Download HIV envelope becomes unhinged by PDI for entry

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critical for hematopoietic effects. These
studies caution against oversimplification in
thinking about the likely complex paths
from MLL to leukemia but further highlight
the potential linkage to Hox genes and the
power of genetic mouse models for investigating human disease.
—Keith Humphries
BC Cancer Agency
1.
Ernst P, Wang J, Korsmeyer SJ. The role of MLL
in hematopoiesis and leukemia. Curr Opin Hematol. 2002;9:282-287.
2.
Buske C, Humphries RK. Homeobox genes in
leukemogenesis. Int J Hematol. 2000;71:301-308.
3.
Owens BM, Hawley RG. HOX and non-HOX homeobox genes in leukemic hematopoiesis. Stem
Cells. 2002;20:364-379.
4.
5.
CD4, although binding by multiple spikes
could increase the avidity of binding.4 An
alternative explanation is that once gp120
detaches, it has a high probability of reattaching to an adjacent CD4 molecule on the
cell surface, producing the appearance of a
long off-rate through a newly recognized
phenomenon termed “allovalency.”5 (This
explains the long-puzzling finding that
soluble CD4 or anti-CD4 antibodies can
prevent HIV infection even if added a few
minutes after virion adsorption.) Eventually,
of neutralizing antibodies is the likely evolutionary reason for this shuffling two-step
at entry, then it would be interesting to
know if a PDI-rearranged envelope is a
better vaccine immunogen for raising neutralizing antibodies. PDI is too ubiquitous
an enzyme to use as a drug target.6
However, just as drugs have been developed that block CD4 binding, chemokine
coreceptor binding, and now, most successfully, gp41-mediated fusion, it will be
interesting to learn if the PDI-rearrangement
step in gp120 could provide a new therapeutic target.
—Richard S. Kornbluth
University of California, San Diego
Lam DH, Aplan PD. NUP98 gene fusions in hematologic malignancies. Leukemia. 2001;15:
1689-1695.
School of Medicine
Ayton PM, Cleary ML. Transformation of myeloid
progenitors by MLL oncoproteins is dependent on
Hoxa7 and Hoxa9. Genes Dev. 2003;17:2298-2307.
HIV envelope becomes
unhinged by PDI
for entry
Almost 10 years ago, Ryser et al1 reported that
cleavage of 2 disulfide bonds in the gp120
surface component of the HIV-1 envelope is
required for virion entry into CD4-bearing cells
and that cell surface protein disulfide isomerase
(PDI) is responsible for this effect. Since that
initial report, there have been numerous structural and mechanistic studies of envelope
binding, yet exceedingly few of these studies
have incorporated any model of dynamic
changes in gp120 disulfide bonding. The
notable exceptions are papers from Fenouillet
et al2 and Barbouche et al3 that have confirmed
the original Ryser et al findings. Now, in this
issue of Blood, Markovic and colleagues (page
1586) weigh in as the third group to confirm
these findings, and they provide new information about the location of PDI in previously
undescribed domains of the cell membrane.
The basic information is as follows: HIV
virions, which bear perhaps only a dozen or
so envelope spikes, use gp120 to bind to
CD4, but this alone serves only to attach
the virion loosely to the cell surface. Biophysical evaluation indicates that gp120 has
a relatively short off-rate from monomeric
BLOOD, 1 MARCH 2004 䡠 VOLUME 103, NUMBER 5
however, gp120 moves laterally along the
membrane surface until it collides with a
patch of PDI in a domain of the membrane
that Markovic et al distinguish from a
typical lipid raft. There, PDI reduces 2 disulfide bonds in gp120, producing conformation changes that likely stabilize the
binding of gp120 to CD4 and expose the
V3 loop for subsequent binding to the chemokine coreceptor. Following this, gp41
undergoes rearrangement into its fusigenic
intermediates and entry occurs (Markovic
and colleagues and Reyser et al,1 Fenouillet
et al,2 Barbouche et al,3 and Gallina et al6).
Taken in aggregate, the reports from
these 3 groups have profound implications
for our understanding of the HIV virion
surface. As shown by Kwong et al,4 the relatively invariant CD4 binding site in gp120
is kept recessed to prevent access by otherwise neutralizing antibodies. The initial
CD4 binding event is but a prelude to PDImediated reduction that unfolds the envelope into a more open conformation that
presumably binds more favorably to CD4
and to the chemokine coreceptor. If evasion
1.
