cell sorter (FACS; Becton Dickinson Immunocytometry Systems, Mountain View, CA). Analysis was performed on either the FACS Vantage or on a
Becton Dickinson FACScan instrument with CellQuest
analysis software. Thymocytes were recovered from grafts by filtration through nylon mesh bags, and the number of total live cells recovered per graft was determined by hemocytometer counting and trypan blue dye
exclusion. For sorting of thymocyte subclasses, freshly isolated
thymocytes were surface stained with FITC-conjugated anti-CD4,
PE-conjugated anti-CD8, and TRI-COLOR-conjugated anti-CD3. Percentages of single-positive CD4 and CD8 thymocytes
(CD3+CD4+CD8 and
CD3+CD4CD8+), double-positive
thymocytes (CD4+CD8+), and intrathymic
T-cell progenitors
(CD3CD4+CD8) were calculated
within a live cell lymphocyte gate using forward and side scatter
criteria, with positive gates defined by the 99th percentile of isotype
staining.
Progenitor cell assays.
Progenitor cells were enriched from bulk thymocytes by negative
selection with biotinylated anti-CD3 and anti-CD8 monoclonals and
streptavidin-coated magnetic beads (Dynal, Lake Success,
NY) and subsequently divided into aliquots for CD34 staining or plating into methylcellulose assays (to measure colony-forming
units-cells [CFU-C]) or long-term bone marrow assays (to measure
long-term culture-initiating cells [LTC-IC]). The efficiency of bead
depletion was assessed by reanalysis using streptavidin-TRI-COLOR.
CD34+ progenitor cells were enumerated by surface staining
the CD3- and CD8-depleted thymocytes with PE-conjugated anti-CD34
antibody. A total of 100,000 to 500,000 Thy/Liv cells depleted of CD3-
and/or CD8-thymocytes were added to methylcellulose
cultures (Stem Cell Technologies, Vancouver, British
Columbia, Canada) supplemented with 100 ng/mL stem cell factor (SCF)
and granulocyte-macrophage colony-stimulating factor (GM-CSF), 10 ng/mL
interleukin-3 (IL-3) and IL-6, and 2 U/mL erythropoietin
(EPO; all cytokines were obtained from R&D
Systems, Minneapolis, MN). Triplicate plates were scored for
colony-forming units-granulocyte-macrophage (CFU-GM), burst-forming units-erythroid (BFU-E), and colony-forming
units-granulocyte, erythroid, monocyte, megakaryocyte (CFU-GEMM)
after 14 days. LTC-IC were assayed by limiting dilution analysis
of CD3- and CD8-depleted cells as previously described,22
except that cells were grown on irradiated fetal bone marrow stromal
cultures. Cultures were grown for 5 to 6 weeks in the presence of IL-3,
IL-6, and SCF and scored for growth-positive wells. Total CFU-C and
LTC-IC per graft were calculated as total colonies scored in
methylcellulose assay or long-term bone marrow culture, respectively,
divided by the fraction of postdepletion cells plated in each assay,
divided by the fraction of total cells set aside for bead depletion.
The total number of CD34+ cells per graft was calculated as
the percentage of bead-depleted cells positive for CD34 staining,
multiplied by the number of cells recovered after bead depletion,
divided by the fraction of total cells set aside for bead depletion.
Polymerase chain reaction (PCR) amplification of HIV-1 proviral
sequence.
Cells recovered from Thy/Liv grafts were stained with monoclonal
antibodies to CD3, CD4, CD8, and/or CD34. Live cells were defined by forward and side scatter, and 2,000 cells of each subset (total thymocytes, CD34+,
CD3+CD4+CD8, or
CD3CD4+CD8) were sorted on a
Becton Dickinson FACS Vantage cell sorter. Sorted cells were lysed in
20 µL of PCR buffer with 100 µg/mL proteinase K, digested for 30 minutes at 65°C, and then inactivated at 95°C for 15 minutes.
Lysates were serially diluted before 40-cycle PCR amplification of gag
sequences, as previously described.23 Methycellulose
colonies containing approximately 103 to 104
cells were lysed similarly. Lysates of ACH-2 cells served as internal
controls to document copy number sensitivity. Endpoint dilution
estimates of proviral copy number from replicate samples were derived
using the method of Reed and Muench,24 which averages data
from replicate samples to interpolate a copy number endpoint.
