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Blood, Vol. 91 No. 5 (March 1), 1998:
pp. 1479-1495
REVIEW ARTICLE
By
From the Oregon Cancer Center at Oregon Health Sciences University;
the Portland VA Medical Center; and the Departments of Medicine,
Molecular Microbiology and Immunology at Oregon Health Sciences
University, Portland.
THROMBOCYTOPENIA, anemia,
lymphocytopenia, monocytopenia, and neutropenia and permutations of
these abnormalities are found in most patients with acquired
immunodeficiency syndrome (AIDS). In virtually all patients with
advanced AIDS (group IV), pancytopenia is the rule. More than 90% of
such patients are anemic and an equal fraction have either neutropenia
or monocytopenia.1 Although immune thrombocytopenia is a
common cause of low platelet counts in human immunodeficiency virus
(HIV)-infected patients, the majority of other types of cytopenias
usually reflect bone marrow (BM) dysfunction. Even so, the causes of
these cytopenias are clearly heterogeneous and can, in a large number
of cases, be attributed to the widely recognized hematopoietic
suppressive effects of certain types of intercurrent infections (eg,
cytomegalovirus, parvovirus, hepatitis virus, and mycobacterial
infection), or of drugs commonly used in AIDS patients (zidovudine,
gancyclovir, trimethoprim/sulfa). The multiple causes of
marrow failure in patients with AIDS1-3 account for the
mixed histological findings on BM examinations of these
patients.1 BM biopsy samples and aspirates are most often
nonspecifically abnormal. To be sure, certain findings are more than
nonspecific. The discovery of abundant megakaryocytes in the BM of a
patient with isolated thrombocytopenia, for example, is highly
suggestive of idiopathic thrombocytopenic purpura (ITP). Erythroid
hypoplasia suggests either parvovirus infection (a rare cause of anemia
in patients with HIV infection4) or infection of the marrow
with mycobacterium avium complex.1 Interestingly, frank
hypocellularity is the exception and aplasia is rare. Taking these
diagnostic complexities into account, it has been impossible, from
examination of clinical material alone, to determine whether HIV-1
itself has any direct impact on hematopoietic activity.
We seek in this review not to catalogue the spectrum of hematopoietic
defects that occur in patients with AIDS, but to focus specifically on
the influence HIV-1 itself imposes on hematopoietic cells. For more
than a decade, research teams worldwide have sought to identify a
causal role for HIV-1 and its gene products in the hematopoietic
defects that develop in patients with AIDS and more clear paradigms
have emerged. The most important of these is that the greatest impact
of viral infection on growth and differentiation of hematopoietic
progenitor cells results from the capacity of the virus to infect and
perturb the hematopoietic regulatory function of auxiliary cells, not
from its capacity to infect progenitors and stem cells themselves. Here
we review the evidence in support of this model. We will focus on two
commonly encountered AIDS-related hematopoietic abnormalities in
clinical practice, regenerative marrow failure and lymphoid neoplasms.
Because BM failure and lymphomas are common consequences of AIDS
progression, and limit both survival and quality of life, a clear
pathophysiological picture of these disorders and the molecular
mechanism(s) by which HIV-1 causes or sets the stage for them, is an
essential prerequisite for the development of rational strategies for
therapy and prevention.
Recovery from myelosuppression induced by treatment with antivirals and
with antilymphoma regimens is consistently more toxic to hematopoietic
tissues of AIDS patients than in those of non-AIDS patients. Although
many AIDS patients have BM failure before therapy,5-12 a
greater number experience inordinate myelosuppressive toxicity after
conventional antilymphoma13 or antiviral14
chemotherapy unless hematopoietic growth factors are
used.14-16 Even when growth factors are used, conventional
therapy is extremely toxic. Levine et al17 recently
described the results of their study using ABVD (Adriamycin [Pharmacia
& Upjohn, Kalamazoo, MI], bleomycin, Velban [Lilly, Indianapolis,
IN], and Dacarbazine [Bayer, West Haven, CT]) with
granulocyte colony-stimulating factor (G-CSF) support of 21 HIV+ patients with Hodgkin's disease, in which nearly
every patient had either severe and prolonged thrombocytopenia
and/or neutropenia.17 Theoretically, causes of
regenerative failure might reflect dysfunction of the hematopoietic
progenitor cell population, dysfunction of cells that control the
regenerative response by releasing hematopoietic growth factors, or
activation of gene programs that serve to inhibit one or both of these
two cell types.18 The weight of evidence today quite
clearly suggests that the progenitor populations are intact and largely
uninfected, but that auxiliary cells are very consistently infected and
broadly dysfunctional.