Ryser HJ, Levy EM, Mandel R, DiSciullo GJ. Inhibition of human immunodeficiency virus infection
by agents that interfere with thiol-disulfide interchange upon virus-receptor interaction. Proc Natl
Acad Sci U S A. 1994;91:4559-4563.
2.
Fenouillet E, Barbouche R, Courageot J, Miquelis
R. The catalytic activity of protein disulfide
isomerase is involved in human immunodeficiency virus envelope-mediated membrane fusion after CD4 cell binding. J Infect Dis. 2001;
183:744-752.
3.
Barbouche R, Miquelis R, Jones IM, Fenouillet E.
Protein-disulfide isomerase-mediated reduction
of two disulfide bonds of HIV envelope glycoprotein 120 occurs post-CXCR4 binding and is required for fusion. J Biol Chem. 2003;278:
3131-3136.
4.
Kwong PD, Doyle ML, Casper DJ, et al. HIV-1
evades antibody-mediated neutralization through
conformational masking of receptor-binding sites.
Nature. 2002;420:678-682.
5.
Klein P, Pawson T, Tyers M. Mathematical modeling suggests cooperative interactions between a
disordered polyvalent ligand and a single receptor site. Curr Biol. 2003;13:1669-1678.
6.
Gallina A, Hanley TM, Mandel R, et al. Inhibitors
of protein-disulfide isomerase prevent cleavage
of disulfide bonds in receptor-bound glycoprotein
120 and prevent HIV-1 entry. J Biol Chem. 2002;
277:50579-50588.
Monoclonal antibodies in
the treatment of chronic
lymphocytic leukemia:
if only it were simple
The necessary condition to cure any malignancy is to achieve a complete response
(CR), which for years has been extremely
rare in chronic lymphocytic leukemia
(CLL). Fortunately, the days in which treatment of CLL revolved around the use of
1567
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chlorambucil—an agent with which less
than 10% CR was achieved—are over.
Treatment of CLL has significantly improved over the last 2 decades. First, with
the use of purine analogs, particularly fludarabine, the CR rate increased to 20% to
30%. Second, the combination of fludarabine with other cytotoxic agents and/or
monoclonal antibodies has increased the CR
rate up to 40% to 60%, with many of these
responses being molecular (ie, without evidence of minimal residual disease as assessed by cytofluorometry or polymerase
chain reaction [PCR]). Of note, there is
already some indication that fludarabinebased regimens result not only in a higher
CR but also longer response duration and, it
is hoped, a prolonged survival.1,2
The 2 monoclonal antibodies most
widely employed in CLL therapy are rituximab (an anti-CD20 monoclonal antibody
that adds efficacy to chemotherapy) and alemtuzumab (an anti-CD52 agent that is particularly useful to improve responses obtained with chemotherapy). There are other
monoclonal antibodies that offer promise in
CLL treatment, including anti-CD22 (BL-22,
epratuzumab), anti–HLA-DR (1D09C3), antiCD23 (IDEC-152, lumiliximab), and anti-1D10
(Hu1D10, apolizumab).
The mechanism of action of monoclonal
antibodies varies from one antibody to
another and includes triggering of apoptosis
by caspase-dependent or -independent pathways, antibody-dependent cellular cytotoxicity, complement-mediated cytotoxicity, and
generation of reactive oxygen species
(ROS).3 Things, however, are never simple.
Mone and colleagues (page 1846) report in
this issue a series of elegant studies
showing that Hu1D10 has a paradoxical
effect in CLL leukemic cells. Thus, Hu1D10
induces caspase-independent apoptosis and
ROS generation (a desirable effect since it
induces CLL leukemic cells’ death), but it
also activates the AKT survival pathway (an
undesirable effect since this protects leukemic cells from death). In other words, the
same agent leads to both death and survival
signals in CLL leukemic cells. To overcome
the negative effect of AKT activation, the
1568
authors combine Hu1D10 with the selective
phosphatidylinositol 3 (PI3) kinase inhibitor
LY294002, leading to an enhanced activity
of the antibody. This opens the door for
clinical studies in which Hu1D10 will be
combined with inhibitors of the AKT survival pathway such as UCN-01 (7-hydroxystaurosporine).