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RESULTS |
Time-dependent depletion of mature and immature thymocytes by HIV-1.
Previous work with the SCID-hu Thy/Liv model demonstrated a
time-dependent depletion of
CD3+CD4+CD8+ and
CD3+CD4+CD8 thymocytes after
infection with primary strains of HIV-1 or with the molecular clone
NL4-3.6-8,25 In contrast, depletion of intrathymic T-progenitor cells, which carry the surface phenotype
CD3CD4+CD8, was found to be
greater in grafts infected with NL4-3 than in those infected by the
primary HIV-1 strain, JD.5 At day 9 to 14 after infection
in these experiments, we also found that each of the three viral
strains tested (NL4-3, JD, and PD) resulted in depletion of both total
thymocytes and intrathymic T-progenitor cells (Fig
1). Consistent with earlier findings, only
NL4-3 induced significantly greater depletion of the intrathymic
T-progenitor cells than of the more mature
CD3+CD4+CD8 cells. Thus, viral
strain differences accounted for discernible differences in the pattern
of thymocyte depletion after infection, but all strains tested resulted
in thymocyte depletion of both mature and immature thymocytes.
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| Fig 1.
HIV-1-induced depletion of mature and immature thymocyte
subsets in the SCID-hu Thy/Liv mouse. Depletion of thymocyte subsets by
HIV-1 strains NL4-3, JD, and PD was assessed at day 9 to 14 after
infection. Cell numbers are expressed as percentages of values from
mock-infected control grafts (Mean ± SEM). Data for NL4-3 summarize
10 separate experiments with 57 animals; data for JD summarize 5 experiments with 26 animals; and data for PD summarize 2 experiments
with 10 animals. Each experiment used SCID-hu mouse cohorts made with
fetal tissue from separate donors. *P < .01 (unpaired
t-test) for difference between depletion of CD3CD4+CD8 and
CD3+CD4+CD8 cells. ( )
Total thymocytes; ( )
CD3+CD4+CD8; ( )
CD3CD4+CD8.
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Early depletion of hematopoietic progenitor cells by HIV-1.
The finding that multiple HIV-1 strains depleted thymic progenitors
prompted us to determine whether earlier hematopoietic progenitor cells
were also affected by HIV-1 infection in the SCID-hu Thy/Liv mouse. We
therefore measured the clonogenic capacity of multilineage and
lineage-restricted hematopoietic progenitor cells from grafts infected
either with NL4-3 or with medium. At early and late time points after
infection, aliquots of harvested thymocytes were subjected to
quantitative immunophenotyping with antibodies to CD3, CD8, and CD4 or
depleted of mature cells with antibodies to CD3 and CD8 and then either
assayed for expression of CD34 or for hematopoietic clonogenic capacity
in methylcellulose or in long-term bone marrow cultures. At days 4 to
11 after infection, significantly fewer CD34+ cells
remained in grafts infected with NL4-3 compared with controls (Fig
2). At this early time point there was no
depletion of lineage-restricted progenitor cell activity as measured by
methylcellulose colony-forming units (CFU-C) or of total thymocytes. At
days 12 to 14 after infection, both CD34+ cells and
lineage-restricted progenitors were diminished relative to controls,
and the degree of depletion exceeded that of total thymocytes
(P < .05). By days 17 to 21 after infection, all
hematopoietic elements in the Thy/Liv grafts, including total
thymocytes, CFU-Cs, and CD34+ cells, were severely
depleted. Thus, depletion of both functional (lineage-restricted) and
phenotypic progenitors preceded the rapid decrease in total thymocyte
numbers seen between day 11 and 21 after infection in this model.
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| Fig 2.
Early selective depletion of CD34+
hematopoietic progenitor cells and CFU-C by NL4-3. Data are shown from
three pooled experiments at 8 different time points: three time points
with 21 animals from one donor at days 4 to 11, three time points with
23 animals from three donors at days 12 to 14, and two time points with
13 animals from two donors at days 17 to 21. *Depletion values that are
significantly different (P < .05, unpaired t-test)
from the value for total thymocytes. () Total thymocytes per graft;
() CFU-C per graft; () CD34+ cells per graft.