Infection of Hematopoietic Progenitor Cells Is Infrequent and not
Substantially Involved in the Pathogenesis of Marrow Failure
Infected Auxiliary Cells and Regenerative Failure
T cells.
The release of hematopoietic growth factors by T cells is variably
influenced by HIV-1 infection. Although IL-6 production is
increased,34 production of IL-2 is reduced by
HIV-135 possibly via the effects of HIV-1
nef,36 which is known to bind protein kinase C Monocyte/macrophages.
HIV-1 tat and gp120 induce cytokine expression in monocytes, but
whether HIV-1 infection of monocytes achieves the same level of
induction is arguable. Molina et al41 report that
peripheral blood mononuclear cells (PBMC) infected with myriad strains
of HIV-1 do not express IL-1, IL-6, or tumor necrosis factor- Microvascular endothelial cells (MVEC).
MVEC from a variety of organs including the brain,48,49
liver,50 kidney,51 and BM3,19 are
permissive for HIV-1 infection. Of greater relevance to the issue of
regenerative marrow failure, BM MVEC cells are always found to be
infected by HIV-1 in seropositive patients regardless of the stage of
their disease.19 Moreover, while constitutive production of
hematopoietic growth factors by such cells (either alone or admixed
with other BM stromal cell types) is normal, IL-1 induced production of
G-CSF and IL-6 is significantly reduced.19 This suggests
that HIV-1 infection of BM MVEC reduces the capacity of hematopoietic
stroma to respond to regulatory signals that normally augment blood
cell production during periods of increased demand. The dysfunction in
marrow stroma does not seem to derive simply from direct interdiction
of IL-1 responses in MVEC because pure populations of MVEC, at least
from brain, do not respond abnormally to IL-1 after infection (Moses et
al, unpublished, April 1997). Therefore, it is likely that
the MVEC infection induces release of factors that influence the
behavior of other IL-1-responsive cells in the stroma, most of which
are not infected (Fig 1). The mechanisms by
which this occurs are currently under investigation in our
laboratories. The recent report of hematopoietic support dysfunction of
HIV-1-infected mixed BM stromal cell cultures containing only 2%
MVEC52 supports the notion that collaboration between infected and uninfected cells results in the failure of the stroma to
support myeloid hematopoiesis.
Uninfected (bystander) Auxiliary Cells and Regenerative Marrow
Failure
T cells.
The clonal suppressive effect of CD8+ hematopoietic
inhibitory T cells (HIT cells) has been recognized for
decades.53,54 Such cells have been discovered in
HIV-1-infected patients.55 Specifically, clonal growth of
CFU-GEMM, BFU-E, and CFU-GM from marrows of HIV-1+ patients
significantly increased after depletion of CD8+,
Monocyte/macrophages.
Apoptosis of lymphoid cells in nodal tissues of patients with HIV-1
infection occurs in cells that are not themselves infected by HIV-1.
Priming of the Fas pathway has also been shown in lymphocytes from
HIV-1-infected individuals, but cells undergoing apoptosis can be
virus free. Badley et al56 have found that HIV-1 induces Fas ligand (FasL) expression in infected monocytes and that this effect
may account, indirectly, for apoptotic signals to both lymphocytes and,
in our view, possibly progenitor cells (Fig 2). In this report, the
investigators argue that this bystander effect, in which HIV-1 induces
both Fas and FasL, is a mechanism that can account for lymphocyte
depletion during the course of HIV-1 disease. Hematopoietic progenitor
cells are also quite susceptible to Fas-induced apoptosis and this
particular apoptotic pathway likely accounts for a variety of BM
failure states (Fig
2).57-59Therefore, it is likely that FasL induction in auxiliary cells may
be of substantial relevance, particularly if the Fas pathway is primed
by IFN-
BM stromal cells.
Zauli et al33 evaluated the effect of a short-term exposure
(2 hours) to two different lymphocytotropic strains of HIV-1 (HIVIIIB
and ICR-3) on the survival of a factor-dependent CD34+
hematopoietic cell line (TF-1). Although HIV-1-treated TF-1 cells underwent programmed cell death, the response was reversible with optimal doses of IL-3 or GM-CSF or both. Moreover, this group found no
signs of productive or latent infection of these cells but did notice
that treatment of TF-1 cells with recombinant gp120 plus a polyclonal
anti-gp120 antibody, or with anti-CD4 monoclonal antibody (MoAb) plus
rabbit anti-mouse IgG, significantly increased the percentage of cells
undergoing apoptosis. They reasoned that the apoptotic response was the
result of an interaction of gp120 with the CD4 receptor, which was
expressed at a low level on the surface of TF-1 cells.