Chemoimmunotherapy is gaining wide
acceptance in the treatment of different oncohematologic disorders. What the Mone et
al study illustrates is that mechanisms of
action of monoclonal antibodies are
complex and that when devising chemoimmunotherapy combinations, not only the
different targets but also the mechanism of
action of the agents, as well as the way to
enhance their effects, should be considered.
By pursuing this approach the CR rate in
patients with CLL will continue to increase
and, one hopes, this form of leukemia will
eventually become curable.
—Emili Montserrat
University of Barcelona
1.
Eichorst BF, Busch R, Hopfinger G, et al. Fludarabine plus cyclophosphamide (FC) induces higher
remission rates and longer progression free survival than fludarabine (F) alone in first line
therapy of advanced chronic lymphocytic leukemia (CLL): results of a phase III study (CLL4 protocol) of the German Study Group (GCLLSG) [abstract]. Blood. 2003;102:72a. Abstract 243.
2.
Byrd JC, Rai KR, Peterson BL, et al. The addition
of rituximab to fludarabine significantly improves
progression-free and overall survival in previously
untreated patients with chronic lymphocytic leukemia (CLL) patients. Blood. 2003;102:73a. Abstract 245.
3.
Villamor N, Montserrat E, Colomer D. Mechanism
of action and resistance to monoclonal antibody
therapy. Semin Oncol. 2003;4:424-433.
T-ALL: smoking guns
and genes of interest
Nonrandom chromosomal translocations are
a common finding in the malignant cells of
patients with acute and chronic leukemia. In
general, these translocations lead to 1 of 2
molecular consequences. One class of translocation leads to the production of a fusion
gene, such as the BCR-ABL oncoprotein
associated with chronic myelogenous leukemia (CML); a second class of translocations leads to the unscheduled expression of
a “proto-oncogene,” which is often a transcription factor involved in normal developmental regulation. This unscheduled expression of proto-oncogenes is most often
caused by translocations that juxtapose regulatory regions of antigen receptor genes
(immunoglobulin or T-cell receptor genes)
and commonly involves transcription factors
such as MYC, LMO2, or SCL (TAL1). Given
that this second class of translocation involves antigen receptor genes, it is not surprising that translocations that activate
proto-oncogenes are most commonly seen in
lymphoid rather than myeloid leukemias.
However, the same genes that are activated via chromosomal translocation can
also be activated via unknown mechanisms.
This is true for both human and mouse
T-cell acute lymphoblastic leukemia
(T-ALL).1,2 For instance, gene profiling
studies have indicated that SCL and LMO1
or LMO2 are expressed in almost 50% of
T-ALL patients. Furthermore, MSH2deficient mice, which frequently develop
T-ALL, activate both SCL and LMO2. A
“smoking gun,” in the form of a chromosomal rearrangement that juxtaposes an
antigen receptor gene regulatory region with
the proto-oncogene, can be identified in
some of the T-ALL patients. However, in
many patients—perhaps more than half—no
such rearrangement can be found. There are
at least 2 models that can be developed to
explain this finding. The regulatory region
of the proto-oncogene may have undergone
a subtle mutation, leading to unscheduled,
inappropriate activation of the protooncogene. Alternatively, a transcription
factor that controls expression of the protooncogene may be inappropriately activated,
leading to unscheduled expression of the
proto-oncogene. These 2 models lead to a
testable hypothesis. In the first case, expression of the proto-oncogene should be monoallelic; in the second case, expression of the
proto-oncogene should be biallelic.
In this issue, Ferrando and colleagues
(page 1909) report their study of allelespecific expression of SCL, LMO2, and
HOX11. As anticipated, in each case where
there was a smoking gun, in the form of a
BLOOD, 1 MARCH 2004 䡠 VOLUME 103, NUMBER 5
From www.bloodjournal.org by guest on August 3, 2017. For personal use only.
2004 103: 1567-1568
doi:10.1182/blood-2003-12-4387
Monoclonal antibodies in the treatment of chronic lymphocytic
leukemia: if only it were simple
Emili Montserrat
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