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Analysis of the distribution of colonies of specific lineages arising
from progenitor cells showed no difference between infected and
uninfected grafts (Fig 3), suggesting that the
impairment of progenitor activity occurred before the stage of lineage
commitment. To determine directly whether HIV-1 infection affects
multilineage hematopoietic progenitors, we measured the frequency of
LTC-IC in NL4-3 and mock-infected grafts in three experiments performed 14 to 21 days after infection. In each experiment, the absolute number
of CD34+ cells, of CFU-C, and of LTC-IC per HIV-1-infected
graft (expressed as a percentage of values from uninfected control
grafts) decreased equivalently (Fig 4A). Thus, HIV-1
infection resulted in depletion of multipotent hematopoietic progenitor
cells contemporary with, and equivalent to, the depletion of
lineage-committed progenitor cells.
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| Fig 3.
Lineage-independent depletion of hematopoietic progenitor
cells by NL4-3. Each colony lineage is expressed as a percentage of
total colonies recovered (mean ± SEM). The data are aggregated from
9 time points sampled in three experiments, including 13 animals in
week 1, 24 animals in week 2, 18 animals in week 3, and 6 animals in
week 4 after infection. Compared with uninfected controls,
HIV-1-infected grafts showed a mean reduction of 28% in total
thymocytes and of 43% in CFU-C over all time points sampled. ()
CFU-GM; ( ) BFU-E; () CFU-GEMM.
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| Fig 4.
Depletion of LTC-IC, CFU-C, and CD34+ cells
by HIV-1 (NL4-3). (A) Primitive hematopoietic progenitor cells (LTC-IC)
are depleted synchronously with CFU-C and CD34+ cells in
HIV-1-infected SCID-hu Thy/Liv. () CD34+ progenitor
cells, () CFU-C, and () LTC-IC were determined in parallel 14 to
21 days after infection of grafts with HIV-1 strain, NL4-3. The total
number of each is expressed as a percentage of the total number
obtained from mock-infected, control grafts. (B) Relative enrichment of
all progenitor classes in thymocyte-depleted grafts. Data from
experiments in (A) are expressed as cell number per 106
surviving thymocytes. (C) Absolute depletion of all progenitor classes
in thymocyte-depleted grafts. Data from experiments shown in (A) are
now expressed as total number of cells per graft. () Control; ()
NL4-3.
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In addition to the early depletion of progenitor cells, HIV-1 infection
results in the infection and death of thymocytes at more mature
stages.5-8 Depletion of both progenitor cells and more
mature thymocytes over time would be expected to result in a more
accelerated decline in the numbers of the more mature cells. This was
observed to be the case in experiments in which LTC-IC, CFU, and
CD34+ phenotypic progenitors were measured from day 14 to
21 after infection (Fig 4B). In HIV-1-infected grafts, the prevalence
of all three progenitor subsets (expressed as a fraction of surviving cells) actually increased relative to uninfected controls in a time-dependent fashion. However, even though hematopoietic progenitor cells comprise a greater fraction of the surviving total from HIV-1-infected grafts, these cells clearly undergo early and specific depletion when their numbers are expressed as total cells per graft
(Fig 4C).
Progenitor depletion is a property shared by a primary HIV-1 strain
and a molecular clone.
To determine whether depletion of hematopoietic progenitors was a
property shared by primary HIV-1 strains, SCID-hu Thy/Liv grafts were
infected in parallel with NL4-3 or the primary isolate JD (Fig
5). At late (day
28) time points after infection, each virus was found to deplete both
total thymocytes and CD34+ progenitor cells as well as
colony-forming cells. However, at day 12 after infection, grafts
infected with either virus showed normal numbers of total thymocytes
but decreased numbers of CFU-C and CD34+ progenitor cells.
These data suggest that the ability of HIV-1 to impair thymopoiesis
through progenitor depletion is shared by a primary HIV-1 strain and by
the molecular clone NL4-3.
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| Fig 5.
Early depletion of CD34+ progenitor cells
and CFU-C is a feature of both a primary isolate and a T-tropic
molecular clone of HIV-1. Thy/Liv grafts were infected with either
NL4-3 or HIV-1 strain JD, as described in the Materials and Methods.