Blunted Inductive Responses in Other Auxiliary Cells
AIDS patients are at increased risk for developing clinically
aggressive B-cell non-Hodgkin's lymphomas (NHL).63-66
Unlike other AIDS-associated malignancies, the AIDS-associated NHL
(AIDS-NHL) develop in every population group at risk for AIDS. Current
estimates indicate that 5% to 10% of HIV-1-infected patients develop
this life-threatening disease. The etiology of AIDS-NHL is unknown and
is likely to be complex. With some interesting
exceptions,67,68 the malignant B cells in AIDS-NHL are not
directly infected by HIV-1,69-72 suggesting that HIV-1
contributes to B-cell neoplasia via indirect mechanisms. Given the high
degree of molecular heterogeneity seen within this group of neoplasms,
it is likely that multiple pathways operate individually or in concert
within the context of HIV-1 infection to promote lymphomagenesis.
Distinctive Features of AIDS-NHL
Clinical behavior.
Biggar et al74 recently linked AIDS and cancer registry
data for the 1980-1990 decade to evaluate the overall lymphoma risk for
persons with AIDS and determined a risk of 348-fold for high-grade lymphomas but only 14-fold for low-grade lymphomas. In another study,
over 80% of AIDS-NHL were classified as high-grade tumors while less
than 40% of non-AIDS NHL qualified as high-grade
neoplasms.75 The aggressive clinical behavior of the
AIDS-NHL has necessitated the creation of a separate classification
system. Histologically, the majority of systemic AIDS-NHL fall into one
of three main categories: (1) high-grade, small noncleaved cell
(Burkitt's and Burkitt's-like) lymphomas (SNCCL), (2) high-grade,
large cell immunoblastic lymphomas (IBL), and (3) intermediate grade,
large noncleaved cell lymphomas (LNCCL). Because of their aggressive clinical behavior, the LNCCL have been functionally classified along
with the high-grade IBL as diffuse large cell lymphomas (DLCL). A
subtype of "intermediate" lymphomas exhibiting features of both
SNCCL and immunoblastic DLCL has also been described.76 The
recently described CD30+ anaplastic
lymphomas,77 body-cavity-based or primary effusion lymphomas (BCBL/PEL),78,79 and plasmablastic lymphomas
(PBL) of the oral cavity80 have also been included in this
category, although recent opinion suggests the reclassification of the
PEL and PBL, as well as the "intermediate" NHL, as separate
pathologic entities.81 Collectively, DLCL comprise about
two thirds of the systemic NHL while SNCCL make up approximately one
third. T cell, non-T/non-B cell, and low-grade NHL comprise the
remainder. The primary central nervous system lymphomas (PCNSL), which
account for approximately 20% of all AIDS-NHL, fall almost exclusively into the high-grade immunoblastic subtype of DLCL.
Extranodal involvement.
The extent of extranodal involvement is a characteristic feature of
AIDS-NHL. Malignant cells arising in the lymph node may seed to
extranodal sites, or the tumor may be exclusively extranodal with no
overt involvement of the lymph nodes.82 The most common sites for extranodal involvement include the gastrointestinal tract,
liver, BM, and meninges for systemic NHL and perivascular cuffing
within the brain parenchyma for the primary CNS NHL.63,83 As the name suggests, PEL do not seed from solid tumors but present exclusively in the body cavities as extranodal lymphomatous effusions.
Association with EBV.
While posttransplant NHL arising in immunocompromised patients are
invariably EBV-associated, only about half of the AIDS-associated systemic NHL are EBV+.69,70,84-86 Approximately
30% of SNCCL are EBV+ and the transforming antigens EBNA-2
and LMP-1 are not expressed.87 The incidence of EBV among
the large cell lymphomas is about 60% to 70%; almost 100% for the
immunoblastic subtype where EBNA-2 and LMP-1 are expressed and a lower
incidence amongst the LNCCL, which have a latency pattern resembling
that of the SNCCL.87 The primary CNS lymphomas are almost
exclusively EBV-infected with a latency pattern characterized by
expression of EBNA-2 and LMP-1.88 EBV-driven
lymphoproliferation in the setting of immunodeficiency is likely to
play a central role in the development of EBV+ AIDS-NHL, as
it does for posttransplant lymphomas. However, the high frequency of
EBV Genetic diversity.