Data (mean ± SEM) summarize two experiments with animals from two
donors, with 21 animals at day 12 and 21 animals at day 28.  .1 > P > .05 and *P < .05 for difference between value
and total thymocytes (unpaired t-test). () Total; ()
CFU-C; () CD34+.
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HIV-1 proviral DNA accumulates in intrathymic T-cell progenitors but
not in earlier progenitors.
Because HIV-1 infection may diminish hematopoietic progenitor capacity
either by direct means (eg, lytic viral infection of progenitor cells)
or by indirect means (eg, upregulation of hematosuppressive cytokines
or disruption of stromal cell support), we evaluated the possibility
that hematopoietic progenitor cells in the SCID-hu Thy/Liv graft were
infected by HIV-1. First, DNA from colonies generated in
methylcellulose culture was tested for the presence of proviral HIV-1
DNA using the PCR. Between 5 and 28 days after infection of grafts with
NL4-3 or JD, only 4 of 1,293 colonies tested were positive for gag
sequences (Table 1). This rate of PCR
signal positivity is no higher than what might have arisen from
carryover DNA in the culture, suggesting either that progenitor cells
are uninfected by HIV-1 or that infected progenitor cells fail to
generate colonies in methylcellulose assays. Secondly, sort-purified
subpopulations of cells within the Thy/Liv implant were subjected to a
quantitative, endpoint-dilution PCR analysis for the presence of HIV-1
proviral genomes. Among various potential target cells, intrathymic
T-progenitor cells consistently harbored the highest frequency of HIV-1
genomes (Table 2). Intermediate levels of
infection were observed in more mature
CD3+CD4+CD8 thymocytes, whereas
CD34+ cells showed the lowest frequency of infection.
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DISCUSSION |
HIV-induced impairment of hematopoietic progenitor function has been
studied by a variety of in vitro methods with equivocal results.16,17,26 Major limitations of these methods include lack of control of maturation in tissue culture, nonphysiological development, and incomplete representation of stromal elements that may
participate in HIV-1-induced pathology. In this study, we have
addressed the effects of HIV-1 infection with an in vivo model, the
SCID-hu Thy/Liv mouse, which encompasses the hematopoietic function of
both thymus and fetal liver. We were thus able to observe effects on
thymopoiesis and multilineage hematopoiesis simultaneously and to
measure effects of HIV-1 infection on each. This model has been shown
to recapitulate primary HIV-1 strain-specific pathology seen in
vivo.6-8 With it, we have shown that HIV-1 infection
impairs hematopoietic progenitor capacity in vivo at a stage as early
as the multilineage progenitor population. In a kinetic analysis of
thymocyte depletion, the impairment of lineage-restricted and
multilineage progenitors was found to precede by several days the rapid
decline in more mature thymocyte numbers. This observation was valid
for both a molecular clone of HIV-1 and a primary strain, suggesting
that hematopoietic progenitor cell depletion may be a common feature of
HIV-1 pathology. We conclude that the rapid decline in thymocyte
numbers seen in the SCID-hu model is likely to be the consequence of
concurrent depletion of both thymocyte progenitor cells and more mature
CD4+ thymocytes.
Prior studies in this model5-8,27 emphasized that infection
and destruction of intrathymic T-progenitor cells and their progeny was
the major pathological mechanism of HIV-1-induced thymocyte depletion.
Our findings prompt a reappraisal of this model and suggest that
destruction of less mature hematopoietic progenitor cells may be as
important as infection and death of more mature thymocyte
subpopulations. Although experimental data in the SCID-hu model have
recently suggested that thymopoiesis can be restored in HIV-1-infected
grafts after treatment with potent antiretroviral compounds
and/or progenitor cell transplantation,28 the
effects of these strategies were not durable. This is consistent with
our finding that hematopoietic progenitor cells were the first cells
depleted after HIV-1 infection and that such cells remain severely
depleted at later stages despite their enrichment relative to other
surviving cells. To the extent that this population of cells
and/or its supportive microenvironment may be adversely affected by HIV-1 infection, resumption of thymopoiesis may be limited
if present at all.
Our studies underscore an important methodologic point pertinent to the
interpretation of studies in the SCID-hu mouse model. Thus, markedly
different conclusions arise depending on how cell populations are
sampled and quantitated: when expressed as a fraction of
106 surviving cells, the percentage of hematopoietic
progenitor cells appears to be increasing in the Thy/Liv graft after
infection (Fig 4B); measured in absolute terms (Fig 4A and C), the
number of such cells per graft is actually decreasing. This dichotomy is the result of the different rates of depletion of different cell
subpopulations that occur during a period when the total number of
thymocytes is rapidly decreasing. Consequently, studies that rely
solely upon percentage data and ignore total cell populations (eg,
those studies that use serial biopsies of infected grafts; see, eg,
Jamieson et al27 and Withers-Ward et al28) are
prone to errors in interpretation that may underestimate the degree of
depletion of a relatively spared subpopulation of cells. A similar
problem confronts analyses of cell subpopulations in humans; eg,
measurements of CD4+ T cells from samples of peripheral
blood or of isolated lymph nodes do not permit quantitation of the
total body CD4+ T-cell compartment.29
These findings also raise a question critical for treatment strategies:
are thymocyte progenitor cells and hematopoietic progenitor cells
themselves directly infected by HIV-1 or, alternatively, is their
decrease due to indirect factors? We found that the intrathymic T-progenitor cell harbored large numbers of HIV-1 proviruses relative to more mature progeny. Even though CD34+ hematopoietic
progenitor cells had a relatively low viral burden, these cells (as
well as LTC-IC and CFU-C) were depleted at early time points after
infection. It is therefore likely that HIV-1 destroys earlier
hematopoietic progenitors by indirect means. Candidate mechanisms
responsible for such destruction include altered cytokine environments
in the infected thymus,30-32 dysregulation of other stromal
developmental signals,33-35 and/or direct toxic effects of gp120.36 An alternative explanation for the
robust and early depletion of progenitors without accumulation of viral genomes is that progenitor cells are rapidly cleared after infection by
HIV-1. Our finding of early depletion of thymocyte progenitors differs
importantly from other investigations into HIV-1-induced pathology in
the SCID-hu model27 in that we demonstrate the death of
progenitor cells at a phase of infection before depletion of total
thymocytes or CD4+ thymocytes. Diminished thymopoiesis due
to death of progenitor cells thus contributes to thymocyte depletion
induced by HIV-1. Direct viral killing may be an additional mechanism
of HIV-1-induced thymocyte depletion, although it is not the only one.
The significance of this finding for treatment in humans is that
durable suppression of viral replication may not be sufficient to
restore hematolymphoid microenvironments that have been damaged by
HIV-1 infection.
The importance of the thymus in peripheral T-cell homeostasis in
children is established,37 and the role of the thymus in supporting peripheral T-cell numbers in the HIV-1-infected adult has
been recently noted.38 The data presented here suggest that destruction of progenitor cells at the thymic and/or prethymic stage may contribute to the failure to maintain normal CD4+
T-cell counts in HIV-1 disease. The depletion of hematopoietic progenitor capacity may explain the preferential loss of naive T cells
in during the course of HIV-1 disease.39,40 Impaired progenitor capacity may contribute to peripheral CD4+
depletion regardless of whether the rate of CD4+ T-cell
loss is high or low.29,41,42 HIV-1 infection in the SCID-hu
Thy/Liv model may also model events in late stage HIV-1 disease,25 when T-cell numbers decrease more rapidly and
when other hematopoietic lineages are more significantly
affected.16 These contributions of HIV-1-induced
hematopoietic deficiency to the pathology of HIV-1 infection underscore
the importance of augmenting combination antiviral regimens with
therapies designed to restore or to improve hematopoietic function.
| |
FOOTNOTES |
Submitted December 1, 1997;
accepted January 12, 1998.
Supported by grants (to J.M.M.) from the National Institutes of Health
(NIH; R01-AI40312) and from the Pediatric AIDS Foundation. M.J. is
supported by a grant from the NIH (K08 AI01425). J.M.M. is an Elizabeth
Glaser Scientist supported by the Pediatric AIDS Foundation.
Address reprint requests to Joseph M. McCune, MD, PhD, Gladstone
Institute of Virology and Immunology, PO Box 419100, San Francisco, CA
94141-9100.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
The authors thank Robert M. Grant, MD, MPH, for advice on statistical
analysis of data in this report.
| |
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Abstract
Introduction
Abstract