Genetic lesions characteristic of AIDS-NHL are heterogeneous and tend
to segregate with certain histologic subtypes. For example, the
c-myc gene rearrangement is found in almost all SNCCL, but occurs in only one quarter of DLCL and is absent in the primary CNS
lymphomas.89 Inactivation of the tumor suppressor gene p53 occurs in up to 60% of SNCCL but is seen in only a fraction of DLCL,89 while rearrangements of the bcl-6 gene are seen
almost exclusively in DLCL.90 The PEL are generally lacking
any of these genetic lesions but are exclusively and consistently
infected with HHV-8.78,79 The lack of universality of EBV
association and the different patterns of EBV gene expression
contribute further to the genetic diversity of the AIDS-NHL.
Host Factors Contributing to the Development of AIDS-NHL
Chronic immune stimulation.
Primary HIV-1 infection is frequently associated with a persistent and
generalized lymphadenopathy (PGL), characterized by expansion of lymph
node germinal centers in response to the recruitment, proliferation,
differentiation, and apoptotic death of antigen-reactive B
cells.92 HIV-1 itself, as well as other environmental or
self antigens, may contribute to this polyclonal B-cell hyperplasia and
hypergammaglobulinemia. Antigen-driven B-cell hyperproliferation would
not only increase the risk for genetic accidents and the emergence of
transformed B-cell clones, but would contribute to the expansion of
such neoplastic clones. In support of a role for chronic antigen
stimulation in the development of AIDS-NHL, Riboldi et al93
showed that Burkitt's lymphomas derived from AIDS patients produced
self-reactive IgM antibodies, and that somatic mutations within the IgM
VH segment were reminiscent of those seen in Ig genes from
other autoreactive B-cell clones.
Cytokines.
A characteristic feature of AIDS is the existence of a deregulated
cytokine network.92 Some of the key cytokines that regulate B-cell growth and differentiation, such as IL-6, IL-9, and IL-10, are
produced by CD4+ T cells,34,94 dendritic
cells,95,96 and macrophages47,97-99 following
HIV-1 infection or in response to viral proteins, suggesting a
potential role for these cytokines in B-cell lymphomagenesis. Indeed,
high serum levels of IL-6 may be predictive of the development of
NHL.100 Once a lymphoma is established, its growth and
survival may then be sustained through paracrine and autocrine growth
loops.101,102 Interestingly, studies by Benjamin et
al103 have shown that autocrine production of IL-10 is a
feature of AIDS-associated Burkitt's lymphomas and is not seen in
sporadic or endemic cases.
Impaired immune surveillance.
There is a positive correlation between immunodeficiency, as measured
by decreasing CD4 counts, and the development of
AIDS-NHL.104 This correlation applies particularly to the
risk for developing large cell NHL, because SNCCL may develop when
immunity is relatively intact.84,100 Independent of CD4
counts, the duration of the immunodeficent state was also found to
increase the risk of developing AIDS-NHL.100 This implies
that as patients survive longer with improved retroviral treatment, the
incidence of AIDS-NHL may increase.105 Impaired
immunosurveillance as a risk factor for AIDS-NHL can be explained by an
inability of the host to contain EBV-driven B-cell expansions that may
precede malignancy, and the defective response of tumor-infiltrating T
cells which are known to play an important role in the containment of
NHL.106 In addition, generalized immunodeficiency and
consequent secondary infections would exacerbate conditions of chronic
B-cell stimulation and cytokine deregulation.
Infection with oncogenic viruses.
Viruses that have been causally linked to AIDS-NHL to date include the
herpesviruses EBV and, more recently, HHV-8. The oncogenic potential of
EBV is demonstrated by the ability of this virus to transform B cells
in vitro107 and the capacity of EBV-infected B cells to
cause lymphomas in severe combined immunodeficient (SCID)
mice.108 However, because EBV infection is not universal amongst the AIDS-NHL, the absolute role of EBV in the development of
these neoplasms is unclear. Importantly, EBV infection is highest in
primary CNS lymphomas and systemic IBL which arise in the setting of
severe immunodeficiency, and lowest in the SNCCL which frequently present while immune competence is relatively preserved. In addition, expression of the transforming antigens EBNA-2 and LMP-1 is restricted to AIDS-NHL associated with advanced
immunodeficiency.87,109 This observation strongly suggests
that, while the oncogenic potential of EBV is undisputed, the degree to
which EBV contributes to AIDS lymphomagenesis depends largely on the
degree to which virus replication and gene expression is influenced by
the host immune status.
A Role for Nonmalignant Accessory Cells in AIDS-NHL
Hematopoietic Stromal Cells Influence B Lymphopoiesis An essential accessory cell network for normal B-cell lymphopoiesis and homing in vivo, as well as for B-cell growth in vitro, is provided by the BM stroma.118-122 Depending on the conditions under which cells are cultured, BM stromal cultures can be made to be supportive of either lymphopoiesis, as in the Whitlock-Witte or related systems122-125 or myelopoiesis as in the Dexter system.126,127 Clear differences in growth factor production have not been clarified, and while IL-7 production is produced by the majority of cells in stromal cultures that support B-cell growth and differentiation,123 other factors clearly play a role in the support of B cells by marrow stromal elements. Marrow stromal cells support normal and leukemic B-cell progenitor survival and growth128,129 through mechanisms requiring attachment of the cell populations128 via adhesion molecule/ligand interactions such as VCAM-1/VLA-4,130,131 and ICAM-1/LFA-1.132 These interactions represent more than mere physical attachment. By attaching to stromal elements, B lymphoma cells induce tyrosine phosphorylation of a number of proteins in stromal cells and, perhaps of more relevance to a juxtacrine mechanism of B-cell growth, B cells induce the release of IL-6.133HIV-infected MVEC-enriched stroma supports B-lymphoma cell growth.
Stromal MVEC as well as fibroblasts are effective in supporting B-cell
proliferation.134 Indeed, McGinnes et al122
reported that MVEC-enriched stroma derived from BM spicules was more
effective at supporting B-cell growth than fibroblast-rich
aspirate-derived stroma. As previously mentioned, our group and others
have shown HIV-1 infection of stromal MVEC within the BM of patients
with AIDS and ARC.3,19 More recently, we reported that ex
vivo HIV-1 infection of MVEC-enriched stroma isolated from the BM of HIV-1 seronegative lymphoma patients induced the outgrowth and survival
of autologous B-lymphoma cells, while such stroma was not supportive of
autologous lymphoma growth in the absence of HIV-1
infection.135 In addition, culture of MVEC-enriched stroma isolated from the BM of AIDS patients with B-cell NHL promoted the
survival and outgrowth of autologous stromal-dependent malignant B
cells. These phenomena were observed for NHL of both the large and
small noncleaved B-cell types and included both EBV+ and
EBV HIV-infected brain MVEC support B-lymphoma cell growth. HIV-1 is known to infect brain microvascular endothelial cells (brain MVEC) in AIDS patients48,136 and cultured MVEC from normal brain tissue can be productively infected in vitro.49 Recent studies from our laboratory have shown that normal brain MVEC cultured in vitro were moderately supportive of the adhesion and growth of B-lymphoma cells added in coculture (Fig 4). Importantly, HIV-1 infection of these brain MVEC dramatically increased the subsequent adhesion and proliferation of cocultured B-lymphoma cells.135 Physical separation of MVEC and B cells, achieved by culturing B-lymphoma cells in transwell filter chambers over HIV-1-infected MVEC monolayers, suggested that enhanced proliferation was dependent on initial MVEC-B cell attachment. Interactions between the adhesion molecule VCAM-1 and the B-cell integrin VLA-4 play a central role in the adhesion of B cells to MVEC and other stromal elements,118,121,122,134,137,138 implicating VCAM-1 as a potential mediator of the enhanced B-lymphoma cell adhesion. Although VCAM-1 expression on brain MVEC is not induced by HIV-1 infection per se,139 expression of the cytokine receptor CD40 by brain MVEC is upregulated after HIV-1 infection of these cells.135 Recent in vitro studies have shown that CD40 is also expressed on dermal and umbilical vein endothelial cells and that CD40 triggering using soluble CD40 ligand (CD40L) increases the constitutive expression of VCAM-1 by these cells.140-142 Studies from our laboratory have shown that while CD40 triggering results in a modest induction of VCAM-1 on uninfected brain MVEC, VCAM-1 is significantly induced following CD40 triggering of HIV-1-infected MVEC.135 The ability of CD40 triggering to preferentially induce VCAM-1 on HIV-1-infected MVEC in vitro suggests that a similar mechanism could operate in vivo. While CD40L expression was first identified on activated T cells,143 additional cell types including macrophages, dendritic cells, smooth muscle cells, endothelial cells, and fibroblasts also express CD40L in certain inflammatory states.144,145 In vivo, interaction of HIV-1-infected MVEC with any of these cell types could induce VCAM-1 expression and create a microenvironment conducive to adhesion and growth of malignant B cells. In addition, because CD40L expression by malignant B cells has also been reported,135,146,147 CD40L+ B-lymphoma cells could themselves induce the adhesion phenotype. In support of this hypothesis, the adhesion and growth of a CD40L+, VLA-4+ AIDS-SNCCL cell line on HIV-1-infected MVEC is specifically inhibited by blocking functional CD40-CD40L interactions between the cells.135 Interactions between CD40 and CD40L may also play a role in the development of other types of malignancies. For example, van den Oord et al148 analyzed malignant melanoma (MM) lesions for expression of CD40 and CD40L and found that 45% of CD40+ MM coexpressed CD40L. Interestingly, patients whose tumors expressed both CD40 and CD40L had a poorer prognosis than those expressing CD40 only. The investigators in this study observed that coexpression of CD40 and CD40L usually occurred in the same area of the tumor, and proposed the existence of CD40-CD40L-mediated autocrine growth loops in the vertical growth phase of MM.
Patients with HIV-1 infection commonly develop pancytopenia, but the causes are heterogeneous and commonly iatrogenic or multifactorial. The most consistent hematopoietic defects that occur in seropositive patients as a result of HIV-1 infection per se include, first, regenerative BM failure in which on-demand hematopoiesis is suppressed, and second, a high frequency of unusually aggressive, extranodal NHLs. It is clear that neither BM failure nor lymphomagenesis results from infection of stem cells or lymphoid or myeloid progenitor cells in vivo. Indeed, it is clear that infection of such cells is not only rare29,150,151 but that the growth and differentiation of the few cells that may be infected is in no way impaired. However, infection of auxiliary cells, particularly macrophages and microvascular endothelial cells, induces a substantial alteration in the supportive function of the hematopoietic stromal tissues such that myeloid hematopoiesis is suppressed and at the same time, primitive lymphoid cell growth is augmented. We argue that a full molecular clarification of these phenomena should lead to opportunities for the rational design of preventive strategies for both regenerative failure and outgrowths of lymphoid neoplasms.
Submitted May 12, 1997;
accepted October 15, 1997.
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Introduction
References
cells from peripheral blood of healthy
volunteers, cultured the cells at densities of 104/mL in
the presence of saturating quantities of Steel factor, erythropoietin
(Epo), GM-CSF, and IL-3, pelleted the cells, and resuspended them in 50 mL in the presence of HIV-1, HIVIIIB, or NL4-3 strains for 2 hours. The
cells were then diluted to 200 mL, cultured overnight, and were then
washed and plated in methylcellulose medium at a density of one cell
per plate. Colonies were plucked for p24 analysis (enzyme-linked
immunosorbent assay [ELISA]) and for HIV-1 tat mRNA reverse
transcriptase-polymerase chain reaction (RT-PCR). Twelve percent of
CFU-GM colonies were p24 antigen+ and 23% were positive
for tat mRNA. Seventeen percent of BFU-E colonies were tat
mRNA+ but only 1 of 37 clones was positive for p24. No
CFU-GEMM progeny were positive for virus. Appropriate control vectors,
including heat-inactivated virus, were used. Consequently, under these
clearly defined ex vivo conditions, progenitor cells are infectable,
but, more importantly for further consideration of the question of marrow failure, HIV-1 infection ex vivo does not impair the capacity of
either CFU-GM or BFU-E to undergo clonal replication or differentiation because differentiated colonial progeny contain the provirus.
(PKC
(TNF-
(IFN-
, IL-6, and IL-8 was stimulated, expression of M, G-,
and GM-CSF was inhibited.
+, and d-TCS-1+ T cells. No such effect
was seen in cultures of normal marrow samples. Further experiments
showed that direct cellular contact between effector and hematopoietic
progenitor cells was essential and that IFN-
, release IL-10 in an
autocrine fashion. MVEC infected with HIV-1 express CD40 and bind to
lymphoma cell CD40L, a process that activates VCAM-1 expression and
subsequent binding with its cognate ligand VLA-4.
Introduction